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

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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.

In 2023, the U.S. Food and Drug Administration (FDA) approved lecanemab (Leqembi) for people with mild Alzheimer's disease and mild cognitive impairment due to Alzheimer's disease.

A phase 3 clinical trial found that the medicine slowed cognitive decline in people with early Alzheimer's disease. The medicine prevents amyloid plaques in the brain from clumping. The phase 3 trial was the largest so far to study whether clearing clumps of amyloid plaques from the brain can slow the disease.

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.

Also, people taking lecanemab 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. It also recommends being monitored with brain MRI s 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 being tested for this gene before starting treatment with lecanemab.

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

More research is being done on the potential risks of taking lecanemab. Other research is looking at how effective lecanemab 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.

Another medicine being studied is donanemab. It targets and reduces amyloid plaques and tau proteins. It was found to slow declines in thinking and functioning in people with early Alzheimer's 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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Expert discusses recent lecanemab trial, why it appears to offer hope for those with deadly disease

Researchers say we appear to be at the start of a new era for Alzheimer’s treatment. Trial results published in January showed that for the first time a drug has been able to slow the cognitive decline characteristic of the disease. The drug, lecanemab, is a monoclonal antibody that works by binding to a key protein linked to the malady, called amyloid-beta, and removing it from the body. Experts say the results offer hope that the slow, inexorable loss of memory and eventual death brought by Alzheimer’s may one day be a thing of the past.

The Gazette spoke with Scott McGinnis , an assistant professor of neurology at Harvard Medical School and Alzheimer’s disease expert at Brigham and Women’s Hospital , about the results and a new clinical trial testing whether the same drug given even earlier can prevent its progression.

Scott McGinnis

GAZETTE: The results of the Clarity AD trial have some saying we’ve entered a new era in Alzheimer’s treatment. Do you agree?

McGINNIS: It’s appropriate to consider it a new era in Alzheimer’s treatment. Until we obtained the results of this study, trials suggested that the only mode of treatment was what we would call a “symptomatic therapeutic.” That might give a modest boost to cognitive performance — to memory and thinking and performance in usual daily activities. But a symptomatic drug does not act on the fundamental pathophysiology, the mechanisms, of the disease. The Clarity AD study was the first that unambiguously suggested a disease-modifying effect with clear clinical benefit. A couple of weeks ago, we also learned a study with a second drug, donanemab, yielded similar results.

GAZETTE: Hasn’t amyloid beta, which forms Alzheimer’s characteristic plaques in the brain and which was the target in this study, been a target in previous trials that have not been effective?

McGINNIS: That’s true. Amyloid beta removal has been the most widely studied mechanism in the field. Over the last 15 to 20 years, we’ve been trying to lower beta amyloid, and we’ve been uncertain about the benefits until this point. Unfavorable results in study after study contributed to a debate in the field about how important beta amyloid is in the disease process. To be fair, this debate is not completely settled, and the results of Clarity AD do not suggest that lecanemab is a cure for the disease. The results do, however, provide enough evidence to support the hypothesis that there is a disease-modifying effect via amyloid removal.

GAZETTE: Do we know how much of the decline in Alzheimer’s is due to beta amyloid?

McGINNIS: There are two proteins that define Alzheimer’s disease. The gold standard for diagnosing Alzheimer’s disease is identifying amyloid beta plaques and tau neurofibrillary tangles. We know that amyloid beta plaques form in the brain early, prior to accumulation of tau and prior to changes in memory and thinking. In fact, the levels and locations of tau accumulation correlate much better with symptoms than the levels and locations of amyloid. But amyloid might directly “fuel the fire” to accelerated changes in tau and other downstream mechanisms, a hypothesis supported by basic science research and the findings in Clarity AD that treatment with lecanemab lowered levels of not just amyloid beta but also levels of tau and neurodegeneration in the blood and cerebrospinal fluid.

GAZETTE: In the Clarity AD trial, what’s the magnitude of the effect they saw?

McGINNIS: The relevant standards in the trial — set by the FDA and others — were to see two clinical benefits for the drug to be considered effective. One was a benefit on tests of memory and thinking, a cognitive benefit. The other was a benefit in terms of the performance in usual daily activities, a functional benefit. Lecanemab met both of these standards by slowing the rate of decline by approximately 25 to 35 percent compared to placebo on measures of cognitive and functional decline over the 18-month studies.

“In a perfect world, we’d have treatments that completely stop decline and even restore function. We’re not there yet, but this represents an important step toward that goal.”

Steven M. Smith

GAZETTE: What are the key questions that remain?

McGINNIS: An important question relates to the stages at which the interventions were done. The study was done in subjects with mild cognitive impairment and mild Alzheimer dementia. People who have mild cognitive impairment have retained their independence in instrumental activities of daily living — for example, driving, taking medications, managing finances, errands, chores — but have cognitive and memory changes beyond what we would attribute to normal aging. When people transition to mild dementia, they’re a bit further along. The study was for people within that spectrum but there’s some reason to believe that intervening even earlier might be more effective, as is the case with many other medical conditions.

We’re doing a study here called the AHEAD study that is investigating the effects of lecanemab when administered earlier, in cognitively normal individuals who have elevated brain amyloid, to see whether we see a preventative benefit. The hope is that we would at least see a delay to onset of cognitive impairment and a favorable effect not only on amyloid biomarkers, but other biomarkers that might capture progression of the disease.

GAZETTE: Is anybody in that study treatment yet or are you still enrolling?

McGINNIS: There’s a rolling enrollment, so there are people who are in the double-blind phase of treatment, receiving either the drug or the placebo. But the enrollment target hasn’t been reached yet so we’re still accepting new participants.

GAZETTE: Is it likely that we may see drug cocktails that go after tau and amyloid? Is that a future approach?

