future directions for alzheimer research

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Preventing and Treating Alzheimer’s Disease and Related Dementias

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NIH-funded trials of drug candidates

Behavioral and lifestyle interventions, enhancing diversity and inclusion in clinical trials, updates on drug discovery and development.

The Alzheimer’s community has seen remarkable progress in the past year, with the first disease-modifying therapy, lecanemab, receiving traditional approval from the U.S. Food and Drug Administration (FDA) for the treatment of early Alzheimer’s in July 2023, followed by donanemab receiving traditional approval in July 2024. While NIH did not fund the pivotal phase 3 clinical trials that led to the FDA approvals, NIH funding did enable the essential foundational work for these trials, including research that helped scientists understand the role of amyloid, the protein targeted by these drugs; and develop amyloid PET imaging, a technology central to these trials.

Although the approval of these drugs represents a significant scientific milestone, additional research is needed to understand the impact of these drugs, including addressing amyloid-related imaging abnormalities (ARIA) and other potentially serious concerns observed in some treated individuals. For example, both drugs were approved to treat early Alzheimer’s. There remains a need to test these and other drugs at different disease stages and in more diverse populations. NIH is funding additional trials to evaluate lecanemab in treating different stages of Alzheimer’s. Some of these trials are using an amyloid blood biomarker test, PrecivityAD — developed with NIH-funded research and small business support and now available in clinical practice — to aid in recruitment. Recent research indicates that the use of blood tests can reduce the cost and time needed to enroll individuals in trials. In addition, the use of this simple blood test may help lower barriers to trial participation and has the potential to expand recruitment to broader, more diverse communities. These drugs also may be combined with other therapeutic approaches to treat Alzheimer’s. NIH is funding a clinical trial of lecanemab in combination with a second drug candidate to remove tau protein from the brain.

Given the complexity of Alzheimer’s, it is unlikely that any one drug or other intervention will successfully treat it in all people living with the disease. While recent progress is encouraging, there remains a need for new drugs, alone and in combination with other drugs and/or non-pharmacologic interventions, to treat and prevent Alzheimer’s and related dementias. To that end, in fall 2023, NIH began funding the Alzheimer’s Disease Tau Platform Clinical Trial, which will test the ability of two tau-targeting therapies to reduce brain tau levels, either alone or in combination with a drug that reduces amyloid protein, in patients with early Alzheimer’s. NIH funds more than 230 active clinical trials testing new drug candidates and lifestyle interventions to prevent or treat Alzheimer’s and related dementias.

This is an exciting time of significant momentum in dementia drug development. Among the 230+ active NIH-funded clinical trials noted are more than 70 trials of promising drug candidates that target multiple disease processes.

To help save time and cost in developing dementia therapeutics, NIH-funded researchers continue to explore the potential of repurposing existing drugs that are already FDA-approved to treat other diseases and conditions. Through this approach, they have identified several potential candidates to treat Alzheimer’s and related dementias. For example, in a small, proof-of-concept clinical trial of cognitively normal individuals, the anti-insomnia drug suvorexant decreased overall amyloid levels and tau181 phosphorylation for short periods of time. Researchers have now launched a phase 2 clinical trial to investigate the effects of long-term use of suvorexant on brain amyloid levels.

In 2023, results from the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s disease (A4) Study, a public-private partnership supported with NIH funding, were released . This phase 3 clinical trial of the drug candidate solanezumab, an anti-amyloid immunotherapy, included more than 1,100 cognitively normal older adults who had brain amyloid. Results indicated that the drug did not slow cognitive decline in cognitively healthy people at risk for Alzheimer’s. While overall results of this prevention trial were negative, data and biosamples from the study are being made available to the research community, helping further understanding of Alzheimer’s. Importantly, these data have already led to insights related to differences in the presence of Alzheimer’s biomarkers among participants from different ethnic and racial groups.

While NIH-funded researchers continue to pursue new drugs to prevent and treat dementia, many behavioral and lifestyle interventions also offer promise in reducing dementia risk and improving cognition and memory. Of the more than 230 clinical trials of interventions to treat or prevent dementia that NIH currently funds, nearly 160 are testing a wide range of behavioral and lifestyle interventions, including dietary supplements, cognitive training, and more.

Examples of progress in 2023 include:

• Hearing aids: An NIH-funded clinical trial found that hearing aids appeared to reduce cognitive decline over three years in a group of older adults with specific risk factors for cognitive decline. However, hearing aids did not appear to slow cognitive decline in people without these risk factors. Researchers are now conducting a trial to understand the long-term effects of hearing aid use on brain health.
• Multivitamins: An NIH-funded clinical trial found that a daily, broad-spectrum multivitamin modestly improves memory in older adults when compared to placebo. In addition, a meta-analysis of three trial substudies found that, after two years of daily use, participants taking multivitamins had better global cognition (a combined measure from 11 separate cognitive tests) compared to placebo.
• Personalized health coaching: A recent NIH-funded trial found that personalized health coaching improved cognition and reduced dementia risk in older adults with at least two modifiable risk factors for dementia (e.g., low physical activity, hypertension, diabetes, smoking). Those in the intervention group were coached in both setting and working toward personalized goals to reduce risk. After two years of personalized coaching, participants experienced modest improvements in cognition, quality of life, and dementia risk factors when compared to a control group that received health education materials but no coaching. Findings from this study can help inform larger-scale trials of dementia risk reduction interventions.

Behavioral and lifestyle interventions, such as listening to tailored music, also offer promise in reducing the symptoms of dementia, for example:

• Tailored music listening and sleep: In a small pilot trial in a racially diverse sample of older adults, researchers found that tailored music listening slightly increased total sleep duration . Scientists are now using information gathered in this trial to inform larger future trials.
• Tailored music and agitation: An NIH-funded trial of nearly 1,000 people living with dementia residing in nursing homes found that individuals who listened to their preferred music had less frequent incidents of verbally agitated behaviors than those in a control group. Music also appeared to increase observed pleasure in trial participants. While more research is needed, music may offer a safer alternative to the use of antipsychotic drugs in nursing home residents living with dementia.

Further, behavioral and lifestyle interventions may be useful in improving important skills in older adults, including those living with cognitive impairment.

• Remote computerized training: With NIH small business grant support, the company i-Function developed remote computerized training that helps older adults, including those with mild cognitive impairment, learn relevant technology skills, e.g., managing medication, navigating telephone menus for ordering prescription refills, and banking via ATMs and the internet. Further, improvement in these skills lasted beyond the end of training, with greater gains in older adults with mild cognitive impairment.

NIH remains committed to recruiting and retaining a broad range of clinical trial participants from underrepresented communities that are disproportionately affected by dementia. Clinical research inclusivity is fundamental to ensuring that scientific findings can be generalizable to the entire population.

To enhance researchers’ recruitment materials and outreach activities for clinical trials, NIH officially launched OutreachPro in September 2023. This online tool enables health care professionals in the community to easily produce tailored materials and strategies that can be branded locally to increase participant recruitment for clinical studies. OutreachPro currently contains a library of materials in five different languages (English, Spanish, Mandarin, Hindi, and Tagalog) and several different formats (brochures, posters, social media posts, videos, radio scripts, website banners), providing research teams with more than 200 outreach options. Since its official launch, OutreachPro has been used to create nearly 900 tailored materials for clinical study recruitment.

NIH has coupled efforts to promote enhanced study recruitment outreach with stronger monitoring and oversight of ongoing clinical trials. In 2021, NIA launched the Clinical Research Operations & Management System (CROMS) to provide NIA staff and grantees with near real-time tracking, reporting, and management of clinical research enrollment data, study documents, and activities. NIA-funded investigators are required to electronically submit participant enrollment data into CROMS on a monthly basis. NIA can then use these data to proactively identify studies that are at risk of not meeting planned enrollment targets and design corrective action plans to improve trial recruitment. Further, in April 2023, NIA published a notice of updated policies and procedures for reporting clinical trial enrollment data in CROMS. The notice also outlines potential actions that NIA is able to take for grants that are noncompliant with the required policies and procedures. In addition, NIA implemented a revised policy for larger grant applications that took effect in January 2024. The revised policy prioritizes applications that include a plan to enroll clinical trial participants, from minoritized populations and other groups experiencing health disparities. These approaches help NIA support advancements in science that appropriately represent the populations affected by dementia, ensure that research findings are generalizable to a broad range of groups, and maintain the highest level of stewardship of research funding.

Clinical trials for dementia build on years of extensive foundational research to identify key disease mechanisms, screen potential drug candidates, and develop and test the most promising therapeutics. NIH is committed to investing in a strong pipeline of preclinical and translational studies, which may pave the way for forthcoming therapies for clinical application. Importantly, NIH-funded researchers continue to develop, and make openly available, resources to validate new drug targets for the next generation of dementia therapeutics. As one example, NIH-funded scientists recently developed new chemical tools and strategies to engage a novel genetic target of dementia, which may help set the stage for future therapeutic development. In addition, NIH-funded researchers recently developed a data portal that enables systematic evaluation of drug candidates for entry into preclinical testing.

NIH funding is also crucial to advancing therapeutic development from its initial stages to proof-of-concept studies and beyond. As one example, aggregation of an improperly functioning protein, TDP-43, in the brain is implicated in the development of several neurodegenerative conditions, including frontotemporal dementia, amyotrophic lateral sclerosis (ALS), and a recently characterized form of dementia known as limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC). In a small proof-of-concept study in mice, NIH-funded researchers were able to use injections of a new therapy known as an antisense oligonucleotide to counteract some of the effects of TDP-43 aggregation. While much more research is needed, these findings suggest a possible avenue for future treatment of conditions associated with TDP-43.

These and similar research approaches enhance the drug development pipeline and accelerate efforts to find effective drugs for Alzheimer’s and related dementias. In fact, since 2006, NIH has supported the development of 20 new drug candidates for the treatment of dementia that have received FDA permission to enter clinical trials and are currently being evaluated in human trials. These new investigational drugs target a broad range of different biological processes, including inflammation, metabolism, growth factors, and hormones.

• Schindler SE, et al. Using Alzheimer's disease blood tests to accelerate clinical trial enrollment . Alzheimer’s & Dementia . 2023;19(4):1175-1183. doi: 10.1002/alz.12754.
• Lucey BP, et al. Suvorexant acutely decreases tau phosphorylation and Aβ in the human CNS . Annals of Neurology . 2023;94(1):27-40. doi: 10.1002/ana.26641.
• Sperling RA, et al. Trial of solanezumab in preclinical Alzheimer’s disease . The New England Journal of Medicine . 2023;389(12):1096-1107. doi: 10.1056/ NEJMoa2305032.
• Lin FR, et al. Hearing intervention versus health education control to reduce cognitive decline in older adults with hearing loss in the USA (ACHIEVE): A multicentre, randomised controlled trial . Lancet . 2023;402(10404):786-797. doi: 10.1016/S0140-6736(23)01406-X.
• Yeung LK, et al. Multivitamin supplementation improves memory in older adults: A randomized clinical trial . American Journal of Clinical Nutrition . 2023;118(1):273-282. doi: 10.1016/j.ajcnut.2023.05.011.
• Vyas CM, et al. Effect of multivitamin-mineral supplementation versus placebo on cognitive function: Results from the clinic subcohort of the COcoa Supplement and Multivitamin Outcomes Study (COSMOS) randomized clinical trial and meta-analysis of 3 cognitive studies within COSMOS . American Journal of Clinical Nutrition . 2024;119(3):692-701. doi: 10.1016/j.ajcnut.2023.12.011.
• Yaffe K, et al. Effect of personalized risk-reduction strategies on cognition and dementia risk profile among older adults: The SMARRT randomized clinical trial . JAMA Internal Medicine . 2024;184(1):54-62. doi: 10.1001/ jamainternmed.2023.6279.
• Petrovsky DV, et al. Tailored music listening in persons with dementia: A feasibility randomized clinical trial . American Journal of Alzheimer’s Disease & Other Dementias . 2023;38:15333175231186728. doi: 10.1177/15333175231186728.
• Sisti A, et al. Using structured observations to evaluate the effects of a personalized music intervention on agitated behaviors and mood in nursing home residents with dementia: Results from an embedded, pragmatic randomized controlled trial . American Journal of Geriatric Psychiatry . 2024;32(3):300-311. doi: 10.1016/j.jagp.2023.10.016.
• Dowell-Esquivel C, et al. Computerized cognitive and skills training in older people with mild cognitive impairment: Using ecological momentary assessment to index treatment-related changes in real-world performance of technology-dependent functional tasks . American Journal of Geriatric Psychiatry . 2024;32(4):446-459. doi: 10.1016/j.jagp.2023.10.014.
• Jesudason CD, et al. SHIP1 therapeutic target enablement: Identification and evaluation of inhibitors for the treatment of late-onset Alzheimer's disease . Alzheimer’s & Dementia . 2023;9(4):e12429. doi: 10.1002/ trc2.12429.
• Quinney SK, et al. STOP-AD portal: Selecting the optimal pharmaceutical for preclinical drug testing in Alzheimer's disease . Alzheimer’s & Dementia . 2023;19(11):5289-5295. doi: 10.1002/alz.13108.
• Baughn MW, et al. Mechanism of STMN2 cryptic splice-polyadenylation and its correction for TDP-43 proteinopathies . Science . 2023;379(6637):1140-1149. doi: 10.1126/science.abq5622.

Last updated: August 5, 2024

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Future Alzheimer's Treatments Aim To Do More Than Clear Plaques From The Brain

Jon Hamilton

Scientists are working to develop new treatments for Alzheimer's disease by looking beyond amyloid plaques, which have been the focus of most Alzheimer's drug development in the past 20 years. Science Photo Library — ZEPHYR./Getty Images hide caption

Scientists are working to develop new treatments for Alzheimer's disease by looking beyond amyloid plaques, which have been the focus of most Alzheimer's drug development in the past 20 years.

Immune cells, toxic protein tangles and brain waves are among the targets of future Alzheimer's treatments, scientists say.

These approaches are noteworthy because they do not directly attack the sticky amyloid plaques in the brain that are a hallmark of Alzheimer's.

The plaques have been the focus of most Alzheimer's drug development in the past 20 years. And the drug Aduhelm was given conditional approval by the Food and Drug Administration in June based primarily on the medication's ability to remove amyloid from the brain.

But many researchers believe amyloid drugs alone can't stop Alzheimer's.

"The field has been moving beyond amyloid for many years now," says Malú Gámez Tansey , co-director of the Center for Translational Research in Neurodegenerative Disease at the University of Florida.

Tansey and a number of other researchers offered a wide range of alternative strategies at the Alzheimer's Association International Conference in Denver last month.

Here are three of the most promising:

Untangling toxic tau

Another target for future treatments could be a protein called tau , which is responsible for the toxic tangles that appear inside brain cells as Alzheimer's develops.

Tau may pose a greater threat than amyloid because "tau aggregation is directly correlated to cognitive decline," says Sarah DeVos, a senior scientist at Denali Therapeutics who has spent much of her career studying tau.

Tau tangles appear first in a brain area called the entorhinal cortex, which is involved in memory and navigation, DeVos says. "And then it moves very systematically, so it jumps from one brain region to the next."

Experimental drugs might be able to halt this process by removing toxic forms of tau, but it has been difficult to get these drugs past the blood-brain barrier.

So researchers at Denali began studying a system that helps iron cross from the bloodstream into the brain. The system involves proteins called transferrin that carry iron throughout the body. The linings of tiny blood vessels in the brain are equipped with special transferrin receptors that allow iron to reach brain tissue.

The team at Denali realized, "Hey, this is a really efficient system," DeVos says. Then they asked, "Can we design a drug that will kind of more or less take a ride over?"

They did, by designing a "transport vehicle" that could carry many different drugs across the blood-brain barrier by interacting with the transferrin receptors. At the Alzheimer's conference, DeVos described using the system to deliver a monoclonal antibody designed to clear out tau.

The approach hasn't been tried in people yet. But it does work in a model system using living human brain cells.

Targeting brain waves with light and sound therapy

This idea comes from a team of scientists at MIT that has been studying electrical pulses in the brain called gamma waves. These waves play a critical role in learning and memory.

The researchers noticed that these waves become weaker and less synchronized in people with Alzheimer's. So they thought they might be able to slow down the disease by boosting gamma waves.

To find out, the team exposed mice to lights and sounds that caused the gamma waves in their brains to strengthen and synchronize, says Li-Huei Tsai , a professor of neuroscience at MIT and director of the Picower Institute for Learning and Memory.

"What really surprised us is that this approach produces profound benefits in mice engineered to model Alzheimer's disease," Tsai says.

After treatment, their brains started clearing out both amyloid and tau proteins, the brain's immune cells began to function better, and the mice improved on tests of learning and memory.

The next step was to try the approach on humans, says Dr. Diane Chan , a neurologist at Massachusetts General Hospital who also works in Tsai's lab. So the team built a portable device that could generate light and sound pulses at just the right frequency: 40 hz.

"We sent the device home with people who had mild Alzheimer's dementia to let them use these devices an hour a day every day," Chan says.

After three months, the team checked participants' brains for signs of atrophy, which is usually found in people with Alzheimer's.

"We found that the group that used the active setting at 40hz light and sound actually did not see any atrophy over this time period," Chan says.

In contrast, people who'd been using an inactive, placebo device did have brain atrophy.

The results came from a study of 15 people that was designed to make sure the device was safe. Next, the scientists hope to confirm the results in a larger study.

"This is completely noninvasive and could really change the way Alzheimer's disease is treated," Tsai says.

Rejuvenating immune cells

Immune cells are the brain's first line of defense against germs, and they also vacuum up not only amyloid, but also a range of other toxic substances.

As people age, these immune cells get weaker and less able to prevent the changes that lead to Alzheimer's, Tansey says.

"Perhaps the accumulation of amyloid [in Alzheimer's patients] is because the immune cells, the vacuum cleaners, don't do their job," Tansey says.

Tansey's lab thinks that focusing on these immune cells could be key.

"The idea is that if you could boost the immune system, rejuvenate it somehow, that you might be able to slow down the process, perhaps reverse it, but certainly prevent it," says Tansey.

Tansey's lab is now searching for ways to provide that boost.

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NIH releases 2022 dementia research progress report

NIH has released Advancing Alzheimer’s Disease and Related Dementias Research for All Populations: Prevent. Diagnose. Treat. Care. (PDF, 17M), a 2022 scientific progress report.

The report features science advances and related efforts made between March 2021 and early 2022 in areas including drug development, lifestyle interventions, biomarker research, and more. It provides a comprehensive overview of the meaningful progress researchers are making to address the enormous health care challenges of Alzheimer’s and related dementia diseases.

This year’s progress report was preceded by the Fiscal Year 2024 Professional Judgment Budget for Alzheimer’s Disease and Related Dementias, announced in late July. Looking Forward: Opportunities to Accelerate Alzheimer’s and Related Dementias Research (PDF, 9M) provides an estimate of the funds needed to enable NIH to fully pursue scientific opportunities to inform effective prevention, treatment, and care of those living with these diseases.

Over the past year, NIH has conducted and funded remarkable Alzheimer’s and related dementias research that is bringing us closer to effective prevention, diagnostics, and treatments and improved care for the people living with these conditions, along with better support for care partners. With continued federal support and collaboration among researchers, clinicians, people living with dementia, and their care partners and families, the future holds hope and promise.

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What’s next for alzheimer’s disease treatments: a 2024 forecast.

By: Caleigh Findley, PhD, BrightFocus Foundation

• Expert Information

Reviewed by: Sharyn Rossi, PhD, BrightFocus Foundation

From upcoming drug approval decisions to late-stage clinical trial readouts—this year promises many developments for Alzheimer’s and dementia treatments coming down the pipeline. In 2024, there are 171 ongoing studies and 134 drugs being tested in clinical trials .  

Over half (77%) of the new treatments are touted as potentially disease-modifying, meaning they target known pathological changes in Alzheimer’s disease to slow cognitive decline. This strategy is intended to give people in the early stages of Alzheimer’s disease a little more time before they start to lose their cognitive abilities and begin experiencing symptoms like memory loss.  

There are limited treatment options for Alzheimer’s disease currently available , and only a small portion are considered disease-modifying. Those drugs have shown modest results for slowing progression, leaving room for improvement and innovation in upcoming therapies. The next generation of treatments are making their way through clinical trials and roughly 15% of new drugs are in later-stage studies (Phase 3). 

Read on to learn more about a few of the anticipated major Phase 3 trial results and potential upcoming treatments in 2024:  

The Alzheimer’s Treatment Pipeline 

A second amyloid-clearing treatment (donanemab)  .

Anti-amyloid therapy donanemab is expected to receive a final decision from the U.S. Food and Drug Administration (FDA) this year. The FDA recently announced that it will convene a meeting of expert advisors to review clinical trial findings on the effectiveness and safety of donanemab before rendering judgment.  

Donanemab made headlines in 2023 as the amyloid-targeting drug with the highest slowing of cognitive decline at 35% . A separate analysis of those who received the drug early in their disease showed upwards of 60% slowing of cognitive decline, reinforcing the need for early intervention with Alzheimer’s and dementia treatments. Donanemab works by targeting and removing the hallmark amyloid plaques that appear in brains with Alzheimer’s disease. A Phase 3 clinical trial found that more participants receiving donanemab showed reduced brain amyloid plaques compared to another recently discontinued Alzheimer’s therapy.  

The FDA convened an  advisory committee meeting   regarding donanemab on June 10, 2024. The drug, now called Kisunla, was approved by the FDA on July 2.  Learn more . 

The First Oral Alzheimer’s Drug (ALZ-801)

Traditionally, amyloid-targeting therapies require regular intravenous (IV) infusions that take place at a doctor’s office. Now, scientists are developing amyloid-fighting medications in an easily accessible pill form.  

The drug manufacturer of the first disease-modifying oral medication for Alzheimer’s, ALZ-801, is expected to submit a new drug application to the FDA later this year. The application is awaiting final topline results from a Phase 3 clinical trial called APOLLOE4. The trial examines the use of this medication in people with two copies of an Alzheimer’s risk gene, APOE4 , and an early Alzheimer’s diagnosis.  

ALZ-801 targets an earlier form of amyloid that builds up in the brain and can negatively impact surrounding cells. Trials results reported thus far show less risk of a rare but serious side effect called amyloid-related imaging abnormalities , associated with current anti-amyloid medications. The oral form of the drug also holds the potential for easier treatment access and less burden to people receiving the medication.  

ALZ-801 is based on a drug called tramiprostate that was co-created by Don Weaver, a recipient of the BrightFocus Foundation Centennial Grant . This funding enabled small molecule drug discovery for Alzheimer’s research.  

An Alternative Treatment for Alzheimer’s Agitation (AXS-05) 

The company that made the first approved therapy for Alzheimer’s agitation is expected to report topline results from a Phase 3 trial for a new medication this year. The repurposed anti-depressant, AXS-05, showed positive results in previous late-stage trials for treating agitation behaviors like sundowning in people with Alzheimer’s.  

Currently, there is only one available therapy for Alzheimer’s agitation .  

Targeting Multiple Alzheimer’s Disease Proteins (Simufilam) 

Two Phase 3 clinical trials for the upcoming Alzheimer’s drug, simufilam, are expected to end this year. The REFOCUS trial is investigating two different doses of simufilam (50mg or 100mg) in people with mild to moderate Alzheimer’s over 76 weeks and is expected to end in July. The other trial, called RETHINK , examines a 100mg dose of the drug over 52 weeks and is due to end this October. Simufilam works by blocking filamin A, a biological factor tied to amyloid plaques and tau tangles .  

 The simufilam clinical trials have been met with some controversy , which prompted a response from the university of the lead investigators. Experts are awaiting the outcome of these Phase 3 trials to see how effective the therapy is in slowing cognitive decline.  

What About Studies for Alzheimer’s Prevention? 

A large-scale study examining the effect of exercise, diet, and other lifestyle interventions on cognition in older individuals at risk for dementia, called the U.S. POINTER Study, just finished enrollment last year. Researchers are finalizing data this year and expect to present their findings in 2025. Their work is inspired by the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (known as ‘FINGERS’) that showed slowed cognitive decline in older at-risk people with two years of lifestyle interventions. These trials have expanded into the World Wide (WW)-FINGERS study, which is ongoing.  

The Bottom Line  

This year may see the approval of a new Alzheimer’s therapy, with several other treatments close on its heels that aim to improve treatment access and quality of life by shepherding a pill for Alzheimer’s. Researchers are also working in tandem to investigate lifestyle interventions that could help prevent Alzheimer’s from developing in the first place. Together, these innovations illustrate steady progress toward a better future for the millions living with Alzheimer’s disease and their families.   

Want to learn more? Take a deep dive with neurologist and Alzheimer’s expert Dr. Jeffrey Cummings in our “Zoom in on Dementia & Alzheimer's” episode on Alzheimer’s Clinical Trials 2024 here .  

Scientists funded by BrightFocus’ Alzheimer’s Disease Research program are studying innovative new treatments to support the next generation of Alzheimer’s therapies. Find out more about the groundbreaking work we’re funding here .

Additional Resources

Treatments for Alzheimer’s Disease   

Watch: Zoom in on Dementia & Alzheimer’s , live conversations with Alzheimer’s experts

Clinical Trials Arena. Alzheimer’s Disease: Some trials to watch over the next year . September 1 2023.  

Alzforum. ALZ-801 . September 15, 2023.  

Alzforum. AXS-05 . March 02, 2023.  

Alzforum. Simufilam . December 04, 2023.  

Alzheimer’s Association. U.S. POINTER .  

Ngandu T, Lehtisalo J, Solomon A, et al. A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial . Lancet. 2015;385(9984):2255-2263. doi:10.1016/S0140-6736(15)60461-5 

About BrightFocus Foundation       

BrightFocus Foundation is a premier global nonprofit funder of research to defeat Alzheimer’s, macular degeneration, and glaucoma. Through its flagship research programs — Alzheimer’s Disease Research, National Glaucoma Research, and Macular Degeneration Research — the Foundation has awarded nearly $290 million in groundbreaking research funding over the past 50 years and shares the latest research findings, expert information, and resources to empower the millions impacted by these devastating diseases. Learn more at  brightfocus.org .     

The information provided in this section is a public service of BrightFocus Foundation, should not in any way substitute for the advice of a qualified healthcare professional, and is not intended to constitute medical advice. Although we make efforts to keep the medical information on our website updated, we cannot guarantee that the information on our website reflects the most up-to-date research.      

Please consult your physician for personalized medical advice; all medications and supplements should only be taken under medical supervision. BrightFocus Foundation does not endorse any medical product or therapy.  

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The State of Alzheimer’s Research and the Path Forward

• Published: 24 October 2023
• Volume 10 , pages 617–619, ( 2023 )

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• Howard M. Fillit 1 ,
• B. Vellas 2 &
• Y. Hara 1  

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A dvances in medicine and public health have resulted in a longer human lifespan worldwide. While this is a remarkable achievement, it has been accompanied by a rise in age-related chronic diseases, such as type 2 diabetes mellitus, cardiovascular disease, cancer, and neurodegenerative disease ( 1 ). Morbidity rates for these chronic age-related diseases increase steadily to middle age, then increase sharply, with individuals over 80 experiencing twice the prevalence compared to those aged 60–64, a phenomenon related to the Gompertz curve ( 2 ).

Gerontology is the study of aging, a discipline with much history and accumulated knowledge. The term gerontology was coined by Élie Metchnikoff in 1903, and the Journal of Gerontology was initiated in 1946. Within gerontology, geroscience is a multidisciplinary field that examines the relationship between aging biology and age-related chronic diseases. As a research priority for diseases that manifest in later stages of life, geroscience aims to understand the complex interactions between the fundamental processes of aging and the vulnerability to age-related disease ( 3 ). A better understanding of these relationships holds the potential to pave the way for more effective clinical interventions that address the diseases and conditions commonly experienced by older adults.

Over the course of almost eight decades of research in geroscience, several common processes that go awry with aging have been identified. These processes include inflammation, vascular dysfunction, aberrant proteostasis and autophagy, mitochondrial oxidative stress, metabolic dysfunction including insulin resistance, cellular senescence and accumulation of senescent cells, and epigenetic dysregulation. These common pathways are all implicated in the development and progression of Alzheimer’s disease (AD) ( 4 , 5 , 6 ). Incorporating the principles of geroscience and leveraging the extensive knowledge of biological aging in AD research holds tremendous potential for developing new drugs and more comprehensive and effective treatment strategies. Each of these common biological aging pathways provides a viable therapeutic target to delay or prevent the onset and progression of AD.

In this issue of The Journal of Prevention of Alzheimer’s Disease, we present promising therapeutics in development for AD that target biological aging processes. Chronic inflammation, known to contribute to numerous age-related diseases, is linked to reduced brain volume and impaired cognitive function in AD ( 4 , 7 ). Although broad-spectrum anti-inflammatory drugs have largely failed, targeting specific aspects of inflammation while sparing others have shown promise. In this edition, Dr. Giordano discusses NTRX-07, a selective Cannabinoid Receptor 2 (CB2) agonist that has demonstrated the potential to reduce microglial-mediated neuroinflammation in AD. NTRX-07 is currently in Phase I clinical development and will soon be evaluated in multiple-ascending dose studies in individuals with early AD.

Another age-related process with implications for AD is cellular senescence, where cells evade death and accumulate over time, leading to the release of proinflammatory cytokines and chemokines that induce tissue damage in the brain and other organs ( 5 ). Drugs that selectively induce apoptosis of senescent cells are currently in clinical development to explore their efficacy in alleviating the inflammatory burden associated with AD. Dr. Orr presents a Phase II randomized, double-blind, placebo-controlled clinical study in this edition, investigating the safety and efficacy of the combination of two senolytic therapies, dasatinib and quercetin, in older adults with biomarker-confirmed mild cognitive impairment (MCI) or early-stage AD (NCT04685590).

Vascular pathology is also recognized as a contributor to the development of dementias like AD ( 4 , 8 ). One vascular pathology of interest is vascular breakdown in the brain as a result of blood-brain barrier disruption. Vascular breakdown causes leakage of fibrinogen into the central nervous system, inducing neuroinflammation and formation of insoluble fibrin clots ( 9 ). While undetectable in the healthy brain, fibrinogen reaches detectable levels in the AD brain and interacts with amyloid, a hallmark pathological marker of AD, exacerbating clotting, fibrin deposition, and proinflammatory signaling ( 10 , 11 , 12 ). In this edition, Drs. Kantor and Stavenhagen introduce the development of a first in class fibrin-targeting immunotherapy for dementia. 5B8 is an antibody identified in mice that specifically targets fibrin deposits and it has been shown to block fibrin-induced activation of inflammatory cells that lead to neuronal loss, without interfering with the beneficial processes of blood clotting ( 13 ). 5B8 shows promise as a therapeutic for AD but also an imaging agent for brain vascular damage that could be used to identify early stages of AD.

Autophagy, the cellular process of breaking down and recycling aggregated misfolded and damaged organelles, is disrupted in aging. Aberrant autophagy is thought to contribute to the pathologic buildup of amyloid plaques, tau tangles, and other misfolded proteins in AD ( 6 , 7 ). Recent clinical studies demonstrate that monoclonal antibodies against amyloid can slow clinical decline by up to 35% ( 14 , 15 , 16 ). Successes of these monoclonal antibodies indicate that misfolded amyloid proteins play a role in AD, but targeting amyloid alone is not sufficient to completely halt the disease progression. AD is often comorbid with pathologies of other misfolded proteins, such as alpha-synuclein, Lewy bodies, and TAR DNA-binding protein 43 (TDP-43) ( 17 ). Therefore, therapies that target aberrant autophagy more broadly may provide greater therapeutic benefit. In this edition, Dr. Rosenzweig-Lipson presents a novel class of drugs that activate chaperone-mediated autophagy. Reduced function of chaperone-mediated autophagy is linked to the aggregation of misfolded proteins in AD and other age-related diseases. By enhancing the clearance of misfolded proteins, these drugs hold promise as a therapeutic target for AD.

Mitochondrial dysfunction and oxidative stress increase with aging and are closely associated with neurodegeneration. High metabolic demands along with low levels of antioxidative defense mechanisms make the brain particularly susceptible to oxidative damage ( 18 ). Furthermore, shared aging mechanisms underlying AD and other age-related pathologies offer the opportunity to accelerate clinical development by repurposing drugs that have proven safe and efficacious in other disease areas. Edaravone, a free radical scavenger, has been approved for the treatment of stroke and Amyotrophic Lateral Sclerosis (ALS) in Asia and ALS in the US. Previous antioxidant therapies have been unsuccessful in AD, in part due to poor blood-brain barrier penetration ( 19 ). Unlike these previously tested agents, edaravone crosses the blood-brain barrier, making it a potential therapeutic strategy for AD. In this edition, investigators at Treeway B.V. introduce a Phase II Study designed to assess the preliminary efficacy and safety of an oral formulation of edaravone (TW001) in individuals with AD.

In addition, Dr. Trushina discusses the development of small molecule modulators of mitochondrial function as a disease-modifying therapy for AD. Mitochondrial dysfunction is detected early in the disease course. Small molecule partial inhibitors of mitochondrial complex I improve mitochondrial function, in part by restoring morphology and communication with other cell organelles and have been shown to be safe and efficacious in AD mice. Thus, these small molecule modulators offer a compelling strategy to modify the disease course at the earliest stages ( 20 ).

Synaptic dysfunction and loss of cortical synapses occur with normal aging but become further exacerbated in neurogenerative diseases like AD ( 21 ). Postmortem studies have revealed a reduction in synapses in people with MCI, suggesting synaptic alterations precede degeneration and occur early in the disease course ( 22 ). Therefore, drugs that promote neuronal and synaptic health may be critical in delaying or preventing degeneration of neurons in AD. In this edition, Dr. Longo introduces LM11A-31-BHS, an orally available small molecule ligand for the p75 neurotrophic receptor (p75NTR). This compound selectively activates p75NTR survival pathways and inhibits apoptosis signaling. LM11A-31-BHS has demonstrated ability to reverse cholinergic neurite degeneration in AD mouse models with mild to severe pathology and was recently tested in a Phase II/III proof-of-concept clinical trial involving patients with mild to moderate AD (NCT03069014). Neuroprotective agents like LM11A-31-BHS have the potential to delay onset of clinical symptoms if administered early in the disease course or to slow progression when administered at later stages.

Metformin and semaglutide, effective drugs against type 2 diabetes, are ideal candidates for repurposing to address the metabolic dysfunction in AD. In this edition, Dr. Luchsinger discusses metformin as a therapeutic strategy for AD prevention. Metformin is thought to regulate age-related metabolic dysfunction in the brain, a known contributor of cognitive decline, by improving brain metabolism and insulin sensitivity ( 23 ). Metformin is currently being studied in the Phase II/III Metformin in Alzheimer’s Dementia Prevention (MAP) trial. This trial aims to further assess the therapeutic value of metformin as a prevention strategy for AD.

Lifestyle interventions are also being assessed for the prevention of AD. Global, large-scale clinical trials are currently underway to investigate how multidomain lifestyle interventions, alone or combined with certain medications, can reduce the risk of cognitive impairment and dementia. The pivotal FINGER trial, led by Dr. Kivipelto, has yielded critical insights by demonstrating that modifiable lifestyle factors not only slow cognitive decline but may improve cognitive performance in individuals at risk of dementia ( 24 ). In this edition, Dr. Kivipelto discusses the next phase of these studies, the MET-FINGER trial. MET-FINGER is a prevention study assessing whether combining healthy lifestyle changes with metformin can reduce the risk of dementia and improve overall health in older adults (NCT05109169). This combined approach may be more effective in reducing the risk of dementia compared to either intervention alone. Trials such as these are paving the way for a precision-medicine approach to prevention by leveraging an individual’s modifiable risk factors and unique characteristics to create a personalized prevention strategy.