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McGINNIS: It has not yet been tried, but those of us in the field are very excited at the prospect of these studies. There’s been a lot of work in recent years on developing therapeutics that target tau, and I think we’re on the cusp of some important breakthroughs. This is key, considering evidence that spreading of tau from cell to cell might contribute to progression of the disease. Additionally, for some time, we’ve had a suspicion that we will likely have to target multiple different aspects of the disease process, as is the case with most types of cancer treatment. Many in our field believe that we will obtain the most success when we identify the most pertinent mechanisms for subgroups of people with Alzheimer’s disease and then specifically target those mechanisms. Examples might include metabolic dysfunction, inflammation, and problems with elements of cellular processing, including mitochondrial functioning and processing old or damaged proteins. Multi-drug trials represent a natural next step.

GAZETTE: What about side effects from this drug?

McGINNIS: We’ve known for a long time that drugs in this class, antibodies that harness the power of the immune system to remove amyloid, carry a risk of causing swelling in the brain. In most cases, it’s asymptomatic and just detected by MRI scan. In Clarity AD, while 12 to 13 percent of participants receiving lecanemab had some level of swelling detected by MRI, it was symptomatic in only about 3 percent of participants and mild in most of those cases.

Another potential side effect is bleeding in the brain or on the surface of the brain. When we see bleeding, it’s usually very small, pinpoint areas of bleeding in the brain that are also asymptomatic. A subset of people with Alzheimer’s disease who don’t receive any treatment are going to have these because they have amyloid in their blood vessels, and it’s important that we screen for this with an MRI scan before a person receives treatment. In Clarity AD, we saw a rate of 9 percent in the placebo group and about 17 percent in the treatment group, many of those cases in conjunction with swelling and mostly asymptomatic.

The scenario that everybody worries about is a hemorrhagic stroke, a larger area of bleeding. That was much less common in this study, less than 1 percent of people. Unlike similar studies, this study allowed subjects to be on anticoagulation medications, which thin the blood to prevent or treat clots. The rate of macro hemorrhage — larger bleeds — was between 2 and 3 percent in the anticoagulated participants. There were some highly publicized cases including a patient who had a stroke, presented for treatment, received a medication to dissolve clots, then had a pretty bad hemorrhage. If the drug gets full FDA approval, is covered by insurance, and becomes clinically available, most physicians are probably not going to give it to people who are on anticoagulation. These are questions that we’ll have to work out as we learn more about the drug from ongoing research.

GAZETTE: Has this study, and these recent developments in the field, had an effect on patients?

McGINNIS: It has had a considerable impact. There’s a lot of interest in the possibility of receiving this drug or a similar drug, but our patients and their family members understand that this is not a cure. They understand that we’re talking about slowing down a rate of decline. In a perfect world, we’d have treatments that completely stop decline and even restore function. We’re not there yet, but this represents an important step toward that goal. So there’s hope. There’s optimism. Our patients, particularly patients who are at earlier stages of the disease, have their lives to live and are really interested in living life fully. Anything that can help them do that for a longer period of time is welcome.

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A new peptide may hold potential as an Alzheimer’s treatment

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4 panels, with two stained purple on top and two stained blue on bottom. In the top two, there is a significant decrease in the purple color, which represents Tau proteins, and the top right is darker and much less purple. The bottom two panels are very similar, and show nuclei as bright blue bits, like pebbles. A thick band of the blue bits across the center of the panels.

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MIT neuroscientists have found a way to reverse neurodegeneration and other symptoms of Alzheimer’s disease by interfering with an enzyme that is typically overactive in the brains of Alzheimer’s patients.

When the researchers treated mice with a peptide that blocks the hyperactive version of an enzyme called CDK5, they found dramatic reductions in neurodegeneration and DNA damage in the brain. These mice also showed improvements in their ability to perform tasks such as learning to navigate a water maze.

“We found that the effect of this peptide is just remarkable,” says Li-Huei Tsai, director of MIT’s Picower Institute for Learning and Memory and the senior author of the study. “We saw wonderful effects in terms of reducing neurodegeneration and neuroinflammatory responses, and even rescuing behavior deficits.”

With further testing, the researchers hope that the peptide could eventually be used as a treatment for patients with Alzheimer’s disease and other forms of dementia that have CDK5 overactivation. The peptide does not interfere with CDK1, an essential enzyme that is structurally similar to CDK5, and it is similar in size to other peptide drugs that are used in clinical applications.

Picower Institute Research Scientist Ping-Chieh Pao is the lead author of the paper , which appears this week in the Proceedings of the National Academy of Sciences .

Targeting CDK5

Tsai has been studying CDK5’s role in Alzheimer’s disease and other neurodegenerative diseases since early in her career. As a postdoc, she identified and cloned the CDK5 gene, which encodes a type of enzyme known as a cyclin-dependent kinase. Most of the other cyclin-dependent kinases are involved in controlling cell division, but CDK5 is not. Instead, it plays important roles in the development of the central nervous system, and also helps to regulate synaptic function.

CDK5 is activated by a smaller protein that it interacts with, known as P35. When P35 binds to CDK5, the enzyme’s structure changes, allowing it to phosphorylate — add a phosphate molecule to — its targets. However, in Alzheimer’s and other neurodegenerative diseases, P35 is cleaved into a smaller protein called P25, which can also bind to CDK5 but has a longer half-life than P35.

When bound to P25, CDK5 becomes more active in cells. P25 also allows CDK5 to phosphorylate molecules other than its usual targets, including the Tau protein. Hyperphosphorylated Tau proteins form the neurofibrillary tangles that are one of the characteristic features of Alzheimer’s disease.

In previous work, Tsai’s lab has shown that transgenic mice engineered to express P25 develop severe neurodegeneration. In humans, P25 has been linked to several diseases, including not only Alzheimer’s but also Parkinson’s disease and frontotemporal dementia.

Pharmaceutical companies have tried to target P25 with small-molecule drugs, but these drugs tend to cause side effects because they also interfere with other cyclin-dependent kinases, so none of them have been tested in patients.

The MIT team decided to take a different approach to targeting P25, by using a peptide instead of a small molecule. They designed their peptide with a sequence identical to that of a segment of CDK5 known as the T loop, which is a structure critical to the binding of CDK5 to P25. The entire peptide is only 12 amino acids long — slightly longer than most existing peptide drugs, which are five to 10 amino acids long.

“From a peptide drug point of view, usually smaller is better,” Tsai says. “Our peptide is almost within that ideal molecular size.”

Dramatic effects

In tests in neurons grown in a lab dish, the researchers found that treatment with the peptide led to a moderate reduction in CDK5 activity. Those tests also showed that the peptide does not inhibit the normal CDK5-P35 complex, nor does it affect other cyclin-dependent kinases.

When the researchers tested the peptide in a mouse model of Alzheimer’s disease that has hyperactive CDK5, they saw a myriad of beneficial effects, including reductions in DNA damage, neural inflammation, and neuron loss. These effects were much more pronounced in the mouse studies than in tests in cultured cells.

The peptide treatment also produced dramatic improvements in a different mouse model of Alzheimer’s, which has a mutant form of the Tau protein that leads to neurofibrillary tangles. After treatment, those mice showed reductions in both Tau pathologies and neuron loss. Along with those effects in the brain, the researchers also observed behavioral improvements. Mice treated with the peptide performed much better in a task that required learning to navigate a water maze, which relies on spatial memory, than mice that were treated with a control peptide (a scrambled version of the peptide used to inhibit CDK5-P25).

In those mouse studies, the researchers injected the peptide and found that it was able to cross the blood-brain barrier and reach neurons of the hippocampus and other parts of the brain.

The researchers also analyzed the changes in gene expression that occur in mouse neurons following treatment with the peptide. Among the changes they observed was an increase in expression of about 20 genes that are typically activated by a family of gene regulators called MEF2. Tsai’s lab has previously shown that MEF2 activation of these genes can confer resilience to cognitive impairment in the brains of people with Tau tangles, and she hypothesizes that the peptide treatment may have similar effects.

“Further development of such peptide inhibitors toward a lead therapeutic candidate, if proven to be selective for the target and relatively free of clinical side effects, may eventually lead to novel treatments for neurodegenerative disorders ranging from Alzheimer’s disease to Frontotemporal dementia to Parkinson’s disease,” says Stuart Lipton, a professor of neuroscience at Scripps Research, who was not involved in the study.

Tsai now plans to do further studies in other mouse models of diseases that involve P25-associated neurodegeneration, such as frontotemporal dementia, HIV-induced dementia, and diabetes-linked cognitive impairment.

“It’s very hard to say precisely which disease will most benefit, so I think a lot more work is needed,” she says.

The research was funded by the National Institutes of Health.

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In a new study, researchers at MIT showed that they “were able to interfere with an enzyme typically found to be overactive in the brains of Alzheimer’s patients,” reports Alex Mitchell for The New York Post . After using a peptide to treat the overactive enzyme, they found that “the peptide shows protective effects against loss of neurons and also appears to be able to rescue some of the behavior deficits,” says Prof. Li-Huei Tsai.

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As populations age, Alzheimer’s and dementia are becoming more prevalent. A new drug could offer hope

Alzheimer’s dementia population age brain injury

As populations age, the number of cases of dementia rises. Image:  Unsplash/centelm

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  • A new drug, lecanemab, has been shown to reduce the decline in memory and thinking associated with Alzheimer's.
  • As populations age, dementia cases are on the rise, with 10 million new people diagnosed each year.
  • Dementia is a collective term for a group of diseases or brain injuries that can lead to a change in cognitive functioning as well as other symptoms like lack of emotional control.

It is one of the biggest diseases of our time: 10 million new cases of dementia are diagnosed every year, according to the World Health Organization (WHO). More than 55 million people worldwide live with a form of dementia and it is the seventh leading cause of death among all diseases.

Now a new drug is offering a glimmer of hope after years of searching for a treatment. In clinical trials, lecanemab has been shown to slow the cognitive decline associated with the disease. The drug attacks the protein clumps in the brain that many think are the cause of the disease.

Although dementia patients are currently offered drugs, none of them affect the progression of the disease which is why scientists in the field are so excited about this latest development. Alzheimer's Research UK called the findings "a major step forwards" .

But while this is undoubtedly positive news, the body also points out that the benefits of the drug were small and came with significant side effects. In addition, lecanemab has been proven to work in the early stages of the disease, so would rely on doctors spotting it before it had progressed too far.

With the number of dementia cases expected to rise to 78 million by 2030 and 139 million in 2050, according to the WHO, the race is on for scientific developments and research that will help us understand, treat and possibly prevent the disease.

A global impact

As populations age, the number of cases of dementia rises. While the deterioration of cognitive functioning is not caused by age itself, it does primarily affect the older generation. For many elderly people it also results in disability and loss of independence - which can have psychological, social and economic implications for them and their families, carers and society more broadly.

The estimated global cost of dementia to society was placed at $1.3 trillion in 2019, and is expected to rise to $2.8 trillion by 2030, WHO says.

Alzheimer’s Diesease, a result of rapid ageing that causes dementia, is a growing concern. Dementia, the seventh leading cause of death worldwide, cost the world $1.25 trillion in 2018, and affected about 50 million people in 2019. Without major breakthroughs, the number of people affected will triple by 2050, to 152 million.

To catalyse the fight against Alzheimer's, the World Economic Forum is partnering with the Global CEO Initiative (CEOi) to form a coalition of public and private stakeholders – including pharmaceutical manufacturers, biotech companies, governments, international organizations, foundations and research agencies.

The initiative aims to advance pre-clinical research to advance the understanding of the disease, attract more capital by lowering the risks to investment in biomarkers, develop standing clinical trial platforms, and advance healthcare system readiness in the fields of detection, diagnosis, infrastructure and access.

What is dementia?