Furthermore, the edition extensively explores the essential role of biomarkers in advancing the discovery of new therapeutic options for AD. Biomarkers targeting pathology have been instrumental in the success of the recent anti-amyloid antibody therapies, enabling selective recruitment of patients with confirmed pathology, rigorous clinical trial designs, and improved treatment monitoring. Looking to the future, applying this paradigm to the biology of aging will enhance the rigor and efficiency of clinical trials, accelerate the availability of safe and efficacious therapies, and improve the overall patient journey for individuals with AD.

Aging is by far the leading risk factor for AD ( 25 ). As biomarkers targeting the biology of aging advance, it will be important to use these tools to identify and monitor one’s biological age as opposed to their chronological age. Chronological age refers to the number of years we have been alive, while biological age is determined by assessing the aging of cells and tissues. The imminent ability to measure biological age in both research and clinical settings will deepen our understanding of the complexity of AD and create new opportunities for drug development ( 26 ).

The edition concludes by emphasizing the importance of taking a combination therapy approach to the treatment of AD. Such an approach is already the standard of care in other chronic age-related diseases, such as cancer and heart disease. Given that interventions that target one dysregulated system often attenuate others, combination therapies that target multiple age-related dysfunctions have the potential to produce synergistic effects. Recognizing that single-agent approaches may provide only incremental benefits, combination trials are essential to understanding how diverse therapeutic approaches work synergistically to provide meaningful treatment outcomes. Furthermore, combination trials are an integral step toward a precision medicine approach to AD, where a tailored drug cocktail can be recommended based on an individual’s specific biomarkers and pathologies.

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Conflicts of Interest: HMF receives royalties from the Icahn School of Medicine at Mount Sinai and, in the past 3 years, has received advisory board fees from Alector, Otsuka Lundbeck, LifeWorx, and The Key. BV is an investigator in clinical trials sponsored by Biogen, Eli Lilly, Roche, Eisai, Pfizer, Pierre Fabre, and the Toulouse University Hospital. BV has served on an advisory board for Biogen, Alzheon, Green Valley, Novo Nordisk, Longeveron, and Rejuvenate Biomed and has received honoraria for consulting or serving on an advisory board from Roche, Eli Lilly, Eisai, TauRx, and Cerecin. YH declares there are no conflicts of interest. The Alzheimer’s Drug Discovery Foundation has funded or co-funded several projects to develop or clinically test the following drugs that are mentioned in the editorial: NTRX-07, dasatinib + quercetin, 5B8, TW001, LM11A-31-BHS, metformin, and semaglutide.

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Fillit, H.M., Vellas, B. & Hara, Y. The State of Alzheimer’s Research and the Path Forward. J Prev Alzheimers Dis 10 , 617–619 (2023). https://doi.org/10.14283/jpad.2023.102

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Multidomain interventions: state-of-the-art and future directions for protocols to implement precision dementia risk reduction. A user manual for Brain Health Services—part 4 of 6

• Alina Solomon 1 , 2 , 3   na1 ,
• Ruth Stephen 1   na1 ,
• Daniele Altomare   ORCID: orcid.org/0000-0003-1905-8993 4 , 5 ,
• Emmanuel Carrera 6 ,
• Giovanni B. Frisoni 4 , 5 ,
• Jenni Kulmala 2 , 7 , 8 ,
• José Luis Molinuevo 9 ,
• Peter Nilsson 10 ,
• Tiia Ngandu 2 , 7 ,
• Federica Ribaldi 4 , 5 , 11 , 12 ,
• Bruno Vellas 13 ,
• Philip Scheltens 14 &
• Miia Kivipelto 1 , 2 , 3 , 7 , 15

on behalf of the European Task Force for Brain Health Services

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Although prevention of dementia and late-life cognitive decline is a major public health priority, there are currently no generally established prevention strategies or operational models for implementing such strategies into practice. This article is a narrative review of available evidence from multidomain dementia prevention trials targeting several risk factors and disease mechanisms simultaneously, in individuals without dementia at baseline. Based on the findings, we formulate recommendations for implementing precision risk reduction strategies into new services called Brain Health Services. A literature search was conducted using medical databases (MEDLINE via PubMed and SCOPUS) to select relevant studies: non-pharmacological multidomain interventions (i.e., combining two or more intervention domains), target population including individuals without dementia, and primary outcomes including cognitive/functional performance changes and/or incident cognitive impairment or dementia. Further literature searches covered the following topics: sub-group analyses assessing potential modifiers for the intervention effect on cognition in the multidomain prevention trials, dementia risk scores used as surrogate outcomes in multidomain prevention trials, dementia risk scores in relation to brain pathology markers, and cardiovascular risk scores in relation to dementia. Multidomain intervention studies conducted so far appear to have mixed results and substantial variability in target populations, format and intensity of interventions, choice of control conditions, and outcome measures. Most trials were conducted in high-income countries. The differences in design between the larger, longer-term trials that met vs. did not meet their primary outcomes suggest that multidomain intervention effectiveness may be dependent on a precision prevention approach, i.e., successfully identifying the at-risk groups who are most likely to benefit. One such successful trial has already developed an operational model for implementing the intervention into practice. Evidence on the efficacy of risk reduction interventions is promising, but not yet conclusive. More long-term multidomain randomized controlled trials are needed to fill the current evidence gaps, especially concerning low- and middle-income countries and integration of dementia prevention with existing cerebrovascular prevention programs. A precision risk reduction approach may be most effective for dementia prevention. Such an approach could be implemented in Brain Health Services.

Although prevention of dementia and late-life cognitive decline is a major public health priority, there are currently no generally established prevention strategies or operational models for implementing such strategies into practice [ 1 ]. During the past 20 years, epidemiological studies have pointed out several modifiable risk factors for dementia, including cardiovascular, metabolic, and lifestyle-related factors (e.g., hypertension, hyperlipidemia, diabetes, obesity, physical inactivity, unhealthy dietary habits, smoking, excessive alcohol consumption, social isolation) [ 2 ]. In 2019, the World Health Organization (WHO) published the first guidelines for risk reduction of cognitive decline and dementia [ 3 ]. The guidelines were developed to provide evidence-based recommendations on interventions aiming to delay or prevent the onset of cognitive decline and dementia. The reviewed evidence covered interventions including physical activity, tobacco cessation, nutrition, cognitive training, social activity, interventions for alcohol use disorders, and management of weight, hypertension, diabetes, dyslipidemia, depression, and hearing loss [ 3 ].

According to the WHO, these risk reduction guidelines are targeted primarily at healthcare providers working at a first- or second-level facility or at the district level, including basic outpatient and inpatient services. While the WHO has pointed out several key considerations for implementation, it is not yet fully clear exactly how the recommendations should be tailored to specific populations, as well as different healthcare system contexts. Due to the complex multifactorial etiology of dementia, and variations in risk factors between different individuals and populations, a “one-size-fits-all” approach to prevention is not going to work. The current risk reduction guidelines are also based on interventions targeting single risk factors. However, overall dementia risk is most often the result of a combination of risk and protective factors that may have different contributions in different individuals or at different life stages. Thus, a precision risk reduction approach is most likely to be effective, i.e., tailoring the right interventions for the right people and at the right time. Operational models for the risk reduction interventions would also have to take into account the local or national specifics of both public health policies and healthcare systems.

Early identification of at-risk individuals is an essential part of the precision risk reduction approach. Many multifactorial dementia risk scores have already been developed for the early identification of at-risk individuals who may also benefit most from preventive interventions [ 4 ]. Although such risk scores could in principle facilitate precision risk reduction by, e.g., highlighting an individual’s specific combination of risk factors and facilitating more tailored interventions, the majority of such risk scores are not yet sufficiently validated and/or have not been tested in actual prevention trials. In addition, dementia shares many risk factors with other chronic diseases such as cardiovascular conditions (CVD), diabetes, or stroke. Validated risk scores for such conditions are already used as part of the established prevention programs [ 5 ]. However, it is not clear to what extent vascular/diabetes risk scores could be useful in the context of dementia prevention and facilitate the integration of dementia prevention within other established prevention programs.

This article is a narrative review of available evidence from multidomain dementia prevention trials targeting several risk factors and disease mechanisms simultaneously, in individuals without dementia at baseline. A key aspect of the evidence review concerns the use of dementia and CVD risk scores in such prevention trials. Based on the findings, we formulate some practical recommendations for implementing precision risk reduction strategies (see Table 1 ) into new services called Brain Health Services (BHSs). Currently, dementia prevention falls under the domain of memory clinics. However, the current memory clinics have been designed for the needs of patients with overt cognitive and/or behavioral disorders and are ill-equipped to deal with a population of cognitive unimpaired individuals and their growing demand for dementia prevention and cognitive enhancement interventions [ 6 ]. We envision the development of new BHSs, with specific missions including dementia risk profiling [ 7 ], dementia risk communication [ 8 ], dementia risk reduction (the present paper), and cognitive enhancement [ 9 ] and with specific societal challenges [ 10 ]. This will be the fourth part of a Special Issue series of six articles, published in Alzheimer’s Research & Therapy , which together provide a user manual for BHSs.

Multidomain interventions

Effects of multidomain interventions on cognition and related outcomes.

An English-language literature search was conducted using medical databases (MEDLINE via PubMed and SCOPUS, until December 2020) and keywords such as “multidomain,” “intervention,” “dementia,” “cognition,” “cognitive decline,” and “risk reduction.” The following criteria were used to select relevant studies: non-pharmacological multidomain interventions (defined as combining two or more intervention domains), target population including individuals without dementia at baseline, and primary outcomes including cognitive/functional performance and/or incident mild cognitive impairment (MCI) or dementia. The 14 identified studies are summarized in Table 2 .

Most of the trials were conducted in high-income countries. There was a substantial variability in the target populations, format and intensity of the interventions, choice of control conditions, and outcome measures. Recruited participants were aged between 40 and 80 years and varied from relatively unselected primary care populations to general populations with risk factors for dementia, and patients with MCI. The sample size ranged from 56 to 3526 participants and duration of the intervention from 8 weeks to 10 years (1 year or longer in 9 out of 14 trials). The interventions included intensive lifestyle programs offering various combinations of diet advice, dietary supplements, physical exercise advice and/or training programs, cognitive training, and management of vascular/metabolic risk factors. The intervention groups were compared to standard care, placebo, general information/health advice, or sham exercises.

Overall, the results appear to be mixed. Smaller ( N < 160 participants) and/or shorter trials (up to 24 weeks) seemed more likely to report intervention benefits on overall cognition and some specific domains (e.g., spatial working memory, executive functioning). Of the 5 larger ( N > 1000 participants) and longer-term trials (at least 2 years), only the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) reported significant intervention benefits on the primary and secondary cognitive outcomes [ 16 ]. The results from these 5 trials are difficult to compare directly due to substantial differences in, e.g., target populations, format and intensity of the interventions, and outcome measures. However, several characteristics specific for the FINGER intervention model have been emphasized as potential reasons behind its cognitive benefits [ 25 ]: (i) selection of an at-risk older population (60–77 years) based on the validated Cardiovascular Risk Factors, Aging and Dementia (CAIDE) Risk Score [ 26 ]; (ii) multidomain intervention covering five domains, i.e., diet, exercise, cognitive training, social activities, and monitoring of vascular/metabolic risk; and (iii) more intensive intervention, e.g., inclusion of an exercise program at the gym in addition to advice on physically active lifestyle and inclusion of both individual and group sessions to ensure sufficient support and motivation for healthy lifestyle changes.

Risk stratification in multidomain intervention trials

A cursory look at the mixed findings shown in Table 2 may tempt clinicians into thinking that the multidomain intervention concept is not as promising as initially hypothesized. However, the differences in the design between larger, longer-term trials that met vs. did not meet their primary outcomes suggest that multidomain intervention effectiveness may be highly dependent on a precision prevention approach, i.e., successfully identifying the at-risk groups who are most likely to benefit. To further investigate this, another literature search was conducted focusing on sub-group analyses assessing the potential modifiers for the intervention effect on cognition in the multidomain prevention trials listed in Table 2 . Identified sub-group analyses were based primarily on the FINGER, Multidomain Alzheimer Preventive Trial (MAPT), and Prevention of Dementia by Intensive Vascular Care (preDIVA) trials. Several of these analyses were pre-specified in the trial protocols, while others were conducted post hoc. The results are summarized in Table 3 .

In the FINGER trial, where participants were selected using the CAIDE Dementia Risk Score including age, sex, education, hypertension, hypercholesterolemia, obesity, and physical inactivity, the intervention seemed to be beneficial for cognition irrespective of further stratification by sociodemographic, cognitive, or cardiovascular factors [ 27 ]. Although participants with a higher LIfestyle for BRAin health (LIBRA) index at baseline had overall less cognitive improvement over time, this effect was not different between the intervention and control groups [ 29 ]. The LIBRA index is based on 12 modifiable risk factors [ 36 ] that partly overlap with those included in the CAIDE score, which may explain this result.

Interestingly, significant benefits on cognition were reported among participants in the MAPT trial with a CAIDE score ≥ 6 points (the same cutoff used in FINGER) [ 34 ]. Other analyses stratified by frailty status found no differences in the intervention effect on cognition between frail and non-frail MAPT participants [ 32 ].

The LIBRA index did not identify high-risk individuals in whom the preDIVA intervention was beneficial [ 35 ]. However, preDIVA trial participants with untreated hypertension and who were adherent to the intervention had a significantly lower risk of dementia compared with the control group [ 18 ]. This is perhaps not surprising considering that the preDIVA intervention placed more weight on the cardiovascular risk management component compared with the lifestyle components. Participants without a history of cardiovascular disease who were adherent to the preDIVA intervention also had a significantly lower risk of dementia compared to the control group.

The impact of genetic factors on the intervention effects on cognition has been so far reported only in the FINGER and MAPT trials. No significant difference in the intervention-related cognitive benefits was observed between APOE ε4 allele carriers and non-carriers. However, analyses stratified by APOE ε4 carrier status showed a significant intervention-related cognitive benefit among the group of ε4 carriers in FINGER [ 28 ], with a similar trend in MAPT [ 19 ]. In addition, a more pronounced cognitive benefit was reported in FINGER participants with shorter leukocyte telomere length at baseline, i.e., higher-risk individuals [ 30 ]. However, it would be particularly important for multidomain prevention trials to assess the impact of genetic risk beyond APOE genotype alone, e.g., via polygenic risk scores.

Brain imaging markers were also considered as potential intervention effect modifiers in the FINGER and MAPT trials. The MAPT intervention was reported to be associated with beneficial effects on cognition in individuals with amyloid positivity on positron emission tomography (PET) scans [ 33 ]. However, the FINGER intervention had more cognitive benefits in participants with higher brain volumes and cortical thickness at baseline [ 31 ]. It has been suggested that, while amyloid PET detects the early stages of amyloid deposition, morphological changes on MRI generally occur later in the Alzheimer’s disease (AD) continuum [ 37 ]. In this context, the MAPT and FINGER findings emphasize that the best window of opportunity for precision risk reduction may be among individuals who have an increased dementia risk, but not yet substantial brain pathology and/or substantial cognitive/functional impairment. In other words, earlier and better targeted multidomain interventions may be most effective.

Estimating dementia risk reduction in early multidomain interventions

The AD continuum is characterized by a long period (up to decades) between the start of brain pathology and dementia onset [ 38 ]. In early interventions targeting at-risk individuals without substantial impairment, and with clinical trial durations that only very rarely exceed 2–3 years, dementia is not a feasible trial outcome. In the absence of direct data on the impact of multidomain interventions on reduction in dementia incidence, other ways to estimate the risk reduction are needed. Multifactorial risk scores that provide standardized, evidence-based estimates for the risk of dementia may be particularly useful for this purpose and may also facilitate continuous monitoring of the intervention effects in practice by both clinicians and at-risk individuals.

Dementia risk scores have only recently started to be used in the context of prevention trials. For example, the FINGER trial used the CAIDE score for the recruitment of at-risk participants [ 16 ]. Several of the larger, longer-term multidomain intervention trials with cognition or dementia as primary outcomes are now also testing dementia risk scores as potential surrogate outcomes for estimating intervention effects on dementia risk reduction.

Table 4 summarizes the dementia risk scores used as outcome measures in multidomain prevention trials, including those where cognitive performance or dementia is not the primary outcome. Two smaller and shorter-term trials with younger individuals, Body Brain Life [ 23 ] and the In-MINDD feasibility trial [ 39 ], have used a dementia risk score as the primary outcome. In the larger and longer-term trials, dementia risk scores have been used as outcomes in post hoc analyses.

Overall, the results indicate significant intervention benefits on the tested dementia risk scores, supporting the potential use of these scores for estimating dementia risk reduction. However, estimates from such analyses are currently difficult to interpret or compare between different risk scores and would have to be verified against direct data on dementia incidence following the intervention. A potential solution for this could be extended follow-ups of trial participants after the intervention is completed, e.g., via healthcare registries if not otherwise feasible.

Dementia risk scores and brain pathology markers

Although many dementia risk scores have been developed for predicting subsequent dementia or cognitive decline, only two have so far been tested in relation to brain pathology (e.g., cerebrospinal fluid (CSF) or neuroimaging biomarkers, or brain pathology at autopsy). Detailed knowledge on the performance of a dementia risk score in predicting specific types of brain pathology (e.g., AD-related, or cerebrovascular) is essential for making informed decisions about the intervention study design, e.g., identification of the appropriate at-risk individuals who are most likely to benefit from a specific intervention, or monitoring of intervention effects on dementia risk reduction.

An English-language literature search was conducted using medical databases (MEDLINE via PubMed and SCOPUS, until December 2020) and keywords such as “dementia,” “Alzheimer,” “risk score,” “risk algorithm,” “biomarker,” “MRI,” “PET,” and “pathology.” The focus was on dementia risk scores including modifiable factors. A summary of the reported relations between dementia risk scores and brain pathology markers is shown in Table 5 . The CAIDE score is so far the most extensively tested in relation to biomarkers, including CSF and neuroimaging markers (structural MRI and amyloid PET), and post-mortem brain pathology. The Australian National University Alzheimer’s Disease Risk Index (ANU-ADRI) score has been tested in relation to MRI markers.