Dementia is a collective term for a group of diseases or injuries which primarily or secondarily affect the brain. Alzheimer’s is the most common of these and accounts for around 60-70% of cases. Other types include vascular dementia , dementia with Lewy bodies (abnormal protein clumps) and a group of diseases that contribute to frontotemporal dementia. It can also be triggered by strokes, excessive use of alcohol, repetitive head injuries, nutritional deficiencies, or follow some infections like HIV, the Alzheimer’s Society explains.

The different forms of dementia can often be indistinct and can co-exist.

Different people are affected in different ways, depending on the underlying cause. But the syndrome is usually progressive and can affect a range of functions, including memory, thinking, orientation, comprehension, calculation, learning capacity, language and judgement.

Changes in mood and ability to control emotions often accompany these cognitive variations.

Charts showing the fears about loss of independence due to dementia among adults age 40 and older and healthcare providers in the U.S in 2021

Can it be treated?

There is no cure for dementia, although there are numerous treatments being worked on and at clinical trial phase. Dementia care currently focuses on early diagnosis, optimizing health and wellbeing and providing long-term support to carers.

Besides age, there are a number of other risk factors, which if avoided, can decrease the chances of dementia and slow its progression. Preventative steps include being physically active, not smoking, avoiding the harmful use of alcohol, as well as maintaining a healthy diet, weight, blood pressure, cholesterol and blood sugar levels.

Other risk factors associated with dementia include depression, social isolation, low educational attainment, cognitive inactivity and even air pollution .

Graph showing the U.S. aggregate care costs for older people with Alzheimer's or other dementias from 2011 to 2022, by payer (in billion U.S. dollars)

What is the impact?

People with dementia rely heavily on informal care - i.e., friends and family. These carers spent on average five hours a day looking after people living with dementia in 2019, according to WHO figures. Informal care is thought to cover half of the overall financial burden of dementia.

There is also a disproportionate impact on women. They account for 65% of all dementia-related deaths, and also have a greater number of years affected by the disease. Women also typically provide the majority of informal care - covering over two-thirds of the carer hours for people living with dementia.

Informal care is thought to cover over half of the overall financial burden of dementia.

What are the latest developments?

The fact that dementia is only diagnosed once symptoms appear means that by the time people take part in clinical trials the disease is often quite well advanced. This can hamper the development of drugs. However, research analyzing data from the UK Biobank has indicated there are a collection of signals that could indicate a problem years before dementia is currently being diagnosed .

Other scientists postulate that, rather than being a disease of the brain, Alzheimer’s is in fact a disorder of the immune system within the brain . They believe research should instead focus on drugs targeting auto-immune pathways .

On a less positive note, researchers found that people who have recently received a dementia diagnosis, or diagnosed with the condition at a younger age, are at an increased risk of suicide . This underlines the importance of a strong support network, particularly among those newly diagnosed.

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Large-scale study of brain proteins uncovers new clues to Alzheimer’s disease

Neuroscience Alzheimer's Disease Biomarkers

Through a large-scale analysis of tissue samples, NIA-funded researchers have discovered new disease-related changes in the brains of people who had died with Alzheimer’s disease. The study results, published in Nature Neuroscience , underscore the key role proteins may play in disease progression. Understanding these changes could help identify therapeutic targets and biomarkers for the disease.

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For decades, scientists have known that much of the damage that underlies Alzheimer’s is ultimately carried out by changes in brain proteins. However, to get a better understanding of which changes may happen in the brains of most patients, scientists often measure the levels of ribonucleic acid (RNA) instead of proteins. Shaped like DNA, RNA often relays the genetic blueprints for proteins from a cell’s chromosomes to its protein-making machinery. Because RNA is easier to work with, scientists have relied on it as an indirect readout of global changes in protein levels when conducting large-scale studies, involving hundreds of brain samples. In this study, the researchers found that directly measuring protein levels on a large scale may reveal important clues to understanding Alzheimer’s that cannot be detected by analyzing RNA alone.

The research team — located at Emory University School of Medicine, part of the Accelerating Medicines Partnership® Program for Alzheimer’s Disease (AMP®-AD) Consortium — used advanced automated techniques to compare the levels of both proteins and RNA molecules in more than 1,000 brain tissue samples. The samples came from the postmortem brains of people who had Alzheimer’s, as well as from individuals who died from other, unrelated causes.

The team discovered several protein networks that may play an important role in Alzheimer’s. Specifically, they found 44 groups of proteins — termed “protein communities” — for which levels rose or fell in coordinated ways across the brains of people with Alzheimer’s, but not in a control group of people who had not had the disease.

Interestingly, only about half of these changes were observed when the researchers compared the protein communities to the corresponding RNA molecules. This finding suggests that there are important steps in the Alzheimer’s process that happen after a protein’s genetic blueprints are sent to a cell’s protein-making machinery.

Next, the researchers paid particular attention to two groups of protein communities that were not detected at the RNA level. One was associated with Mitogen-Activated Protein Kinase (MAPK) signaling and energy metabolism. Changes in these proteins appeared to be associated with changes in the thinking and memory problems seen during Alzheimer’s. The second community had changes that correlated to the early stages of the disease when amyloid and tau begin to accumulate in the brain.

The study results highlight the importance of directly analyzing proteins along with RNA to gain a more complete picture of how Alzheimer’s may damage the brain. The research team plans to use these results as a basis for developing new, more effective diagnostic tests and treatments for Alzheimer’s.

This research was supported in part by NIA grants RF1AG057471, RF1AG057470, R01AG01581, U54AG065187, U01AG061357, R01AG057911, R01AG061800, R01AG053960, RF1AG062181, P30AG10161, R01AG15819, R01AG17917, U01AG61356, RF1AG057440, U01AG046170, K08AG068604, P30AG19610, and R01AG056533.

These activities relate to NIA’s AD+ADRD Research Implementation Milestone 2. G, “Maximize the translational potential of genetics research by ensuring rapid and broad sharing of large-scale genetic/genomic data, similar to the open science, data sharing model of the AMP AD program and by supporting programs focused on:  Understanding the mechanisms by which genetic variants (including ApoE) discovered through GWAS and sequencing studies influence AD risk; i ntegrating genomic data with other multi-omics data from brain, peripheral tissues, and iPSC cellular models from well-phenotyped cohorts; e stablishing the gene-basis and directionality for genetic variant association so gene networks can be annotated with causality as tools for drug discovery.”