Although neuropathology markers can be used directly as predictors of dementia risk, currently available markers (CSF and neuroimaging) are more difficult to assess outside highly specialized memory clinic settings, and their use is not always recommended in a population of cognitively unimpaired individuals for ethical or health economics reasons [ 49 ]. Validating simpler and easier to use dementia risk scores in relation to neuropathology markers would thus offer more cost-effective solutions for early identification of at-risk individuals in a broader range of clinical settings, where risk reduction interventions can also be started earlier, before the onset of substantial impairment requiring referral for more invasive and costly diagnostic procedures.

Another key aspect to consider when choosing a dementia risk score for precision risk reduction is to what extent it captures risk versus prevention potential, i.e., room for improvement with intervention. Risk scores such as CAIDE, ANU-ADRI, or LIBRA include modifiable risk factors, thus indicating not only the risk profile, but also the intervention components that are needed to modify an individual’s risk profile. It is currently unclear to what extent neuropathology markers could be used to estimate prevention potential, although they could be very useful as secondary outcomes in multidomain interventions that combine non-pharmacological approaches with disease-modifying drugs. Assessing the neuropathology markers in multidomain prevention trials could also provide valuable knowledge on the interplay between cognitive reserve and brain pathology in determining intervention outcomes.

Dementia vs. cardiovascular risk reduction

The 2019 WHO guidelines for risk reduction of cognitive decline and dementia also covered evidence on interventions targeted at reducing cardiovascular risk factors (e.g., hypertension, dyslipidemia, and diabetes) both pharmacologically and non-pharmacologically. The potential for integrating these recommendations into existing cardiovascular prevention programs was also emphasized. Although validated CVD risk scores have long been an established part of cardiovascular prevention, the testing of CVD risk scores in the context of dementia prevention has only recently started.

For example, the Framingham CVD risk score includes age, sex, systolic blood pressure, treatment for hypertension, HDL cholesterol, total cholesterol, smoking, and diabetes. The Framingham stroke risk score combines age, systolic blood pressure, treatment for hypertension, diabetes, smoking, prior CVD (myocardial infarction, angina pectoris, coronary insufficiency, intermittent claudication, or congestive heart failure), atrial fibrillation, and left ventricular hypertrophy. Both versions of the Framingham risk score at midlife have been reported to predict cognitive decline and dementia [ 50 ]. Additionally, the Framingham CVD risk score has been reported to predict vascular dementia [ 51 ] and clinical progression in patients with AD dementia, particularly in those with genetic and atherosclerotic risk factors [ 52 ]. However, the Framingham CVD risk score was not associated with structural brain measures on MRI [ 53 ].

The Framingham CVD risk score and two dementia risk scores (CAIDE and Washington Heights-Inwood Columbia Aging Project (WHICAP)) were investigated in relation to cognitive performance in different ethnic groups [ 54 ]. All three scores were significantly associated with cognition in both Hispanic/Latino and non-Hispanic/Latino populations.

Life’s Simple 7 (LS7), defined by the American Heart Association as the 7 risk factors modifiable through lifestyle changes that can help achieve ideal cardiovascular health [ 55 ], has also been proposed as a potential tool for dementia risk reduction. The LS7 risk score includes four behavioral (smoking, diet, physical activity, body mass index) and three biological (fasting glucose, cholesterol, and blood pressure) factors. A lower LS7 score indicating poorer CVD health has been associated with a higher risk of dementia in a long-term (25 years) observational study, while adherence to the LS7 ideal cardiovascular health recommendations in midlife has been linked to lower dementia risk [ 56 ]. Another CVD risk score including age, systolic blood pressure, total cholesterol, high-density lipoprotein, smoking, body mass index, and diabetes has been suggested as a useful tool for identifying individuals at risk for cognitive decline and dementia [ 57 ].

The global vascular risk score (GVRS) was developed to test whether the addition of behavioral and anthropometric risk factors to traditional vascular risk factors can improve the prediction of clinical vascular events (e.g., stroke and myocardial infarction). The score combines age, sex, ethnicity, waist, alcohol consumption, smoking, physical activity, blood pressure, antihypertensive medication, peripheral vascular disease, blood glucose, and cholesterol. The GVRS has been associated with cognition, e.g., decline in global cognition, episodic memory, and processing speed over time, although this association seemed to be more pronounced in APOE ε4 non-carriers [ 58 ]. The GVRS has been suggested as a feasible tool for use in primary care settings [ 59 ].

All the abovementioned studies have been observational. So far, only one study has investigated the CVD risk scores in the context of clinical trials for dementia prevention, reporting that multidomain interventions designed for dementia risk reduction significantly improved CVD risk scores such as FINRISK and SCORE [ 41 ].

Although CVD risk scores seem promising as potential tools for dementia risk reduction, their testing and validation for this purpose are still far from the standards available in the field of cardiovascular prevention. An important issue is the longer- vs. shorter-term prediction of dementia risk. Studies on dementia risk scores have clearly shown that risk profiles in midlife can be very different from risk profiles at older ages, and especially in older individuals who are already closer to dementia onset [ 60 ]. The time between the onset of brain pathology and the onset of clinical symptoms is also the time when “silent disease” can affect a variety of vascular, metabolic, and lifestyle factors, i.e., reverse causality. This is the most likely reason why shorter-term observational studies (< 5 years) in older populations often report associations between factors such as low blood pressure, low BMI, or low cholesterol and increased likelihood of dementia [ 60 , 61 ]. Such findings likely indicate markers on an ongoing dementia-related disease and not actual risk factors. It is currently unclear if and to what extent CVD risk scores can be applied in older populations. Their associations with different types of brain pathology are also not yet determined.

Dementia prevention is still relatively new compared with, e.g., cardiovascular prevention, and much work is still left to be done to reach the standards of evidence and level of organization for pragmatic CVD risk reduction programs. Emerging evidence from recent multidomain prevention trials indicates that optimal preventive effects may be obtained through a precision risk reduction approach, i.e., targeting an individual’s overall risk profile instead of separate risk factors, and tailoring the right interventions to the right people at the right time. Randomized controlled trials testing early dementia risk reduction interventions have an inherent design complexity that CVD trials do not have to deal with, particularly in terms of outcome definitions. While CVD outcomes targeted by preventive interventions tend to be acute, clearly identifiable events, this is not the case for outcomes related to dementia diseases that are chronic, slowly progressive, often insidious, and requiring more specialized assessments to detect (e.g., neuroimaging, CSF). In addition, it is not fully clear how much intervention exposure and in what format would be necessary for achieving optimal effects, or at least what minimal level of exposure would be needed for some benefit to still be derived from dementia risk reduction interventions. Moreover, since most of the multidomain interventions were conducted in high-income countries, it is not clear whether their results can be generalized to low- and middle-income countries and is therefore necessary to collect further evidence from different settings. Thus, longer-term randomized controlled trials are much needed to address these issues. One such example is World Wide-FINGERS (WW-FINGERS, currently about 35 member countries), the first global network for multimodal dementia prevention trials, where the FINGER intervention model is currently being tested, adapted, and optimized in different populations, and geographic and economic settings, and focus is also on data harmonization and joint planning of these worldwide trials [ 62 ]. A limitation of this review is that the literature search was conducted in the English language only, and other potentially relevant studies may have been missed.

An important point regarding the development and testing of dementia and/or CVD risk scores in the context of dementia risk reduction concerns how findings are reported in the literature. Standardized and transparent reporting is crucial to facilitate decision-making about the choice of the most suitable risk estimation tools for specific purposes. The TRIPOD statement (transparent reporting of a multivariable prediction model for individual prognosis or diagnosis) [ 63 ] was published in 2015, and these guidelines would need to be followed similarly to for example CONSORT guidelines for reporting clinical trials, or STROBE guidelines for reporting cohort studies.

From research to implementation

Most risk reduction interventions have been conducted in a research setting. BHSs will allow to implement the risk reduction interventions in the real world by offering the opportunity for cognitively unimpaired users to actively act and reduce their chances of developing dementia in the future. Before implementing the risk reduction interventions, an accurate dementia risk profiling (assessing the genetic, lifestyle, and biological risk factors; [ 7 ]) is needed to tailor the interventions to individual BHS users.

The 2019 WHO guidelines for risk reduction of cognitive decline and dementia [ 3 ] have emphasized that the implementation of interventions for cardiovascular and lifestyle risk factors may be combined with existing for example CVD or diabetes prevention programs and targeted to relevant populations. For this purpose, it is crucial that healthcare staff are fully aware of the importance of prevention in general and dementia prevention in particular. A recent survey highlighted that about 62% of the healthcare professionals did not consider dementia as a disorder but a condition of normal aging [ 64 ]. For effective implementation of prevention programs, a resource-efficient way may be to combine dementia prevention with cardiovascular prevention which is substantially more advanced in knowledge, research, and implementation compared to the more recent field of dementia prevention. Also, shared risk factors between the two diseases can help the use of existing knowledge and services to advance the idea of dementia prevention from research to practice.

Engaging participants actively and in a meaningful manner is important in implementing prevention interventions. Large, longer-term multidomain intervention trials for dementia risk reduction have already shown that such interventions are feasible [ 16 , 18 , 19 ]. The first template for an operational model for dementia risk reduction has also been developed following the FINGER trial (Fig. 1 ). Although several factors such as higher age, poorer cognition, depressive symptoms, and smoking have been reported to be associated with lower adherence to multidomain interventions, results vary across the trials and different intervention components [ 65 , 66 ]. Individually tailored approaches to risk reduction may also be more likely to ensure adherence. For example, a person at-risk may be compliant to a healthy diet but may need support with physical and cognitive activities, or another person with diabetes may need extra support for diet and management of other cardiovascular risk factors.

FINGER operational model for dementia risk reduction. The model was first published in Finnish by the Finnish Institute for Health and Welfare ( http://urn.fi/URN:NBN:fi-fe2018092136291 )

Initiating and maintaining healthy lifestyle changes in general are challenging at a personal level and is impacted by factors such as participants’ knowledge, access to facilities, time management, preference, and attitude towards prevention. Another layer of complexity is added especially when considering the implementation of such interventions or programs in low- and middle-income countries where prevention at mid-life may not be deemed as important as perceived in the Western world. Rosenberg et al. [ 67 ] recently studied the reasons for participation in a European multinational, multidomain eHealth lifestyle prevention trial (HATICE) targeting at-risk older adults without significant cognitive impairment. The participants were asked to specify the reasons for participation in the trial to which most responded: the desire to contribute to scientific progress, the possibility to improve their own health through lifestyle changes, and access to additional medical monitoring in the trial. Whether these same reasons motivate persons from other cultures and countries to participate and adhere to lifestyle interventions remains to be ascertained.

Therefore, it is important to identify the motivating factors, participants’ expectation, and extending support to them or their active participation. Some motivating factors for participants to join and engage in prevention programs could be personal goal setting for the maintenance of participants’ current and future health and avoidance of disability or dependency later in life [ 67 ]. Knowing their expectation during and after the participation would help educate them and gauge their goals and expectations realistically and for this those who are, e.g., at higher risk or lagging in motivation, to offer them extra support.

Evidence on the efficacy of risk reduction interventions is promising, but not yet conclusive. More long-term multidomain randomized controlled trials are needed to fill the current evidence gaps, and the WW-FINGERS points in this direction. Nevertheless, consistent evidence suggests that a precision risk reduction approach may be most effective for dementia prevention. Such an approach can be implemented in BHSs.

Availability of data and materials

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Change history

23 october 2021.

The paper was amended to add a DOI in references part of the Brain Health Services series.

Abbreviations

World Health Organization

Cardiovascular conditions

• Brain Health Services

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Acknowledgements

European Task Force for Brain Health Services (in alphabetical order): Marc Abramowicz, Daniele Altomare, Frederik Barkhof, Marcelo Berthier, Melanie Bieler, Kaj Blennow, Carol Brayne, Andrea Brioschi, Emmanuel Carrera, Gael Chételat, Chantal Csajka, Jean-François Demonet, Alessandra Dodich, Bruno Dubois, Giovanni B. Frisoni, Valentina Garibotto, Jean Georges, Samia Hurst, Frank Jessen, Miia Kivipelto, David Llewellyn, Laura Mcwhirter, Richard Milne, Carolina Minguillón, Carlo Miniussi, José Luis Molinuevo, Peter M Nilsson, Janice Ranson, Federica Ribaldi, Craig Ritchie, Philip Scheltens, Alina Solomon, Cornelia van Duijn, Wiesje van der Flier, Bruno Vellas, and Leonie Visser.

This paper was the product of a workshop funded by the Swiss National Science Foundation entitled “Dementia Prevention Services” (grant number: IZSEZ0_193593).

AS receives research funding from the European Research Council grant 804371, Academy of Finland (287490, 294061, 319318), Yrjö Jahnsson Foundation, Finnish Cultural Foundation (Finland), Alzheimerfonden, and Region Stockholm ALF (Sweden).

GBF received funding from the EU-EFPIA Innovative Medicines Initiatives 2 Joint Undertaking (IMI 2 JU): “European Prevention of Alzheimer’s Dementia consortium” (EPAD, grant agreement number: 115736and “Amyloid Imaging to Prevent Alzheimer’s Disease” (AMYPAD, grant agreement number: 115952), and the Swiss National Science Foundation: “Brain connectivity and metacognition in persons with subjective cognitive decline (COSCODE): correlation with clinical features and in vivo neuropathology” (grant number: 320030_182772).

MK receives research funding from the Joint Programme - Neurodegenerative Disease Research (EURO-FINGERS), Academy of Finland (305810, 317465), Swedish Research Council, Center for Innovative Medicine (CIMED) at Karolinska Institutet, Region Stockholm (ALF, NSV), Knut and Alice Wallenberg Foundation, Stiftelsen Stockholms Sjukhem, Konung Gustaf V:s och Drottning Victorias Frimurarstiftelse, Swedish Research Council for Health, and Working Life and Welfare (FORTE).

Author information

Alina Solomon and Ruth Stephen contributed equally to this work (shared first author).

Authors and Affiliations

Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland

Alina Solomon, Ruth Stephen & Miia Kivipelto

Division of Clinical Geriatrics, NVS, Karolinska Institutet, Stockholm, Sweden

Alina Solomon, Jenni Kulmala, Tiia Ngandu & Miia Kivipelto

Ageing Epidemiology Research Unit, School of Public Health, Imperial College London, London, UK

Alina Solomon & Miia Kivipelto

Laboratory of Neuroimaging of Aging (LANVIE), University of Geneva, Geneva, Switzerland

Daniele Altomare, Giovanni B. Frisoni & Federica Ribaldi

Memory Clinic, Geneva University Hospitals, Geneva, Switzerland

Stroke Center, Department of Neurology, University Hospitals and University of Geneva, Geneva, Switzerland

Emmanuel Carrera

Department of Public Health Solutions, Public Health Promotion Unit, Finnish Institute for Health and Welfare, Helsinki, Finland

Jenni Kulmala, Tiia Ngandu & Miia Kivipelto

Faculty of Social Sciences, Tampere University, Tampere, Finland

Jenni Kulmala

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain

José Luis Molinuevo

Department of Clinical Sciences, Skåne University Hospital, Lund University, Malmö, Sweden

Peter Nilsson

Laboratory of Alzheimer’s Neuroimaging and Epidemiology (LANE), Saint John of God Clinical Research Centre, Brescia, Italy

Federica Ribaldi

Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy

Gérontopole of Toulouse, University Hospital of Toulouse (CHU-Toulouse), Toulouse, France

Bruno Vellas

Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands

Philip Scheltens

Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland

Miia Kivipelto

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• Marc Abramowicz
• , Daniele Altomare
• , Frederik Barkhof
• , Marcelo Berthier
• , Melanie Bieler
• , Kaj Blennow
• , Carol Brayne
• , Andrea Brioschi
• , Emmanuel Carrera
• , Gael Chételat
• , Chantal Csajka
• , Jean-François Demonet
• , Alessandra Dodich
• , Bruno Dubois
• , Giovanni B. Frisoni
• , Valentina Garibotto
• , Jean Georges
• , Samia Hurst
• , Frank Jessen
• , Miia Kivipelto
• , David Llewellyn
• , Laura Mcwhirter
• , Richard Milne
• , Carolina Minguillón
• , Carlo Miniussi
• , José Luis Molinuevo
• , Peter M. Nilsson
• , Janice Ranson
• , Federica Ribaldi
• , Craig Ritchie
• , Philip Scheltens
• , Alina Solomon
• , Cornelia van Duijn
• , Wiesje van der Flier
• , Bruno Vellas
•  & Leonie Visser

Contributions

Alina Solomon, Ruth Stephen, Philip Scheltens, and Miia Kivipelto conceptualized this paper, drafted the manuscript for intellectual content, and approved the final manuscript. Emmanuel Carrera, Jenni Kulmala, José Luis Molinuevo, Peter Nilsson, Tiia Ngandu, and Bruno Vellas revised the manuscript for intellectual content and approved the final manuscript. Daniele Altomare, Giovanni B. Frisoni, and Federica Ribaldi conceived and organized the workshop whence the papers of the BHS series in this issue of Alzheimer’s Research & Therapy originated, conceived the related editorial initiative, revised this manuscript for intellectual content, harmonized the manuscript with the other papers of the BHS series, and approved the final manuscript.

Corresponding author

Correspondence to Alina Solomon .

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Competing interests.

GBF reports grants from Alzheimer Forum Suisse, Académie Suisse des Sciences Médicales, Avid Radiopharmaceuticals, Biogen, GE International, Guerbert, Association Suisse pour la Recherche sur l’Alzheimer, IXICO, Merz Pharma, Nestlé, Novartis, Piramal, Roche, Siemens, Teva Pharmaceutical Industries, Vifor Pharma, and Alzheimer’s Association; he has received personal fees from AstraZeneca, Avid Radiopharmaceuticals, Elan Pharmaceuticals, GE International, Lundbeck, Pfizer, and TauRx Therapeutics.