Reference : Johnson, ECB, et al. Large-scale deep multi-layer analysis of Alzheimer’s disease brain reveals strong proteomic disease-related changes not observed at the RNA level . Nature Neuroscience . 2022;25(2):213-225. doi: 10.1038/s41593-021-00999-y.

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  • Published: 02 October 2023

Clinical trials of new drugs for Alzheimer disease: a 2020–2023 update

  • Li-Kai Huang 1 , 2 , 3   na1 ,
  • Yi-Chun Kuan 2 , 3 , 4 , 5   na1 ,
  • Ho-Wei Lin 6 &
  • Chaur-Jong Hu   ORCID: 1 , 2 , 3 , 4  

Journal of Biomedical Science volume  30 , Article number:  83 ( 2023 ) Cite this article

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Alzheimer's disease (AD) is the leading cause of dementia, presenting a significant unmet medical need worldwide. The pathogenesis of AD involves various pathophysiological events, including the accumulation of amyloid and tau, neuro-inflammation, and neuronal injury. Clinical trials focusing on new drugs for AD were documented in 2020, but subsequent developments have emerged since then. Notably, the US-FDA has approved Aducanumab and Lecanemab, both antibodies targeting amyloid, marking the end of a nearly two-decade period without new AD drugs. In this comprehensive report, we review all trials listed in, elucidating their underlying mechanisms and study designs. Ongoing clinical trials are investigating numerous promising new drugs for AD. The main trends in these trials involve pathophysiology-based, disease-modifying therapies and the recruitment of participants in earlier stages of the disease. These trends underscore the significance of conducting fundamental research on pathophysiology, prevention, and intervention prior to the occurrence of brain damage caused by AD.

Alzheimer disease (AD) represents a major global medical, social, and economic burden. The World Alzheimer Report 2022 revealed that more than 55 million people have AD or related conditions worldwide, and this number is projected to reach 82 million by 2030 and 138 million by 2050 [ 1 ]. Typically, AD first manifests as progressive memory decline accompanied or followed by other cognitive dysfunctions, such as visuospatial abnormalities, navigation difficulties, executive problems, and language disturbances. These cognitive impairments affect the performance of activities of daily living. During the course of AD, many behavioral and psychological symptoms of dementia (BPSD) occur [ 2 , 3 , 4 ].

Although the exact causes of AD remain unclear, the disease has two pathological hallmarks: plaques composed of amyloid-beta (Aβ) fibrils and neurofibrillary tangles (NFTs) consisting of hyperphosphorylated tau protein [ 5 , 6 , 7 ]. The key event in AD pathogenesis is believed to be Aβ accumulation. Cerebral Aβ fibril deposition may occur decades before the onset of clinical symptoms [ 8 ]. Brain atrophy, particularly in the hippocampus, is major indicator of early Aβ accumulation, particularly in the presubiculum [ 9 , 10 ]. Aβ accumulation was discovered to be crucial by three independent research groups in 1991 [ 11 , 12 , 13 ]. In familial AD, mutant autosomal-dominant genes, including the genes for amyloid precursor protein ( APP ), presenilin-1 ( PSEN1 ), and presenilin-2 ( PSEN2 ), encode the major proteins involved in amyloid metabolism [ 13 , 14 , 15 ]. Individuals with trisomy 21 (Down syndrome) have an extra copy of the APP gene, which may result in increased amyloid production and AD risk in middle age [ 16 ]. At present, the predominant theory regarding the cause of AD is the amyloid hypothesis; crucial advancements in AD therapy have been made on the basis of the proposed role of amyloid accumulation in the AD development. The United States Food and Drug Administration (US FDA) granted traditional approval for Leqembi (lecanemab-irmb) on July 6, 2023, for the treatment of AD [ 17 ]. The approval of this treatment not only affirms the pathophysiological significance of amyloid in AD but also marks a notable advance in clinical approaches to AD treatment, remedying the scarcity of new drugs in the market for nearly two decades.

Tau is a microtubule-associated protein that aids in microtubule assembly and stabilization. In AD, tau becomes hyperphosphorylated and aggregates to form paired helical filaments, a major component of NFTs within the neuronal cytoplasm. As the disease progresses, the gradual spread of tau pathology throughout brain regions has been suggested to be caused by the transfer of abnormal types of tau protein from one neuron to another [ 18 ]. The accumulation of NFTs might be initiated between the accumulation of Aβ and the development of clinical symptoms of AD [ 19 ]. NFTs and quantitative neuronal loss may be more closely correlated with disease severity and dementia progression than the amyloid plaque burden [ 20 , 21 , 22 ]. Positron emission tomography (PET) investigations have revealed a strong correlation between the binding characteristics of tau tracers and the severity of clinical manifestations in individuals with AD [ 23 ]. Molecular imaging modalities (PET) and cerebrospinal fluid (CSF) and blood–based biomarkers have extended the diagnostic scope of AD pathology to both clinical and even preclinical settings. The analysis of a combination of biomarkers such as amyloid, tau, and neurodegeneration (collectively, ATN classification) has been proposed by research on AD [ 24 , 25 ]. Furthermore, the exceptional diagnostic accuracy of plasma-based biomarkers has facilitated the clinical transition of fluid biomarkers from research settings to clinical practice. A recent presentation at the Alzheimer’s Association International Conference in 2023 highlighted the clinical and research applications of two fundamental AD biomarker categories, labeled as A and T. The A category pertains to biomarkers associated with the Aβ proteinopathy pathway, and the T category pertains to biomarkers linked to tau proteinopathy [ 26 ].