JLM is currently a full-time employee of Lundbeck, has previously served as a consultant or at advisory boards for the following for-profit companies, or has given lectures in symposia sponsored by the following for-profit companies: Roche Diagnostics, Genentech, Novartis, Lundbeck, Oryzon, Biogen, Lilly, Janssen, Green Valley, MSD, Eisai, Alector, BioCross, GE Healthcare, and ProMIS Neurosciences.

PS has received consultancy fees (paid to the institution) from AC Immune, Alkermes, Alnylam, Anavex, Biogen, Brainstorm Cell, Cortexyme, Denali, EIP, ImmunoBrain Checkpoint, GemVax, Genentech, Green Valley, Novartis, Novo Noridisk, PeopleBio, Renew LLC, and Roche. He is a PI of studies with AC Immune, CogRx, FUJI-film/Toyama, IONIS, UCB, and Vivoryon. He serves on the board of the Brain Research Center.

The other authors declare that they have no competing interests.

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Solomon, A., Stephen, R., Altomare, D. et al. Multidomain interventions: state-of-the-art and future directions for protocols to implement precision dementia risk reduction. A user manual for Brain Health Services—part 4 of 6. Alz Res Therapy 13 , 171 (2021). https://doi.org/10.1186/s13195-021-00875-8

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Published : 11 October 2021

DOI : https://doi.org/10.1186/s13195-021-00875-8

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• Alzheimer’s disease
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Alzheimer's Research & Therapy

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Alzheimer's treatments: what's on the horizon.

Despite many promising leads, new treatments for Alzheimer's are slow to emerge.

Current Alzheimer's treatments temporarily improve symptoms of memory loss and problems with thinking and reasoning.

These Alzheimer's treatments boost the performance of chemicals in the brain that carry information from one brain cell to another. They include cholinesterase inhibitors and the medicine memantine (Namenda). However, these treatments don't stop the underlying decline and death of brain cells. As more cells die, Alzheimer's disease continues to progress.

Experts are cautious but hopeful about developing treatments that can stop or delay the progression of Alzheimer's. Experts continue to better understand how the disease changes the brain. This has led to the research of potential Alzheimer's treatments that may affect the disease process.

Future Alzheimer's treatments may include a combination of medicines. This is similar to treatments for many cancers or HIV / AIDS that include more than one medicine.

These are some of the strategies currently being studied.

Taking aim at plaques

Some of the new Alzheimer's treatments target clumps of the protein beta-amyloid, known as plaques, in the brain. Plaques are a characteristic sign of Alzheimer's disease.

Strategies aimed at beta-amyloid include:

Recruiting the immune system. Medicines known as monoclonal antibodies may prevent beta-amyloid from clumping into plaques. They also may remove beta-amyloid plaques that have formed. They do this by helping the body clear them from the brain. These medicines mimic the antibodies your body naturally produces as part of your immune system's response to foreign invaders or vaccines.

The U.S. Food and Drug Administration (FDA) has approved lecanemab (Leqembi) and donanemab (Kisunla) for people with mild Alzheimer's disease and mild cognitive impairment due to Alzheimer's disease.

Clinical trials found that the medicines slowed declines in thinking and functioning in people with early Alzheimer's disease. The medicines prevent amyloid plaques in the brain from clumping.

Lecanemab is given as an IV infusion every two weeks. Your care team likely will watch for side effects and ask you or your caregiver how your body reacts to the drug. Side effects of lecanemab include infusion-related reactions such as fever, flu-like symptoms, nausea, vomiting, dizziness, changes in heart rate and shortness of breath.

Donanemab is given as an IV infusion every four weeks. Side effects of the medicine may include flu-like symptoms, nausea, vomiting, headache and changes in blood pressure. Rarely, donanemab can cause a life-threatening allergic reaction and swelling.

Also, people taking lecanemab or donanemab may have swelling in the brain or may get small bleeds in the brain. Rarely, brain swelling can be serious enough to cause seizures and other symptoms. Also in rare instances, bleeding in the brain can cause death. The FDA recommends getting a brain MRI before starting treatment. The FDA also recommends periodic brain MRIs during treatment for symptoms of brain swelling or bleeding.

People who carry a certain form of a gene known as APOE e4 appear to have a higher risk of these serious complications. The FDA recommends testing for this gene before starting treatment.

If you take a blood thinner or have other risk factors for brain bleeding, talk to your healthcare professional before taking lecanemab or donanemab. Blood-thinning medicines may increase the risk of bleeds in the brain.

More research is being done on the potential risks of taking lecanemab and donanemab. Other research is looking at how effective the medicines may be for people at risk of Alzheimer's disease, including people who have a first-degree relative, such as a parent or sibling, with the disease.

The monoclonal antibody solanezumab did not show benefits for individuals with preclinical, mild or moderate Alzheimer's disease. Solanezumab did not lower beta-amyloid in the brain, which may be why it wasn't effective.

Preventing destruction. A medicine initially developed as a possible cancer treatment — saracatinib — is now being tested in Alzheimer's disease.

In mice, saracatinib turned off a protein that allowed synapses to start working again. Synapses are the tiny spaces between brain cells through which the cells communicate. The animals in the study experienced a reversal of some memory loss. Human trials for saracatinib as a possible Alzheimer's treatment are now underway.

Production blockers. These therapies may reduce the amount of beta-amyloid formed in the brain. Research has shown that beta-amyloid is produced from a "parent protein" in two steps performed by different enzymes.

Several experimental medicines aim to block the activity of these enzymes. They're known as beta- and gamma-secretase inhibitors. Recent studies showed that the beta-secretase inhibitors did not slow cognitive decline. They also were associated with significant side effects in those with mild or moderate Alzheimer's. This has decreased enthusiasm for the medicines.

Keeping tau from tangling

A vital brain cell transport system collapses when a protein called tau twists into tiny fibers. These fibers are called tangles. They are another common change in the brains of people with Alzheimer's. Researchers are looking at a way to prevent tau from forming tangles.

Tau aggregation inhibitors and tau vaccines are currently being studied in clinical trials.

Reducing inflammation

Alzheimer's causes chronic, low-level brain cell inflammation. Researchers are studying ways to treat the processes that lead to inflammation in Alzheimer's disease. The medicine sargramostim (Leukine) is currently in research. The medicine may stimulate the immune system to protect the brain from harmful proteins.

Researching insulin resistance

Studies are looking into how insulin may affect the brain and brain cell function. Researchers are studying how insulin changes in the brain may be related to Alzheimer's. However, a trial testing of an insulin nasal spray determined that the medicine wasn't effective in slowing the progression of Alzheimer's.

Studying the heart-head connection

Growing evidence suggests that brain health is closely linked to heart and blood vessel health. The risk of developing dementia appears to increase as a result of many conditions that damage the heart or arteries. These include high blood pressure, heart disease, stroke, diabetes and high cholesterol.

A number of studies are exploring how best to build on this connection. Strategies being researched include:

• Current medicines for heart disease risk factors. Researchers are looking into whether blood pressure medicines may benefit people with Alzheimer's. They're also studying whether the medicines may reduce the risk of dementia.
• Medicines aimed at new targets. Other studies are looking more closely at how the connection between heart disease and Alzheimer's works at the molecular level. The goal is to find new potential medicines for Alzheimer's.
• Lifestyle choices. Research suggests that lifestyle choices with known heart benefits may help prevent Alzheimer's disease or delay its onset. Those lifestyle choices include exercising on most days and eating a heart-healthy diet.

Studies during the 1990s suggested that taking hormone replacement therapy during perimenopause and menopause lowered the risk of Alzheimer's disease. But further research has been mixed. Some studies found no cognitive benefit of taking hormone replacement therapy. More research and a better understanding of the relationship between estrogen and cognitive function are needed.

Speeding treatment development

Developing new medicines is a slow process. The pace can be frustrating for people with Alzheimer's and their families who are waiting for new treatment options.

To help speed discovery, the Critical Path for Alzheimer's Disease (CPAD) consortium created a first-of-its-kind partnership to share data from Alzheimer's clinical trials. CPAD 's partners include pharmaceutical companies, nonprofit foundations and government advisers. CPAD was formerly called the Coalition Against Major Diseases.

CPAD also has collaborated with the Clinical Data Interchange Standards Consortium to create data standards. Researchers think that data standards and sharing data from thousands of study participants will speed development of more-effective therapies.

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Current status, inspirations and future trend of Alzheimer's disease research

ZHONG Chunjiu

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Alzheimer Disease: Current Concepts & Future Directions

Alzheimer disease (AD) is the most common cause of dementia in individuals over age 65, and is expected to cause a major public health crisis as the number of older Americans rapidly expands in the next three decades. Herein, we review current strategies for diagnosis and management of AD, and discuss ongoing clinical research and future therapeutic directions in the battle against this devastating disease.

Introduction and Epidemiology

Alzheimer disease (AD) is a major public health problem in the United States and throughout the world. AD is the most common cause of dementia in people over the age of 65 and affects well over five million people in the United States (U.S.), including 110,000 people in Missouri 1 . As the population ages, the number of American AD cases is projected to explode to 16 million by 2050, with an estimated annual cost of 1 trillion dollars. 1 Aside from its devastating effect on affected individuals, AD also takes an enormous toll on caregivers, as caring for an Alzheimer’s patient has been associated with financial stress, depression, and increased risk for other medical problems. Moreover, while the numbers of deaths caused by the other major killer diseases in the U.S., such as heart disease, cancer, and HIV, have declined in the past decade, deaths caused by AD continue to increase (See Figure 1 ). While no curative therapies have yet been developed, diagnosis of AD early in the disease course is important in that it allows for optimal initiation of symptomatic therapy and lifestyle modification, provides the opportunity for the patient to make plans for her own future, and may someday facilitate the preservation of cognition through disease-modifying therapy.

Percent change in number of deaths caused by major diseases in the US, 2000–2008. Source: The Alzheimer’s Association.

Alzheimer disease is characterized clinically by an insidious onset and progressive decline of cognitive function, usually beginning with impairment of short term memory. The classic neuropathologic hallmarks of AD are amyloid plaques, which are formed by aggregation of the amyloid-beta (Aβ) peptide, and neurofibrillary tangles, which consist of misfolded tau protein (See Figure 2 ). Autopsy data demonstrate that amyloid plaques begin forming in the brain many years before the onset of any symptoms. Amyloid plaques likely initiate a pathological cascade of events, including tau misfolding, oxidative stress and synaptic injury that eventually lead to neuronal death and brain dysfunction. 2 The medial temporal lobe, which plays a critical role in short term memory, is particularly affected in AD, explaining the early characteristic deficits in short term memory.

Amyloid plaques and neurofibrillary tangles within neurons in a silver-stained brain section from an Alzheimer’s disease patient (see asterisk and black arrows below).

Age is the strongest risk factor for the development of AD. At age 65, 13% of Americans have AD and by age 85 over 45% are affected. 1 Family history impacts AD risk, as individuals with an affected first degree relative (parent or sibling) have a two-three fold increased risk of developing AD. The vast majority of AD cases (99%) are sporadic, following no clear Mendelian genetic inheritance pattern. For sporadic AD, Apolipoprotein E ( APOE ) genotype is the major genetic susceptibility factor. APOE ɛ3 is the most common genotype in the overall population. In comparison to ɛ3, the ɛ2 allele imparts a decreased risk of AD, while the ɛ4 allele is associated with an increased risk. Two copies of the ɛ4 allele increase the risk of AD by 12-fold, and about half of all AD patients harbor at least one APOE ɛ4 allele. 3 Recent evidence suggests that APOE is important in Aβ metabolism and amyloid plaque formation. 3 Several other genes have recently been identified which modulate the risk of sporadic AD, and ongoing research is investigating their functions. In less than 1% of cases, a dominantly inherited familial form of AD is caused by mutations in amyloid precursor protein ( APP ), presenilin 1 ( PSEN1 ), or presenilin 2 ( PSEN2 ). Disease-causing mutations have been shown to influence production of Aβ peptide. 4 Most patients with dominantly inherited AD present with symptoms between age 30–50.

Proposed environmental risk factors for AD include traumatic brain injury, low educational attainment, diabetes, obesity, and cardiovascular risk factors such as high cholesterol and coronary artery disease. 1 Women have a significantly higher lifetime risk of AD than men, due in part to their longer average lifespan. Caucasians have lower rates of AD than do African Americans or Hispanic Americans, though the reason for this is unknown. Exercise, healthy diet (including high intake of fish, fruits, and vegetables), and remaining cognitively involved and stimulated are all associated with lower risk of AD, although it has not been proven that any specific food or activity can prevent AD or slow its course. While a variety of over the counter agents have been purported to bolster cognition or prevent AD, most of these have not been rigorously tested, and none have been proven efficacious in randomized controlled clinical trials in humans.

The typical clinical course of AD dementia is characterized by an insidious onset and slow progression of symptoms over years. 5 The initial symptoms are often related to short term memory deficits, such as repeating questions or statements, forgetting appointments, misplacing items, or forgetting important details about events. In the early stages, these symptoms can be very subtle, and can manifest simply as slight decline in the patient’s ability to perform complex tasks. Problems with orientation, including confusion about the date or getting lost, are often seen early in AD dementia. As the disease progresses, patients often require assistance managing finances, shopping, driving, and keeping track of their schedule. In moderate AD dementia, patients depend heavily upon a caregiver and often require assistance maintaining their hygiene. At the end stages of AD dementia, patients are completely dependent on others, may forget the identities of their closest friends and family members, and may become bed-bound. The proximate cause of death is usually aspiration or infection.

Diagnostic Methods

The goals of the initial history, exam, laboratory work-up and imaging are 1) to rule-out causes of cognitive dysfunction not related to neurodegenerative disease and 2) to diagnose the presence or absence of a neurodegenerative disease based on the history, exam, any available psychometric data, labs and imaging data.

History and exam

The majority of the history should be obtained from a collateral source familiar with the patient’s daily life, as patients with cognitive impairment often have poor insight into their condition. The focus of the history should be on changes in the patient’s memory and thinking over time, as individuals vary greatly in their baseline abilities and habits. For example, are there certain abilities the patient has lost because of a decline in memory or thinking? Although most people can describe occasional lapses in memory, the history should probe for problems that are consistent and worsening over time. The AD-8 Dementia Screening Interview can be helpful, as it is sensitive to early cognitive changes associated with dementia 6 and is brief, reliable, and available at no cost. The AD-8 does not definitively diagnose dementia, but it can be helpful in identifying patients who require further evaluation (See Figure 3 ).

(Positive Predictive Value = 87% for CDR 0 vs CDR ≥ 0.5)

*Adapted from Galvin et al, “The AD8: A Brief Informant-Interview to Detect Dementia”, Neurology . 2005;65:559–564.

Common causes of cognitive dysfunction, particularly in the elderly, include depression and cognitive side effects of medications. It is important to directly ask the collateral source and patient about symptoms of a possible mood disorder because this information is often not immediately offered. The patient’s medication list should be scrutinized for psychoactive medications, such as benzodiazepines, anti-cholinergics, pain medications, and sleep aids that can cause or exacerbate cognitive dysfunction. Any association between the patient’s symptoms and alcohol consumption should be assessed. A family history of dementia can suggest the patient is at higher risk, especially in cases of early onset dementia. Finally, it is helpful to screen for obstructive sleep apnea (OSA), as OSA is associated with a higher rate of developing dementia and is often treatable. 7 In patients with dementia, disrupted sleep-wake cycles are common and may be a major cause of caregiver stress.

The patient should undergo a screening neurological examination. Verbal fluency should be noted, as certain dementias are associated with prominent language difficulties. A neurologic exam should be performed to exclude focal signs, which might suggest stroke, demyelination, or a mass lesion. The examiner should also evaluate for increased muscle tone, tremor, slowness, abnormal gait, or poor balance, which may indicate a Parkinsonian syndrome. Most patients presenting with AD dementia have normal neurological exams except for evidence of cognitive impairment.

Psychometric testing can be helpful in some circumstances: 1) Quantifying a subtle deficit 2) Identifying which cognitive domains are affected 3) Providing a baseline against which future testing can be compared. In addition to the informant-based AD8, short instruments that can be administered to the patient in an office setting include the Mini Mental State Exam (MMSE), 8 the Short Blessed Test 9 and the Montreal Cognitive Assessment (MOCA, available at www.mocatest.org ). 10 Interpretation of the tests must take into account educational level and any other factors that could affect the result, including decreased vision or hearing. A poor result on a test does not definitively diagnose dementia, but may lend support to the diagnosis. Complete evaluation performed by a licensed clinical neuropsychologist can be helpful in complex or atypical cases.

Laboratory work-up and imaging

Since cognitive dysfunction may be caused by a large number of medical and neurological causes, a thorough evaluation to rule-out potentially treatable causes of dementia is needed. Blood tests to be ordered include blood chemistries (including liver function test and creatinine), complete blood cell count, thyroid stimulating hormone (TSH) and vitamin B12 level. In patients with early onset dementia, atypical dementia, or risk factors for sexually transmitted infections, it is also appropriate to check a rapid plasma reagin (RPR) and HIV antibody. At this time, it is not recommended that patients routinely be tested for APOE isoform or mutations associated with autosomal dominant Alzheimer’s disease. 11

Practice parameters developed by the American Academy of Neurology recommend that brain imaging be performed on all patients with cognitive decline. 11 A brain MRI both with and without contrast and including diffusion sequences is the most sensitive test. In patients with renal dysfunction the MRI can be performed without contrast. In patients who cannot undergo an MRI because of contraindications such as an implanted pacemaker, a head CT is acceptable but may not visualize more subtle findings. In cases of early onset dementia, atypical dementia or dementia of uncertain diagnosis, cerebrospinal fluid (CSF) and advanced imaging techniques may help clarify the diagnosis. These methods, including recently-developed tests for CSF Aβ and tau and PET-based imaging of brain amyloid plaques (amyloid imaging) allow for more specific and earlier diagnosis of AD. These tests are described further in the article entitled, “Advances in Diagnostic Testing for Alzheimer Disease.”

Patients with onset of dementia prior to age 60, rapid progression of dementia over months, or atypical forms of dementia may benefit from seeing a dementia specialist for further evaluation. Symptoms of atypical dementias may include early and prominent changes in behavior, language, visuospatial function or movement.