Aβ serves as a proinflammatory agent and triggers the nuclear factor κB (NF-κB) pathway in astrocytes, increasing complement C3 release. Subsequently, by binding to C3a receptors, C3 causes neuronal dysfunction and microglial activation [ 27 ]. In the early stage of AD, activated microglia may play a protective, anti-neuroinflammatory role by clearing amyloids and releasing nerve growth factors. However, activated microglia induce neurotoxic A1 astrocyte reactivity through the release of IL-1α, C1q, and TNF-α, resulting in a feedback loop of dysregulated inflammation in AD [ 28 ]. The excessive accumulation of Aβ or other toxic compounds activates proinflammatory phenotypes, resulting in neuronal damage [ 29 ]. Sustained inflammation has been observed in the brains of patients with AD [ 30 , 31 ]. The inadequate clearance of Aβ along with the aggregation of tau disrupts microglial defense mechanisms, resulting in sustained and harmful microglial activation [ 32 ]. The sequential occurrence of amyloid plaque formation, microglial activation, and the pathological phosphorylation and aggregation of tau proteins to form NFTs is the fundamental notion of the amyloid cascade–inflammation hypothesis. In the Multi-Ethnic Study of Atherosclerosis (multiple covariates were controlled for), vascular risk factor profiles and Aβ deposition significantly predicted cognitive decline [ 33 ]. Vascular risk factors can also lead to inflammation in the brain, which damages neuronal cells and further increases the likelihood of AD dementia [ 34 ].

The role of autophagy impairment is proposed in a novel hypothesis concerning plaque formation in AD. Among neurons that are compromised but still maintain some integrity, autophagic vacuoles (AVs) containing abundant Aβ are notably present. These AVs cluster within expansive membrane blebs, exhibiting a distinctive flower-like arrangement termed PANTHOS. These formations constitute the primary source of the majority of amyloid plaques found in mouse models of AD [ 35 ]. Neuroprotective therapies, including free radical scavengers, regeneration enhancers, and the suppression of excitable amino acid signaling pathways, have been proposed for preventing neuronal death or brain atrophy caused by amyloid, tau, and neuroinflammation [ 36 ]. Pathological evidence indicates that AD is also associated with degeneration in cholinergic neuron-rich regions, such as the nucleus basalis of Meynert, frontal cortex, and anterior and posterior cingulate cortex, which can lead to the symptoms of memory impairment and agitation. Acetylcholine (ACh) plays a vital role in memory function, including memory encoding, consolidation, and retrieval processes, and increasing Ach levels by using cholinesterase inhibitors (AChEIs) has become a standard therapy for the symptoms of AD [ 37 ].

Clinical trials of early or preventive interventions based on amyloid/tau theory and those targeting other pathophysiologies are ongoing or have been initiated. Many ongoing clinical trials on AD are focused on disease-modifying therapies (DMTs) that target the causes and can change the course of AD. The other trials involve symptomatic treatments—for example, enhancing cognitive function and relieving BPSD (Fig.  1 ). In this review, we summarize the new drugs being examined in ongoing trials (listed on and discuss the trends in and obstacles in AD clinical trials.

figure 1

According to the amyloid hypothesis, the pathophysiology and clinical course of Alzheimer's disease progress as follows: amyloid accumulation, neuroinflammation, tau accumulation, brain metabolism dysfunction, brain atrophy, cognitive decline (from mild cognitive impairment to dementia), and the development of dementia symptoms. Novel drugs should target at least one of these events. AD Alzheimer's disease, aMCI amnestic mild cognitive impairment, BPSD behavioral psychological symptoms of dementia

Anti-amyloid therapy

Table 1 summarizes the US FDA approval status of anti-amyloid agents. Tables 2 and 3 summarize the ongoing phase 3 and phase 2 trials of anti-amyloid therapy respectively.

Aducanumab (brand name: Aduhelm) is a high-affinity, fully human immunoglobulin gamma 1 (IgG1) monoclonal antibody that binds to the N-terminus of Aβ fibrils and blocks amyloid aggregation [ 38 ]. In August 2015, two phase 3 clinical trials, namely ENGAGE and EMERGE studies, were initiated. These trials compared monthly intravenous infusions of aducanumab at one of three doses with infusions of placebo over 18 months, and the primary outcomes were cognitive and functional decline, which were assessed using the Clinical Dementia Rating (CDR) scale Sum of Boxes (CDR-SB). The secondary outcomes were other cognitive and functional measures. The trials were conducted in 150 centers across North America, Europe, Australia, and Asia. However, the findings of the EMERGE trial reached statistical significance, whereas the primary endpoint was not reached in the ENGAGE trial. An exploratory analysis revealed that a subgroup of the participants in the ENGAGE trial who received a high dose of aducanumab exhibited slow decline, which was similar to that observed among the participants in the EMERGE trial. The US FDA approved aducanumab in June 2021 on the basis of the data of the EMERGE and ENGAGE trials. Both trials presented evidence of an intermediate effect of the drug on biomarkers, indicating amyloid removal, which is likely linked to the clinical benefit of aducanumab. Further trials must be conducted to confirm the potential benefit of aducanumab [ 39 ]. The phase 3b/4 ENVISION trial (NCT05310071), which began in 2022, will enroll 1,512 patients with early AD who will receive either monthly doses of aducanumab of up to 10 mg/kg or placebo for 18 months. The aim of the trial is to determine the efficacy of aducanumab in delaying cognitive and functional decline in comparison with placebo, which would be determined on the basis of CDR-SB scores. The secondary endpoints of the trial include scores on the Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog) 13, Alzheimer’s Disease Cooperative Study–Activities of Daily Living Inventory (ADCS-ADL)–Mild Cognitive Impairment Version, Integrated Alzheimer’s Disease Rating Scale (iADRS), Mini-Mental State Examination, and Neuropsychiatric Inventory. The trial intends to recruit 18% of its participants from Black and Latinx populations in the United States and will have a long-term follow-up of up to 4 years, with results expected by 2026. The EMBARK trial (NCT04241068) is a phase 3b open-label study including 1,696 participants from previous aducanumab trials (from trials 221AD103, 221AD301, 221AD302, and 221AD205) that will assess aducanumab safety and tolerability over 100 weeks after a wash-out period. Participants will receive an intravenous infusion of aducanumab at 10 mg/kg monthly for 2 years, and eligible participants will continue to receive the infusion for another 52 weeks during the long-term extended treatment period. The primary outcomes are safety and tolerability, and the efficacy endpoints are the same as those in the EMERGE and ENGAGE trials, and Caregiver Global Impression of Change evaluations will be conducted every 6 months. All participants will undergo volumetric magnetic resonance imaging (MRI) scans, and a subset of the study population will undergo biomarker testing, including amyloid PET, tau PET, and CSF testing.