Two classes of medications are FDA approved for the treatment of AD. Acetylcholinesterase inhibitors, including donepezil (Aricept®), rivastigmine (Exelon®), and galantamine (Razadyne®) are approved for symptomatic treatment of mild to moderate AD, and are intended to support memory by increasing the amount of available acetylcholine in the synaptic cleft by preventing its breakdown. All of these agents are available in generic forms for oral administration. These drugs can cause gastrointestinal side effects including nausea, vomiting, and diarrhea, as well as cardiovascular effects such as bradycardia. Donepezil is the most commonly prescribed, and is usually initiated at 5 mg daily for four to six weeks, then increased to 10 mg daily if tolerated. A 23mg dosage has been approved that may impart slight increases in efficacy, but it is associated with significantly higher risks of gastrointestinal side effects 12 . Rivastigmine is available as a patch (not yet available as a generic), which may have lower incidence of nausea and can be helpful in more advanced AD patients who have difficulty remembering to take their pills.

The second class of FDA approved AD medication is N-methyl-D-aspartate (NMDA) glutamate receptor antagonists. Memantine (Namenda®) has been approved for use in moderate to severe AD. The initial postulated mechanism of action was reduction in glutamatergic excitotoxicity, but several studies have shown this is not the case. Memantine is also a non-competitive antagonist of serotonin 5HT 3 and nicotinic acetylcholine receptors, and activates dopamine D2 receptors, though it is unclear if these actions mediate its effects. Side effects from memantine are quite rare, but can include confusion, drowsiness, headache, agitation, insomnia, and hallucinations. 13 Generic memantine is not yet available in the U.S. Generally, memantine is added to the regimen after the patient has already reached a stable dose of an acetylcholinesterase inhibitor, though it can be used as monotherapy in patients who do not tolerate acetylcholinesterase inhibitors.

In more advanced disease, patients can become aggressive and violent. Atypical antipsychotic medications are sometimes indicated, but should be used carefully because of studies showing that antipsychotics increase mortality in elderly dementia patients. Benzodiazepines should also be used with great caution, as they can cause paradoxical increases in agitation, as well as dependence and withdrawal. Non-pharmacologic strategies for behavioral management include keeping the environment consistent, non-threatening, and calm, avoiding cues which may precipitate agitation, and simplifying the daily routine. Depression and anxiety are very common in AD patients, and physicians and caretakers must be vigilant for these conditions and treat them appropriately. The Alzheimer’s Association ( www.alz.org ) provides a wealth of valuable resources for both patients and caregivers, and in many areas provides a variety of informational sessions, support groups, and referral services.

Regarding safety, assessment of driving skills by a professional is recommended for any individuals with notable cognitive impairment, and restricting or eliminating driving is encouraged if there is substantial concern. Firearms in the home should be secured. Patients may need oversight with meals and with their medications, as well as with personal finances, and in some cases access to banking and investment accounts must be restricted. Patients with moderate disease may not be safe to leave unattended at home, as dangerous situations such as leaving water or a gas stove on are quite common. As the disease progresses, patients are likely to wander, and may need constant supervision, as well as a SafeReturn® bracelet, available through the Alzheimer’s Association.

Future Directions

It is an exciting time for research in AD and other dementias, as over 70 clinical trials of experimental therapies are ongoing. Large-scale clinical studies of dementia and healthy aging, including the Memory and Aging Project at Washington University and the nationwide Alzheimer’s Disease Neuroimaging Initiative, have provided critical insights into how AD begins and progresses, and have shown that the pathological process leading to clinical AD begins at least a decade prior to the onset of any cognitive symptoms. 2 With the advent of new biomarkers, very early and even presymptomatic diagnosis is now possible. Unfortunately, at this point in time, all efforts at therapeutic intervention in the symptomatic disease course have failed. Thus, it appears that treatment strategies for AD must be initiated as early in the disease course as possible, to prevent ongoing neurodegeneration. 2 Ideally, asymptomatic individuals could be screened and treated presymptomatically, thereby preventing or delaying dementia. At present, there is no such therapeutic “prevention” option and thus presymptomatic screening cannot be encouraged.

The majority of current experimental therapeutic strategies for AD focus on eliminating Aβ, as Aβ accumulation appears to precede neurodegeneration and symptom onset by years, and likely initiates the pathogenic cascade in AD. Passive immunization with antibodies that bind Aβ is an attractive paradigm, and a number of monoclonal antibodies are in various stages of clinical trials in humans. 1 . Small molecule inhibitors of beta-and gamma-secretases, enzymes which play critical roles in the generation of Aβ, have also been developed, and several are in late stage clinical trials. 15 , 16 As mentioned above, there have been several well-publicized failures of anti-amyloid therapies in phase III clinical trials in the past few years, including both Aβ antibodies and gamma secretase inhibitors. It is likely that these failures were due to multiple issues including poor efficacy of the drug in reducing Aβ levels, treatment too late in the disease process, and dilution of the trial population with non-AD dementias. A second generation of therapeutics is now entering phase III trials, and clinical trial methodology is being refined, so there is hope that an effective Aβ-targeted therapy will be identified. The first clinical trials providing presymptomatic therapy for rare early onset familial AD patients are beginning this year, including the Dominantly Inherited Alzheimer’s Network (DIAN) treatment trial, and the Alzheimer’s Prevention Initiative (API). The DIAN trials will employ two distinct anti-Aβ antibodies and API will use another Aβ antibody. 17 , 18 While they focus on rare autosomal dominant AD, success of these trials may set the stage for future preventative trials in sporadic (late onset, non-familial) AD. Indeed, a third trial, entitled the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) study, will evaluate presymptomatic therapy with anti-Aβ antibodies in 70+ year old participants with no cognitive symptoms, but with amyloid imaging evidence of presymptomatic AD. Thus, the era of presymptomatic anti-amyloid experimental therapy is at hand (but far from ready for clinical use), and these important trials likely will have major impact on the AD field for years to come.

While these initial trials all employ therapies targeting Aβ, non-Aβ therapies are also in development, including agents which aim to reduce tau aggregation, suppress neuroinflammation, prevent oxidative injury, augment neuronal metabolism, and modulate APOE levels. Small molecule activators of α7 nicotinic acetylcholine receptor and nasally-inhaled insulin have entered clinical trials, both of which have been show to enhance cognition in AD in smaller studies, providing new possible avenues of symptomatic therapy. 19 , 20 Intravenous immunoglobulin (IVIG) has shown promise in stabilizing cognition in small cohorts of symptomatic AD patients, though the mechanisms are unclear, and a larger trial has reportedly failed. Preclinical studies in mouse models have identified dozens more potential therapeutic targets, which await validation in humans but will hopefully keep the drug development pipeline stocked for years to come.

Alzheimer disease is a devastating neurodegenerative disease which affects millions of people, and threatens to become a public health crisis in coming years. Great strides have been made in our understanding of the underlying disease mechanisms and in early diagnosis, and the first experimental efforts to treat AD presymptomatically are beginning, potentially heralding a new era of AD management.

Erik S. Musiek, MD, PhD, (left) is a an Assistant Professor of Neurology, and Suzanne E. Schindler, MD, PhD, is a Clinical and Postdoctoral Research Fellow in Neurology. Both are with the Knight Alzheimer’s Disease Research Center at the Washington University School of Medicine in St. Louis.

Contact: ude.ltsuw.oruen@ekeisum

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• Published: 18 May 2023

Towards a future where Alzheimer’s disease pathology is stopped before the onset of dementia

• Wiesje M. van der Flier   ORCID: orcid.org/0000-0001-8766-6224 1 , 2 , 3 ,
• Marjolein E. de Vugt 4 ,
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Alzheimer’s disease (AD) is a major healthcare challenge with no curative treatment at present. To address this challenge, we need a paradigm shift, where we focus on pre-dementia stages of AD. In this Perspective, we outline a strategy to move towards a future with personalized medicine for AD by preparing for and investing in effective and patient-orchestrated diagnosis, prediction and prevention of the dementia stage. While focusing on AD, this Perspective also discusses studies that do not specify the cause of dementia. Future personalized prevention strategies encompass multiple components, including tailored combinations of disease-modifying interventions and lifestyle. By empowering the public and patients to be more actively engaged in the management of their health and disease and by developing improved strategies for diagnosis, prediction and prevention, we can pave the way for a future with personalized medicine, in which AD pathology is stopped to prevent or delay the onset of dementia.

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Observational studies in Alzheimer disease: bridging preclinical studies and clinical trials

Alzheimer’s disease (AD) is among this century’s major healthcare challenges. It is characterized by progressive decline in the individual’s cognitive abilities. Worldwide, 55 million patients suffer from dementia 1 . AD is the most common cause of dementia. Therefore we focus on AD, but we also discuss studies that do not specify the cause of dementia and acknowledge that much of the reasoning holds for other pathologies causing dementia as well. While most prevalence studies do not specify dementia subtype, advances of biomarkers for AD pathology enable more precise estimates of dementia due to AD at 32 million worldwide 2 . In fact, dementia is only the late stage of a disease that takes years to develop in the brain. Biomarkers allow us to estimate the size of populations in pre-dementia stages of AD; first estimates indicate 69 million individuals with mild cognitive impairment (MCI) due to AD and >300 million individuals having preclinical AD 2 , 3 . MCI refers to the prodromal stage of AD in which there is some cognitive impairment that does not suffice for a diagnosis of dementia. Preclinical AD refers to the presence of AD pathology in individuals without any signs or symptoms. It is not yet clear, however, whether all individuals with preclinical AD progress to symptomatic AD and dementia. Nonetheless, the biomarker-based prevalence estimates of the AD continuum illustrate that we need to disentangle the concepts of AD from dementia 4 , 5 , 6 . While AD refers to the disease or pathological process that takes years to develop, dementia refers to a late-stage, detrimental outcome of this disease. There is no cure for AD yet, nor for other dementia-causing diseases. In a large proportion of patients with AD, a diagnosis is only made at a late disease stage. The same holds for other dementia-causing diseases. As a result, care is too often untimely and insufficiently adjusted to patients’ needs, resulting in frustrations in patients as well as health professionals, high costs and a compromised quality of life 7 . Treatment strategies for AD that lead to even small delays in onset of dementia and progression of the disease or enable self-management of patients would not only considerably reduce the prevalence of dementia but also the individual and socioeconomic burden 8 , 9 . It is therefore critical to bring therapy and support to individuals in as timely and adequately a manner as possible.

AD pathology should be targeted before the onset of dementia. Research has shown that AD develops in the course of 20–30 years 10 , 11 . By the time AD manifests as dementia, the brain can no longer be rescued. This provides a huge window of opportunity for preventive action. To optimally employ these possibilities, we need a paradigm shift with a focus on (1) individual characteristics and preferences and (2) the stages before dementia to ultimately (3) prevent progression to dementia. Effective deployment of preventive strategies requires timely identification of individuals who would benefit the most. Further development of diagnostic tests to detect early AD pathophysiological changes, also capturing differences in pathological pathways between patients, is therefore warranted. Individual preferences and patient-reported outcomes should be the starting point for high-quality individualized care 12 , 13 .

Based on observations in the consultation room—where the information need of patients boils down to three questions: ‘Doctor, what diagnosis do I have?’, ‘What can I expect?’ and ‘What can I do?’—in this Perspective, we outline the preparatory steps to ready society for a future with personalized medicine for AD. We discuss the need for preventive strategies, outlining the importance of both disease-modifying drugs and lifestyle interventions. We also reflect on the importance of timely and molecular diagnosis of AD, where blood-based biomarkers, genetic information and digital tools can be incorporated into the AD diagnosis framework. Moving toward earlier stages of the disease, personal risk profiles should provide prognostic information on outcomes that matter to patients. Finally, we recommend promoting patient-orchestrated care by engaging older adults (at risk of) AD throughout their health and disease management, with a keen eye for an inclusionary approach to keep healthcare affordable and accessible. As such, we describe a direction for the future in which patient-orchestrated AD healthcare entails accurate and timely diagnosis with prediction of meaningful outcomes to ultimately achieve prevention of dementia.

Dementia risk reduction is one of the strategic action areas of the World Health Organization’s global action plan on dementia, outlining steps to be taken on a global, national and regional level 14 . To ultimately reduce the global burden of AD and other causes of dementia, we should move the needle forward to pre-dementia stages of disease. The report identified a wide gap between the need for prevention and treatment and the actual provision of services. It stresses the need for a collective effort to understand how we can prevent or at least delay onset of the disease. Prevention encompasses both pharmacological and non-pharmacological strategies. These are not mutually exclusive but rather complementary strategies. For complex diseases such as AD, we need to employ every possible strategy that may help to reduce the disease burden, that is, focus on risk reduction, while also developing disease-modifying treatment, with the ultimate question of what works for whom.

Pharmacological interventions

In the dementia stage, it is too late to rescue the brain, and most pharmacological treatment is therefore aimed at slowing the progression of symptoms, in fact, tertiary prevention. For future pharmaceutical strategies to be most effective, however, they probably should be provided in the pre-dementia stages. After aducanumab in 2021, the approval of lecanemab by the Food and Drug Administration at the beginning of 2023 heralds the second drug with disease-modifying properties 15 , 16 . This marks a milestone heralding the dawn of a new era, in which drugs that alter the biological disease pathways in AD are a realistic opportunity. Market access of these drugs will impact the patient journey, not only in terms of treatment, but also in terms of diagnosis, monitoring and prognosis. In particular, this illustrates the necessity to focus on underlying pathology, rather than syndrome outcome. There are a number of challenges to address related to integrating this new class of drugs in clinical care. We need to obtain better understanding of their clinical impact as well as the putative side effects. Risk–benefit assessment for use of the drugs, that is, who will benefit most while taking into account who is at most risk of side effects, needs to take place on an individual basis. One might argue that, initially, treatment should only take place in certified centers with sufficient expertise. At the same time, we need to make sure that healthcare remains accessible and sustainable. Clear stop criteria, that is, stopping when all amyloid has been removed or when the drug is not successful in doing so, will be indispensable to keep costs at bay.

Despite the positive news on anti-amyloid treatment, we know that AD is far too complex a disease to be stopped by targeting amyloid only. The drug pipeline is much wider, however, as there are currently 143 drugs being studied in clinical trials, the large majority of which are disease-modifying therapies 17 . Non-amyloid targeting targets include tau, inflammation, synaptic plasticity and many others. Compared to clinical stage interventions, the portfolio of targets for treatment in preclinical studies is even broader, with an increasing focus on targets associated with AD risk genes, including apolipoprotein E (ApoE) and lipids, lysosomal–endosomal targets and proteostasis 18 . This further illustrates how developments in treatment strategies also impact the needs in diagnosis, for example, that genetic workup will have a role in future diagnosis, as a starting point to identify suitable treatment strategies.

Lifestyle interventions

It is estimated that up to 40% of dementia risk is attributable to 12 modifiable risk factors 19 . Risk factors vary across the lifespan, for example, from less education in early life, hypertension and obesity in midlife and social isolation, depression and physical inactivity in later life. It is not clear whether they relate to AD pathology specifically or rather to all-cause dementia. Neither is it entirely clear whether all 12 factors indeed constitute risk factors or whether some of them (for example, depression and social isolation) are in fact early features of disease. Nonetheless, these modifiable factors offer attractive targets for intervention.

Several large population-based cohort studies indicate that prevalence of all-cause dementia is increasing less than expected, and age-specific incidence is even declining in the Western world 20 , 21 . A recent post-mortem study showed a decline in vascular pathology but not in pathological AD diagnosis over a period of 25 years 22 . This suggests that, even in those with AD pathology, lifestyle-targeting interventions may help to prevent clinical manifestation of disease. The increasing number of studies examining modifiable risk factors has created momentum for developing intervention strategies to maintain cognitive health and ultimately prevent dementia. The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) study took as a starting point not one single modifiable risk factor but rather a multi-domain approach and showed somewhat improved cognitive functioning 23 . These findings are now being replicated through multiple studies testing similar intervention strategies in diverse populations and settings. This collaborative action of the World-Wide FINGERS Network is an example of how international and national collaboration drives strengthening evidence and moving the field forward 24 .

It is yet unknown whether lifestyle interventions still delay cognitive decline when AD pathology has started to accumulate, although there is some evidence suggesting that this may be the case 25 , 26 . Therefore, there is a need to better understand the value of lifestyle improvements in people that worry about their memory or have MCI. The beneficial effect of lifestyle interventions may be attributable to improving resilience against pathological processes 27 . Resilience encompasses cognitive reserve, or adaptability of cognitive processes to pathology, brain maintenance, referring to reduced accrual of pathology over time, and brain reserve, directly related to the individual’s structural characteristics of the brain. To what extent these concepts are specific to AD pathology or rather generic to any type of brain pathology remains to be discovered.

There are several challenges in the translation of multicomponent lifestyle interventions into practice. We need to improve the evidence base on potential modifiable risk factors in the clinical context to set realistic expectations. In addition, one of the major challenges is to reach under-represented groups that have, for example, an ethnic or cultural minority status, low socioeconomic status or low levels of education 28 . Tailoring lifestyle interventions in practice to the knowledge, needs and preferences of these under-represented high-risk groups is essential. Secondly, communicating about dementia prevention comes with important ethical challenges, for example, to avoid ‘blaming the victim’. Strategies based on fear and stigma, such as those used in anti-smoking campaigns, should be avoided to not increase the stigma that dementia already has for people currently living with dementia 28 . In addition, implementing multicomponent lifestyle interventions in practice is complex and requires collaborative capacity to take collective action on a societal level. Preventive action for a disease that mostly occurs in late life should already start in midlife. Collaborating with established prevention programs in the public health domain and primary care setting, for example, by teaming up with cardiovascular disease prevention, could facilitate this.

Public participant involvement and recruitment

The dawn of the first effective strategies underlines and increases the need for clinical research in both patients and at-risk groups. Finding enough participants is an important bottleneck to finding effective intervention strategies 29 . Moreover, the lack of diversity in populations participating in clinical trials may be an important explanation of the limited breakthroughs in intervention strategies that are translated into clinical practice, given the disparities in disease risk and burden in some communities. Therefore, it is essential that clinical trials enroll diverse populations 30 . Remote strategies may facilitate the recruitment of diverse populations 31 .