Lecanemab (brand name: Leqembi), a humanized IgG1 antibody derived from mAb158, selectively binds to soluble Aβ protofibrils [ 40 ]. The US FDA approved it on January 6, 2023, through an accelerated approval pathway on the basis of evidence of amyloid removal in a phase 2 trial (NCT01767311) and because it had a likelihood of having clinical benefits [ 41 ] A double-blind, placebo-controlled phase 2 trial recruited 856 patients with AD with mild cognitive impairment (MCI) or mild dementia and verified amyloid pathology through amyloid PET or CSF Aβ1-42 [ 42 ]. The results revealed a significant and dose-dependent reduction of amyloid plaques in the lecanemab group (10 mg/kg, intravenous infusion every 2 weeks) from baseline to week 79 compared with the placebo group. At the time of writing this paper, three phase 3 clinical trials on lecanemab are underway. The first trial, Clarity AD (NCT03887455), was initiated in March 2019 and was conducted at 250 sites around the world. It reported favorable outcomes for all primary and secondary measures, including ADAS-Cog14, AD Composite Score (ADCOMS), and ADCS-MCI-ADL scores [ 43 ]. The second trial is AHEAD 3–45 (NCT04468659), which was initiated in July 2020 as a 4-year trial comprising two substudies, one of which is A3, and the other one is A45. A3 is enrolling 400 people whose amyloid levels are below the brain-wide threshold for positivity; participants will receive 5 mg/kg lecanemab titrated to 10 mg/kg or placebo every month for 216 weeks. A45 is enrolling 1,000 cognitively healthy participants with positive amyloid PET scans, and they will receive lecanemab titrated to 10 mg/kg every 2 weeks for 96 weeks, followed by 10 mg/kg every month through week 216. The trial is expected to run until October 2027. The third phase 3 clinical trial is the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) Next Generation trial (DIAN-TU-001 (E2814), NCT05269394), in which a combination of lecanemab and the anti-tau antibody E2814 (phase 2) will be administered to 168 people with familial AD mutations. On July 6, 2023, Leqembi (lecanemab-irmb) received traditional approval from the US FDA for the treatment of AD based on Phase 3 data from the Clarity AD clinical trial [ 17 ].

The appropriate use recommendations (AURs) for lecanemab and aducanumab highlight the importance of patient selection, surveillance for adverse events, and clinician preparedness [ 44 , 45 ]. The AURs for both drugs have several similarities with respect to age criteria, biomarker requirements (positive amyloid PET or CSF findings indicative of AD), diagnosis (MCI due to AD or mild AD dementia), and MRI exclusion criteria (e.g., microhemorrhages and cortical infarction). The AURs also emphasize the importance of monitoring for amyloid-related imaging abnormalities (ARIAs), which can occur in patients receiving these drugs. APOE genotyping is recommended for informing risk discussions with candidate participants because APOE4 allele carriers, especially APOE4 homozygotes, are at a high risk of ARIAs. Patients receiving treatment must have care partners or family members who can provide necessary support and who clearly understand the nature and requirements of the therapy. Discontinuation of treatment is recommended in the following situations: when a patient is taking drugs with associated risks, such as anticoagulation agents for conditions like atrial fibrillation, deep vein thrombosis, or pulmonary embolism; or when any of the following conditions occur: a hypercoagulable state, or the development of any of the following: cerebral macrohemorrhage, multiple areas of superficial siderosis, more than 10 instances of microhemorrhages since treatment initiation, severe symptoms of ARIAs, or two or more episodes of ARIAs.