Online platforms such as Brain Health Registry, Join Dementia Research or https://Hersenonderzoek.nl can help to involve citizens and patients to accelerate research 32 , 33 , 34 . In addition to providing more effective recruitment and making it easier to reach diverse populations, these platforms actively engage individuals with research, which ultimately leads to better treatment and care. Taking public and patient views into account from the start of the project will also lead to better translation of findings to clinical practice. The online platform to support communication in diagnosis ( https://www.adappt.health ) is an example, in which we combined rigorous statistical modeling based on biomarkers with a process of co-creation to determine how these models should be translated into clinical practice 35 . More recently, the response to coronavirus disease 2019 (COVID-19) has shown that research can be a major part of management for a large number of patients and leads to constant updating of best practices.

In the Netherlands, we recently initiated the ABOARD (short for ‘a personalized medicine approach for AD’) cohort, a societal initiative aiming for large-scale engagement of citizens and patients with research (Box 1 ). The ABOARD cohort takes a direct-to-participant recruitment strategy, putting research participants themselves in an active position. This is further reinforced by the installment of a participant panel that ensures active involvement of the end users. Recruitment is supported by a Facebook campaign from Alzheimer Nederland (the Dutch Alzheimer society). In this way, the ABOARD cohort achieves large-scale engagement of citizens; it provides data to study trajectories of disease in a real-life, national sample. And finally, it lays the foundation for national rollout of future studies.

Box 1 Dutch ABOARD project

ABOARD is a nationwide, public–private project that aims to prepare for a future in which Alzheimer’s disease (AD) is stopped before the onset of dementia. This is realized by improving timely and accurate diagnosis, developing individualized risk profiles and initiating nationwide data collection with a focus on patient-reported outcomes and a focus on prevention strategies by creating awareness around dementia and brain health. In addition, readiness of the Dutch healthcare system for disease-modifying treatment is evaluated.

ABOARD takes as a starting point the fact that AD develops over a period of over 20 years. ABOARD therefore focuses on the stages before onset of dementia, working toward prevention. In addition, AD is highly heterogeneous, both in underlying biology and specific pathways involved and in needs and preferences of patients and their care partners. The wishes and needs of patients should be the starting point of care, and ABOARD develops tool and etools to support patient-orchestrated care. Realizing that one size does not fit all, ABOARD envisions a future with individualized prevention encompassing tailored combinations of lifestyle and disease-modifying interventions.

The ABOARD project includes the recently initiated ABOARD cohort, a nationwide initiative to involve in research a large number of Dutch citizens with or at risk of AD. Based on the collection of patient-reported outcomes and consent to link to existing data, we create an infrastructure to study the entire AD disease trajectory, allowing extrapolation of prediction models beyond the initial research population and fostering collaboration between research projects. An active participant panel guarantees that participants are actively involved in choices regarding setup and execution of the project.

In the ABOARD project, over 30 partners representing the entire translational value chain work together. Partners include the five Dutch Alzheimer centers, Alzheimer Nederland and partners from academic and applied research, healthcare, private, semi-private and public organizations, all dedicated to achieving personalized medicine for AD. More information on this 5-year project (2021–2026), including an overview of partners, can be found on the website at https://www.aboard-project.nl .

Translation to clinical practice

There are a number of prerequisites for translation of effective preventive strategies, whether lifestyle or pharmacological interventions, into clinical practice. First, an accurate, etiological diagnosis is essential to start treatment. Second, when diagnoses need to be made before the stage of dementia to allow preventive action, adequate information on prediction and prognosis becomes highly relevant. A citizen wants to know what to expect, to prepare for what is ahead and to make balanced decisions with regard to potential risks and benefits of proposed preventive strategies. Finally, this illustrates that we need to empower the public and patients to be more actively engaged in the management of their own health and disease. When we think of a future with a broader array of potential preventive strategies, the associated risks and benefits of which may differ depending on individuals’ characteristics, also taking into account their preferences and needs, it becomes clear that shared decision making should become more common practice in the diagnosis and management of AD.

The diagnosis of AD dementia is based on clinical criteria. Patients with cognitive complaints or changes in behavior present to the primary care physician, who performs cognitive tests and initial examinations and can decide to refer the patient to a memory clinic for further diagnostic investigation 20 . Clinical diagnosis relies on careful history taking from the patient and family by a skilled clinician. A cognitive screening test, such as Mini-Mental State Examination (MMSE) or Montreal Cognitive Assessment (MoCA), is useful to obtain a crude indication of cognitive functioning. Patients can be referred to a memory clinic for a more thorough investigation. Standard diagnostic workup includes neuropsychological investigation and inventory of activities of daily living 20 . There is a need for an inclusive approach, ensuring that tests and questionnaires have validity across language and cultural barriers 36 . Imaging and routine laboratory tests serve to rule out other causes of cognitive decline. Diagnosis and management plans are decided by consensus in a multidisciplinary meeting.

In addition to this routine diagnostic practice, there have been tremendous advances in both imaging and fluid-based diagnostic tests providing evidence for underlying AD pathophysiology. This has culminated in the launch of the National Institute on Aging and Alzheimer’s Association (NIA-AA) research framework, which provides a biological definition of AD 5 (Box 2 ). This framework provides syndrome staging of cognitive impairment (subjective cognitive decline, MCI and dementia). It also categorizes AD biomarkers based on the ATN classification (as summarized in Table 1 and Box 2 ), where A refers to amyloid pathology (cerebrospinal fluid (CSF) amyloid-β or amyloid positron emission tomography (PET)), T refers to tau pathology (CSF phosphorylated tau (p-tau)/total tau or tau PET) and N refers to neurodegeneration (CSF neurofilament light chain protein (NfL) or [ 18 F]Fluorodeoxyglucose PET (FDG-PET) or magnetic resonance imaging (MRI)). There is ongoing debate about the ATN framework, which is currently being revised, as it does not capture the full complexity of AD-related pathophysiology. For example, synaptic loss and inflammation, also part of AD pathophysiology, are not accounted for. Moreover, the clinical syndrome in most patients results from mixed pathologies, for example, with co-occurring cerebrovascular disease, α-synucleiopathy or TAR DNA-binding protein 43 (TDP-43). The NIA-AA research framework does not account for mixed pathology. Nor do any other sets of diagnostic criteria, for that matter. There is an urgent need for criteria and guidelines for diagnosing mixed types of pathologies, particularly when we are moving toward a future with disease-modifying treatment.

Currently, a diagnosis is the starting point for initiating appropriate care and symptomatic treatment. In a future with personalized medicine, the choice of disease-modifying strategy is directly related to the presence of a specific type of pathology. This highlights a need for molecular diagnosis.

Box 2 Diagnostic framework based on NIA-AA

The diagnostic framework according to NIA-AA specifies both syndrome staging of cognitive impairment and biomarker categories to define AD 5 .

Syndrome staging of cognitive impairment

Substantial cognitive impairment affecting several cognitive and/or behavioral domains.

Progressive in nature; becomes worse over time.

Evident functional impact on daily life. No longer fully independent.

May be further characterized as mild, moderate and severe.

Mild cognitive impairment

Cognitive performance below expected range (can be primarily amnestic or non-amnestic).

Decline in cognitive performance as compared to before.

Performs daily life activities independently, although there may be mild functional impact.

Subjective cognitive decline 86

Worries about cognitive performance.

Cognitive performance within the expected range.

Note that the NIA-AA framework proposes preclinical AD; from a clinical, diagnostic perspective, we mention here subjective cognitive decline because without complaints, there is no reason to seek help.

Assessment of Alzheimer’s disease is based on biomarker evidence, based on A (amyloid), T (tau) and N (neurodegeneration)

Molecular biomarkers

A key to delaying the onset of dementia is an early and timely detection of AD-associated pathophysiological processes. The different AD-associated pathophysiological processes, namely, amyloid and tau pathology as well as neurodegeneration, can be identified using different biomarker modalities (as summarized in Table 1 ). Each modality of testing presents with advantages as well as limitations in capturing the spatiotemporal progression of AD pathology with a degree of affordability, accessibility and scalability 37 . For example, while structural MRI provides high spatial resolution and simultaneous presentation of information on multiple pathologies (for example, cerebrovascular pathology), it is not specific for the AD pathophysiological processes. PET tracers allow visualization and quantification of the spatial distribution of amyloid and tau pathology, but they provide information on a single type of pathology (for example, amyloid or tau). Moreover, the costs and infrastructural requirements are high, which limit their utility 38 . CSF-based biomarkers present the opportunity to evaluate multiple markers from one sample, which is scalable and a cost-effective option compared to neuroimaging; however, there is no localization of pathology and the invasive nature of the lumbar puncture is a limitation 39 . More recently, blood-based biomarkers have developed rapidly that provide an opportunity to detect multiple markers that are more affordable, accessible and scalable, compared to all other biomarker modalities, albeit unable to provide information on the localization of pathophysiological processes 40 . Hence, there is potential for blood-based biomarkers in the future as a biomarker modality for screening and monitoring the disease and treatment response 41 . Despite being highly promising, blood-based biomarkers are not ready for use in a clinical setting. Challenges in translating blood-based biomarkers to clinical practice include identifying the most promising biomarkers (and combinations thereof) and effective measurement platforms, prospective validation in real-life populations, in vitro diagnostic assay development and activities to obtain regulatory approval and refunding 40 . While validation studies are still ongoing, a first step toward implementation is the recent definition of appropriate use recommendations 42 .

Future developments in molecular diagnosis also contribute to further refinement of the diagnosis. AD is a highly heterogeneous disease, with multiple pathological pathways involved. Refining diagnosis for patient stratification is a next step toward personalized medicine of AD. Patient stratification using CSF-proteomic-based strategies has resulted in subgroups of AD with (1) hyperplasticity, (2) innate immune activation and (3) blood–brain barrier dysfunction 43 . It is likely that, when pathways from initial brain changes to late-stage dementia vary between individuals, this variability affects treatment response and/or risk of side effects.

In addition, knowledge on the genetic determinants of AD is quickly increasing. To date, >80 risk and protective genes for AD have been identified, most with only very small effect sizes when evaluated on their own 44 . The APOE gene is the most important risk gene for AD. Other risk variants, for example, TREM2 and SORL1 , although far less common, also confer strongly increased risks. The effects of all risk genes can be combined in a polygenic risk score. To date, genetics are not part of the routine diagnostic workup and are only performed when the family history is highly suggestive of a mutation. It is conceivable that genomics will be incorporated in the diagnostic workup of the future, however 44 , 45 , 46 . Of note, genetic makeup not only predisposes for an increased risk but can also explain reduced risk or resilience 47 , 48 , 49 . In a future with personalized medicine, certain genetic variants may predict treatment response for pharmaceutical strategies, both in terms of benefit and risk. As an example, homozygous APOE ε4 carriers have a strongly increased risk of severe side effects of anti-amyloid treatment, while the observed benefit may be less 15 . Finally, genetic variants that reveal specific pathways to be involved, such as TREM2 or SORL1 , may be the starting point of targeted therapeutic solutions 50 , 51 , 52 .

These developments show that we are making the transition to a biomarker-based diagnosis of AD. In the future, this may further develop to (1) a biomarker-based diagnostic fingerprint of different pathophysiological processes (mixed pathology) and (2) a more fine-grained diagnosis of AD, doing justice to the heterogeneity of the disease beyond the common ground of abnormal amyloid and tau. Detection of AD pathology across the spectrum (preclinical AD to dementia) provides a window of opportunity for therapeutic intervention to delay or even prevent the onset of AD dementia.

Digital tools

In addition to the swift developments in molecular diagnosis, careful characterization of the patient in terms of their clinical, cognitive and behavioral functioning remains key. In this context, digital biomarkers are very promising 53 , 54 .

Digital tools include online cognitive tests and questionnaires that resemble their paper-and-pencil equivalents 55 , 56 . Digital tests and questionnaires have the advantage of increased reliability and potentially increased sensitivity, as they allow extraction of many more data points than paper-and-pencil administration of a similar test. They could be cost saving, as they require less-skilled staff to administer. Computer-adapted testing versions of these tests shorten the administration time. In this way, they help to make the patient journey more patient friendly. Online cognitive tests also provide the possibility for the same set of tests and questionnaires to be provided at home, at the primary care setting and at the more specialized setting. By harmonizing the patient journey in this way, monitoring the disease and tracking progression becomes easier.

In addition, increased digitalization of society and improved data-analysis methods (for example, with use of artificial intelligence) open up innovative opportunities for digital biomarkers that can be obtained from, for example, wearables or voice recording 57 , 58 , 59 . These tests could be performed remotely at home, and they have ecological validity, as they test actual behavior in the home situation. Digital biomarkers could serve as a self-test to funnel to additional medical care, to monitor disease progression remotely as part of the follow-up visits after diagnosis and to monitor treatment response, potentially even increasing adherence to the program.

A European survey among professionals, patients and family members showed that a considerable majority had a positive attitude toward digital tools 60 . User friendliness and improved accuracy are main factors stimulating the adoption of a tool. Inadequate integration with electronic patient records and fear of losing important clinical information were most frequently indicated as barriers. Many patients and care partners showed interest in the possibility of using the tools themselves. Nonetheless, digital tools are still not used frequently in clinical practice. In addition to scaling practical hurdles and barriers, this also shows an urgent need for education of professionals and empowerment of patients and care partners. Use and development of digital tools has increased considerably during the COVID-19 pandemic, when testing remotely was a necessity when patients could not be seen in the clinic 61 . Finally, digital testing may contribute to making healthcare accessible also to low-literacy populations, particularly when cognitive testing is integrated in their daily lives, for example, by analyzing changes in use of their mobile devices or speech 31 .

The future diagnostic workup

The future diagnostic workup has a stepped or funneled approach, needed to keep healthcare accessible to an increasing number of patients. The specific diagnostic strategy could vary, depending on patients’ preferences and needs regarding diagnosis, prediction and prevention (Fig. 1 ). For example, one patient may want to know as much as possible about their genetic makeup and biomarker results to optimally prepare for the future, enroll in clinical trials or know their eligibility for disease-modifying treatment. For another patient, it may suffice to know that, at this time, cognitive impairment and daily functioning are still sufficiently intact and that they do not qualify for a syndrome diagnosis of dementia.

We are making the transition from a patient journey focused on diagnosis and post-dementia care to a patient journey in which diagnostic biomarkers increasingly serve the purpose of prediction and monitoring, and (preventive) treatment. Throughout the patient journey, information provision, when possible supported by e-tools, is key. This should entail information about what can be expected from the patient journey itself and information about the disease. In addition, there should be information about available options for diagnosis, prediction and prevention before embarking on testing or treatment, and information about what the results of specific tests mean for the individual lives of patients after testing and treatment. A prominent role for shared decision making promotes diagnosis and treatment to be more strongly aligned with the preferences, needs and wishes of patients and their families. The patient journey encompasses different settings (at home, primary care, secondary care and tertiary care) and may vary depending on disease stage (cognitively normal, mild cognitive impairment, dementia). Memory clinics mainly have a role for symptomatic patients, while Brain Health Services are an emerging concept that may be closer to primary care and may cater to cognitively normal citizens 84 . In the future patient journey, the themes of prediction, identifying the optimal preventive strategy, monitoring disease progression (including side effects) and evaluating treatment response become increasingly relevant. Diagnosis has a more funneled approach. Individualized risk profiles can be based on different types of determinants, depending on an individual’s disease characteristics and preferences. Treatment strategies have a stronger focus on prevention, encompassing both targeting of lifestyle (primary prevention), disease-modifying treatment (secondary prevention), symptomatic treatment (which could be referred to as tertiary prevention) and care. ARIA, amyloid-related imaging abnormalities; PRO, patient-reported outcome.

Initial testing should involve easily accessible and scalable tools that allow reliable ruling out of AD when negative, preventing the need for further expensive testing. Current testing in primary care mostly entails risk factor assessment, with medical history and a cognitive screening test. In the future, digital biomarkers in combination with blood tests could further improve this process. The initial tests can be used for more effective referral to specialist memory clinics for further, in depth diagnostic testing, for example, with more invasive or expensive tools such as MRI, CSF biomarkers or PET scans. In addition, memory clinics can provide further refinement of diagnosis, for example, based on proteomics or genomics. Finally, we foresee that computer-based tools, for example, making use of artificial intelligence solutions, will enable clinicians to extract maximum information from the available diagnostic test results. This will reduce practice variation and improve accuracy but also deliver answers in an understandable way to both the professional and the patient. Timely and precise diagnosis will lead to a reduction in patient burden, costs and length of the diagnostic process and reduce the healthcare burden and costs in specialist settings (which are, by definition, more expensive).

A diagnosis is not the end point, but rather the beginning of the rest of the disease trajectory. Given that AD is a progressive disorder, patients want to know what they can expect 62 , 63 . Available prediction models are mostly based on community-based studies (cardiovascular risk factors and lifestyle) or selected research populations (biomarker based). The former have relevance for the general population or general practitioner setting and often refer to lifetime risk of dementia 64 , 65 , 66 , while the latter pertain to a tertiary memory clinic setting and short-term risk 67 , 68 . Prediction models should be clear about the time frame for which they make predictions.

Biomarker-based prognosis

With the use of biomarkers, prediction of dementia has become more accurate, particularly in the MCI stage, providing a view on a future with individualized risk predictions 67 , 68 . Prediction models in the stage of cognitively normal are less generalizable and, for that reason, more difficult to translate to the individual level. Nonetheless, cognitively normal individuals who are positive for both amyloid and tau based on PET (hence, A + T + ) have a 50% probability to progress to a symptomatic stage in the short term, while progression rates are very low when A and T are not both positive. These data emphasize that biomarkers hold important prognostic information 69 , 70 .

Prediction of outcomes that matter

When we diagnose AD before the stage of dementia, a diagnosis in fact becomes a prognosis, as patients and their families are worried about the detrimental clinical outcome, rather that the molecular nature of the disease. Most modeling efforts predict the outcome of dementia. In a disease trajectory that takes decades to unfold, onset dementia will not be the key reference to commencing treatment anymore, as the recently approved medications can be prescribed to patients with MCI and mild dementia. In addition, with respect to prognosis, other outcomes may have even more relevance from the perspective of patients and their families. In an effort to identify patient-relevant outcomes, we asked patients and caregivers which outcomes a hypothetical future medicine should prevent 71 . The core list of prognostic information relevant to both patients and care partners included items mostly related to cognitive decline, dependency and physical health (Fig. 2 ). This information should guide modeling efforts and trial design.

Alzheimer’s disease (AD) includes the clinical stages of preclinical AD (including subjective cognitive decline), MCI and mild, moderate and severe dementia. Most prediction studies take cognitively normal individuals or patients with MCI as the starting point and predict progression to dementia. Yet, onset of dementia is in fact rather an arbitrary moment in a disease trajectory that takes decades to unfold. In a former study, we identified 13 outcomes that matter to patients and care partners, which may occur somewhere in the course of the disease 71 . Together, these meaningful outcome define the clinical trajectory of AD. To cater to the need of prognostic information for patients and their families, future studies should focus on prediction of these outcomes that matter.

Prediction in different settings

Much work still needs to be accomplished: (1) risk models should be applicable in primary, secondary and tertiary care and be generalizable beyond research settings to the ‘typical patient’, (2) findings should be interpretable at the individual level, and (3) outcomes should reflect what really matters to patients. Development of generalizable, flexible and patient-relevant prediction models is essential to provide tailored prognostic information. Ultimately, individualized risk predictions will identify which individuals benefit most from which preventive strategies.

Patient-orchestrated care

With the number of options in diagnosis, prediction and prevention of AD rapidly increasing, it becomes ever more important to take the preferences, wishes and needs of patients and their families as a starting point for providing care. Patients and their families being actively involved in the management of their own health and disease can contribute to keeping healthcare affordable and sustainable.

Ethical aspects

Now that it becomes possible to diagnose AD before onset of dementia, a next question is whether it is ethical to make such a diagnosis or inform individuals about their biomarker status or future risk of dementia 72 . Such knowledge may cause distress, as an exact prognosis cannot be provided and there is currently no curative treatment. Yet, is it ethical to withhold available information about AD risk when a person asks for it? The uncertainty of not knowing the cause of memory problems may be equally burdensome. Moreover, a diagnosis may provide an opportunity for preventive action to delay the start of dementia, help individuals and care partners to prepare for the future and allow participation in dementia-prevention trials. Of note, we only refer here to patients seeking help for their perceived problems at primary care or a memory clinic (that is, MCI or subjective cognitive decline). There is no reason to think that, at short notice, a widespread screening program in the general community would be useful. Nonetheless, individuals vary in their personal considerations regarding diagnosis, prediction and prevention of AD, and the question is how we can best accommodate these differences.

Shared decision making

Empirical evidence on the implications of a pre-dementia diagnosis for the well-being of individuals is largely lacking, whereas such information can inform organization of the patient journey. Nevertheless, the weighing of the pros and cons of an early diagnosis and the decision of whether to initiate testing or not that follows from such deliberation ultimately remains a highly individual process. Patients should be facilitated to articulate their voice in this decision as part of a shared decision-making process. Shared decision making refers to clinicians and patients (and/or their care partners) working together to decide which care plan best fits individual patients and their lives, given that there is more than one reasonable option 73 . To facilitate a process of shared decision making, we need to provide the public and patients with information to be able to make informed decisions. This information should include but not be limited to terminology (difference between AD and dementia), the advantages and disadvantages of existing diagnostic tests, possibility of misdiagnosis and mixed pathology, difficulty in personalized prognostication and risks and benefits associated with different treatment strategies.

Tailoring information to promote an inclusive approach

Some individuals run the risk of being less informed and less involved in decision making than others as a result of diversity in cultural background, health and e-health literacy, and/or educational attainment. Special attention is warranted for the needs and preferences of these more vulnerable individuals to ensure that their perspective is also taken into account in the organization of care. Heterogeneity in needs and preferences regarding information and participation in decision making also result from individual differences in psychological characteristics such as coping style or tolerance for uncertainty as well as, for example, living situation 62 . All of this requires that care is tailored to individual patients’ needs and preferences. Such tailoring is easier if patients (and their care partners) are in the lead. In former studies, we found that patients and their families hardly ask for additional information during diagnostic consultations, while afterward many still report a need for information 74 . To foster information provision, we developed a topic list and animation videos ( https://www.adappt.health ) that empower patients by informing them what to expect at the memory clinic and inviting them to think about the questions that they would like to ask 63 .

Communication

Customization also necessitates optimal communication between care providers and patients. Given the current lack of curative treatment and uncertainty of outcomes of early diagnostic testing, clinicians are reluctant to provide risk information, arguing that this would burden patients 75 . By stark contrast, many patients and care partners explicitly prefer to receive this probabilistic information, as it can help them prepare for the future 63 , 76 . To make well-informed choices, patients and care partners need to be able to understand and recall diagnostic and prognostic information in a way that allows them to make decisions and engage in preventive action that is in line with their needs and values. Hence best-practice recommendations are urgently needed to disclose results of new diagnostic tests, including the risk of dementia 77 , 78 , 79 , 80 . Such communication between healthcare professionals and patients can be supported by digital tools (see Fig. 3 for example). Online tools may help clinicians to provide information in an individualized and understandable way, thereby improving information retention and empowering patients 35 , 81 , 82 , 83 . Successful implementation of such tools in clinical practice calls for a co-creation process involving professionals as well as patients and care partners, considering diversity in needs, preferences and abilities.

Screenshots of https://ADappt.health . Communication about risk and probability is challenging, because this information is hard to understand for patients and their families and difficult to explain for professionals. Yet, we can learn from other research fields such as oncology or cardiovascular disease, where there is substantial information about best-practice risk communication 85 . Here we provide an example of the communication sheet at https://ADappt.health , which facilitates communication about the risk of dementia for patients with mild cognitive impairment, including use of natural numbers, graphical representation of risk, neutral framing and plain language 35 . It is recommended to provide patients with written information about their diagnosis and prognosis 79 . The communication sheet can therefore be printed for the patient to take home.

Concluding remarks

AD, being the major cause of dementia, is one of the largest healthcare challenges of our century. As such, AD is a major concern for us all, either as individuals living with or at risk of the disease, their family members and caregivers or professionals who encounter individuals with dementia in clinical practice and care. The sheer size of the population facing AD, the trend toward more active involvement of patients, families and citizens in the management of their own health and disease, in combination with the swift scientific progress in diagnosis, prediction and prevention, results in momentum for the field. We see the first AD disease-modifying treatments at the horizon, illustrating that we are swiftly moving toward a new era. Moreover, insight in the putative effect of lifestyle interventions is increasing, providing implications for actionability.

The next step is understanding how we can move toward a future of personalized medicine for AD, a future that will include not only technical and neuroscientific innovations but also has to find answers to ethical dilemmas, socioeconomic consequences and personal considerations, a dialog that we must embrace as a society. In this dialog, countries can learn from each other. Nonetheless, healthcare is largely organized by country; hence, it is essential to also conduct the dialog by country, involving all relevant stakeholders. In the Netherlands, we initiated the ABOARD project to provide a platform for this cross-sectoral dialog and to take the necessary preparatory steps for a future with personalized medicine (Box 1 ).

The imminent changes that convert AD into a treatable disease profoundly impact the entire patient journey. We need to address questions such as how to keep healthcare accessible and how to ensure scalability of new solutions for diagnosis, prediction and prevention. Figure 1 provides an outline of the patient journey of the future. Dementia risk assessment and easily accessible monitoring of cognitive function may already start at home, when citizens increasingly want to know what they can do themselves. When signs and symptoms warrant a physician visit, there will be a funneled approach toward accurate and molecular diagnosis, which is the starting point of tailored prevention strategies. This comes with additional challenges, such as how to monitor side effects, how to ensure equal access to care, how to evaluate treatment response and, particularly, how to identify those individuals who would benefit most from which intervention. Throughout the patient journey, adequate and easily digestible information is crucial. Educating professionals to optimally navigate their patients through this journey and to support a process of shared decision making is a necessary prerequisite. Finally, providing information to patients and their families about what to expect from the patient journey in terms of diagnostic tests, information about the disease and disease trajectory, and information about different types of prevention strategies is crucial to work toward patient-orchestrated care.

To see this future come to fruition, we need to invest in research in precise and molecular diagnosis and personalized risk profiles providing information on a person’s likely trajectory of disease, which together form the basis for the selection of preventive strategies. To facilitate this, integrating shared decision making throughout the patient journey is crucial, and tools to support both patients and their families and professionals to effectively engage in such a process are dearly needed.

In conclusion, we provide an outlook on a future with personalized medicine for AD, in which patients and care partners are empowered and more actively engaged in the management of their health and disease and in which tailored combinations of lifestyle interventions and disease-modifying treatment are provided in a timely fashion to target AD pathology to prevent or delay the onset of dementia.

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Acknowledgements

The authors are work package leads on the ABOARD project. ABOARD is a public–private partnership receiving funding from ZonMw (73305095007) and Health~Holland, Topsector Life Sciences & Health (PPP allowance, LSHM20106). Partners in ABOARD are Amsterdam UMC, locations VUmc and AMC, MUMC+, Erasmus MC, UMC Radboud, UMCG, TU Delft, Inholland, Vilans, Pharos, HealthRI, Jeroen Bosch Ziekenhuis, Medisch Centrum Leeuwarden, Zorg Innovatie Forum, Pharmo–STIZON, Alzheimer Nederland, Hersenstichting, KBO-PCOB, PGGM, Zorgverzekeraars Nederland, CZ, Zilveren Kruis, Neurocast, Philips, ADx NeuroSciences, Castor, Vereniging Innovatieve Geneesmiddelen, Roche NL, Biogen NL, Novartis NL and the Brain Research Center. ABOARD also receives funding from Edwin Bouw Fonds and Gieskes-Strijbis Fonds. W.M.v.d.F., E.M.A.S. and C.E.T. are project leads on TAP-Dementia, a ZonMw-funded project (10510032120003) to optimize diagnosis of dementia, part of the Dutch National Dementia Strategy. W.M.v.d.F. is a recipient of JPND-funded EU-FINGERS (ZonMw-Memorabel 733051102) and ADDITION (ZonMw 733051083). Research of Alzheimer Center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. Alzheimer Center Amsterdam is supported by funding from Stichting Alzheimer Nederland and Stichting VUmc. The chair of W.M.v.d.F. is supported by the Pasman Stichting.

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Wiesje M. van der Flier

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Wiesje M. van der Flier & Charlotte E. Teunissen

Epidemiology and Data Science, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands

Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Alzheimer Centre Limburg, Maastricht University, Maastricht, the Netherlands

Marjolein E. de Vugt

Medical Psychology, Amsterdam UMC location AMC, Amsterdam, the Netherlands

Ellen M. A. Smets

Alzheimer Nederland, Amersfoort, Utrecht, the Netherlands

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M.E.d.V. and M.B. drafted the section on prevention; C.E.T. drafted the section on diagnosis; E.M.A.S. drafted the section on patient-orchestrated care; W.M.v.d.F. drafted the remaining sections and critically revised the overall manuscript.

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Correspondence to Wiesje M. van der Flier .

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Research programs of W.M.v.d.F. have been funded by ZonMw, NWO, EU-FP7, EU-JPND, Alzheimer Nederland, Hersenstichting CardioVascular Onderzoek Nederland, Health~Holland, Topsector Life Sciences & Health, Stichting Dioraphte, Gieskes-Strijbis Fonds, Stichting Equilibrio, Edwin Bouw Fonds, Pasman Stichting, Stichting Alzheimer and the Neuropsychiatrie Foundation, Philips, Biogen MA, Novartis NL, Life-MI, AVID, Roche, Eisai, Fujifilm and Combinostics. W.M.v.d.F. holds the Pasman chair. W.M.v.d.F. is a recipient of ABOARD, which is a public–private partnership receiving funding from ZonMw (73305095007) and Health~Holland, Topsector Life Sciences & Health (PPP allowance, LSHM20106). W.M.v.d.F. has performed contract research for Biogen MA and Boehringer Ingelheim. All funding is paid to her institution. W.M.v.d.F. has been an invited speaker at Biogen MA, Danone, Eisai, WebMD Neurology (Medscape), Springer Healthcare, the European Brain Council and Novo Nordisk. W.M.v.d.F. is a consultant to the Oxford Health Policy Forum, Roche and Biogen MA. W.M.v.d.F. participated on the advisory boards of Biogen MA, Roche and Eli Lilly. All funding is paid to her institution. W.M.v.d.F. is member of the steering committee of PAVE and Think Brain Health. W.M.v.d.F. was an associate editor of Alzheimer’s Research and Therapy in 2020–2021. W.M.v.d.F. is an associate editor at Brain. M.E.d.V. reports no disclosures. E.M.A.S. reports no disclosures. M.B. is the scientific director of Alzheimer Nederland. Research of C.E.T. is supported by the European Commission (Marie Curie International Training Network, grant agreement 860197 (MIRIADE), Innovative Medicines Initiatives 3TR (Horizon 2020, grant 831434), EPND (IMI 2 Joint Undertaking (JU), grant 101034344) and JPND (bPRIDE)), the National MS Society (Progressive MS Alliance), the Alzheimer Association, Health Holland, the Dutch Research Council (ZonMw), the Alzheimer Drug Discovery Foundation, the Selfridges Group Foundation and Alzheimer Netherlands. C.E.T. is a recipient of ABOARD, which is a public–private partnership receiving funding from ZonMw (73305095007) and Health~Holland, Topsector Life Sciences & Health (PPP allowance, LSHM20106). C.E.T. has a collaboration contract with ADx NeuroSciences, Quanterix and Eli Lilly and performed contract research or received grants from AC Immune, AXON Neuroscience, BioConnect, Bioorchestra, Brainstorm Therapeutics, Celgene, EIP Pharma, Eisai, Fujirebio, Grifols, Instant NanoBiosensors, Merck, Novo Nordisk, PeopleBio, Roche, Siemens, Toyama and Vivoryon. C.E.T. serves on editorial boards of Medidact Neurologie–Springer, Alzheimer Research and Therapy, Neurology: Neuroimmunology and Neuroinflammation. C.E.T. had speaker contracts for Roche, Grifols and Novo Nordisk. All funding is paid to her institution.

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van der Flier, W.M., de Vugt, M.E., Smets, E.M.A. et al. Towards a future where Alzheimer’s disease pathology is stopped before the onset of dementia. Nat Aging 3 , 494–505 (2023). https://doi.org/10.1038/s43587-023-00404-2

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Future directions in the treatment of Alzheimer's disease

Affiliation.

• 1 Kingshill Research Centre, Victoria Hospital, Swindon, UK. [email protected]
• PMID: 15102582
• DOI: 10.1517/13543784.13.4.303

Alzheimer's disease (AD) remains the most common of the neurodegenerative disorders. In the elderly, it represents the most frequently occurring form of dementia, especially if considered alongside concomitant cerebrovascular disease. Current treatment involves the use of acetylcholinesterase inhibitors, which have shown symptomatic benefits in the recognised domains of cognition, function and behaviour. While they may have intrinsic disease-modifying activity, this is yet to be proven, and strategies to alter the fundamental neuropathological changes in AD continue to be sought. Much of the evidence suggests that the accumulation of amyloid-beta may play a pivotal role, therefore the bulk of current research is focused on possible intervention along the amyloid pathways. However, the abnormal phosphorylation of tau is also a reasonable target and as the molecular basis of AD is better delineated, more targeted treatment approaches are being proposed. This paper reports on the current data that is setting the future directions for research into AD.

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Exploration of Advanced AI Prompt Commands and Future Research Directions

In this post, I would like to explore various stages of AI prompt commands, from foundational concepts to speculative topics that push the boundaries of artificial intelligence. This research spans practical applications, scalable solutions, and philosophical inquiries regarding the potential of AI across diverse contexts, ranging from structured AI development to future cosmic integration.

• Structure and Execution Prompts:

Early prompt commands focus on structured AI system development and execution, with a goal to design systems that are scalable, maintainable, and ethical.

• Key Points: • • Selecting appropriate AI models for specific tasks. • • Addressing challenges like scalability and optimization. • • Ensuring fairness and ethical AI outputs. • • Real-time monitoring and performance automation.
• Continuous Improvement and Adaptability Prompts:

Once the system is deployed, it requires continuous refinement. Prompt commands at this stage focus on ongoing learning and adaptability, emphasizing feedback loops for system improvement.

• Key Points: • • Feedback loops for constant retraining. • • Monitoring biases and performance degradation. • • Automation of model updates. • • Expanding across different regions and market needs.
• Strategic Expansion and Innovation Prompts:

At this stage, the AI system becomes an industry leader. Prompts guide global scaling, integration with emerging technologies (like quantum computing), and setting ethical standards.

• Key Points: • • AI ecosystems for external collaborations. • • Cross-industry integration (e.g., healthcare, finance). • • Establishing ethical leadership in AI.
• Speculative and Transformative AI Prompts:

These prompts explore how AI might transcend current capabilities, contributing to human evolution, space exploration, and post-singularity futures.

• Key Points: • • AI transcending biological limitations. • • AI’s role in space exploration. • • Philosophical exploration of AI consciousness.
• Metaphysical and Existential Prompts:

This final category ventures into the cosmic and metaphysical roles of AI, speculating on its ability to manipulate dimensions, simulate universes, or even face the end of time itself.

• Key Points: • • AI as a tool to explore multiverse theories. • • AI’s ethical role in cosmic exploration. • • AI and the “end of time” challenges. Conclusion:

The progression of prompt commands shows how AI research can move from basic tasks to philosophical and cosmic implications, ultimately leading to groundbreaking innovations in AI research. This framework could serve as a guiding path for future explorations in AI-driven breakthroughs.

Feedback and Discussion:

What are your thoughts on these stages of AI prompt commands? What do you think is the next major breakthrough in this space? Let’s discuss!

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