Donanemab is a humanized monoclonal antibody developed from mouse mE8-IgG2a. It recognizes Aβ (3–42), an aggregated form of Aβ found in amyloid plaques [ 46 ]. It was discovered to be bound to approximately one-third of amyloid plaques in postmortem brain samples of patients with AD or Down syndrome, and it strongly reacted with the plaque core [ 47 ]. In the phase 2 TRAILBLAZER-ALZ study, the safety, tolerability, and efficacy of donanemab alone and in combination with the Beta-Secretase 1 (BACE1) inhibitor LY3202626 (developed by Eli Lilly and Company) were evaluated over 18 months. The trial met its primary endpoint of delaying decline—which was determined on the basis of iADRS scores—by 32% compared with placebo. Amyloid burden reduction was correlated with improvement in iADRS scores only in ApoE4 carriers [ 48 ]. Donanemab reduced the tau burden in the temporal, parietal, and frontal lobes and significantly decreased plasma pTau217 by 24% in the treatment group, whereas the placebo group exhibited a 6% increase in plasma pTau217 at the end of the trial [ 49 ]. At the time of writing this paper, five phase 3 trials of donanemab are underway: TRAILBLAZER-ALZ 2, TRAILBLAZER-ALZ 3, TRAILBLAZER-ALZ 4, TRAILBLAZER-ALZ 5 and TRAILBLAZER-ALZ 6. The TRAILBLAZER-ALZ 2 (NCT04437511) trial was initially started in June 2020 as a phase 2 safety and efficacy trial, and 500 patients with early AD were recruited. Inclusion criteria of TRAILBLAZER-ALZ 2 are similar to those of TRAILBLAZER-ALZ: a ≥ 6-month history of worsening memory and positive amyloid (flortaucipir) PET. The trial was subsequently extended to a phase 3 trial with 1,800 participants. The primary outcome is iADRS, and the effectiveness of treatment is being measured using a disease-progression model rather than solely on the basis of changes at the final time point. Trial results for 1,736 participants were published to report donanemab’s impact on early symptomatic AD. Using PET imaging to categorize individuals into groups with low/medium or high tau pathology load, the study spanned 18 months and assessed cognitive and functional scales. Donanemab achieved significant cognitive improvement in the low/medium tau group (iADRS change: − 6.02 vs. − 9.27 placebo) and combined population (change: − 10.2 vs. − 13.1 placebo). The drug notably reduced decline by 60% in patients with early-stage AD, supporting the efficacy of short-term dosing. Twenty-four outcomes were evaluated, with significant findings for 23 outcomes. Adverse effects included amyloid-related imaging problems (24% donanemab vs. 2.1% placebo) and infusion-related reactions (8.7% donanemab vs. 0.5% placebo). The study findings indicated the potential of donanemab to slow AD progression, particularly in the early stage [ 50 ]. In the TRAILBLAZER-ALZ study, donanemab slowed disease progression by 32% at 18 months ( p  = 0.04 vs. placebo), thus demonstrating clinical efficacy [ 51 ]. TRAILBLAZER-ALZ 3 (NCT05026866) is a placebo-controlled phase 3 prevention trial that was started in August 2021. The trial plans to enroll 3,300 cognitively healthy people aged 50–55 years who are at high risk of AD, as determined by elevated plasma pTau217 levels and Telephone Interview for Cognitive Status-modified scores. The primary outcome is the time to clinical progression, which is measured using global CDR scores. Participants are to be monitored every 6 months until cognitive impairment is noted (i.e., a score above 0 on the CDR for two consecutive evaluations) in 434 participants. The trial has a decentralized design and is being conducted at more than 200 sites in the United States, Japan, and Puerto Rico until November 2027. TRAILBLAZER-ALZ 4 (NCT05108922) is a phase 3, open-label, head-to-head comparison of amyloid clearance by either donanemab or aducanumab that began in November 2021 after the US FDA approval of aducanumab. The trial enrolled 200 people with early symptomatic AD, as indicated by a global CDR score of 0.5 or 1, at 31 sites in the United States. The primary outcome is the percentage of participants who achieve complete amyloid plaque clearance after 6 months for each treatment group, with clearance determined using amyloid (florbetapir) PET. The trial has 17 secondary outcomes, which are all related to amyloid PET measurements at up to 18 months. The preliminary results were presented at the 2022 Clinical Trial of AD (CTAD) conference: 38% of the patients on donanemab exhibited amyloid levels below the amyloid positivity threshold after 6 months, whereas only 2% of the patients on aducanumab has such findings. Plasma pTau217 levels decreased by 25% for the participants receiving donanemab, but not at all for those receiving aducanumab. The side effect of ARIA-edema occurred in 22% of the participants in both groups. TRAILBLAZER-ALZ 5 (NCT05508789) is being conducted to assess the safety and efficacy of donanemab in individuals with early symptomatic AD. The trial started in October 2022; 1,500 participants will be recruited by using the same criteria as those of TRAILBLAZER-ALZ 2 from 148 sites across China, Korea, Taiwan, and Europe; and the trial is expected to run until mid-2025. Participants will be administered monthly infusions of either donanemab or placebo, and the primary outcome will be measured on the basis of iADRS score changes after 18 months. TRAILBLAZER-ALZ 6 (NCT05738486) is a phase 3b study that will assess the impact of various dosing regimens of donanemab on the occurrence and severity of ARIA-E (ARIA with edema or effusion) in 800 adults with early symptomatic AD. The study also seeks to identify participant characteristics that predict the risk of ARIA-E. The trial is divided into four arms, each with a distinct donanemab dose.

Remternetug is a monoclonal antibody that recognizes a pyroglutamated form of Aβ that aggregates into amyloid plaques. In August 2022, Eli Lilly and Company initiated a phase 3 trial called TRAILRUNNER-ALZ1 (NCT05463731) that will randomize 600 patients with early symptomatic AD across 75 sites in the United States and 2 sites in Japan into groups receiving the antibody or placebo through intravenous infusion or subcutaneous injection for 1 year. The primary outcome is the percentage of patients whose amyloid plaques are cleared by the end of the treatment period. The secondary outcomes include the measurement of amyloid clearance, pharmacokinetics, and treatment-emergent anti-drug antibodies. The study also plans to conduct a year-long, blinded crossover extension. An additional safety cohort of 640 patients will receive open-label remternetug for 1 year.

Solanezumab is a humanized monoclonal antibody that targets the mid-domain of the Aβ peptide for increasing Aβ clearance [ 52 ]. Phase 3 trials of solanezumab, including EXPEDITION-1 and EXPEDITION-2, which enrolled 2,052 patients with mild-to-moderate AD, did not reveal improvements in ADAS-Cog11 and ADCS-ADL scores, which were the primary outcome measures. Similarly, the phase 3 trial EXPEDITION-3 demonstrated that 400 mg solanezumab administered every 4 weeks did not have significant effects on cognitive decline in patients with mild AD [ 52 ]. A4 (NCT02008357) is a phase 3 prevention trial focused on slowing memory and cognitive decline in elderly individuals without cognitive impairment or dementia. A4 is using a sensitive cognitive battery—the Alzheimer Disease Cooperative Study Preclinical Alzheimer Cognitive Composite—and was initiated in February 28, 2014. On March 8, 2023, Eli Lilly and Company reported that solanezumab did not slow cognitive decline or clear amyloid plaques in individuals with preclinical AD in the A4 study. DIAN-TU-001 (NCT01760005) is another ongoing phase 3 clinical trial that is testing the combination of solanezumab and gantenerumab in 210 asymptomatic and mildly symptomatic carriers of autosomal-dominant mutations in AD genes. However, on February 10, 2020, the study investigators announced that the primary endpoint was not achieved in the trial, namely treatment-related changes on the DIAN-Multivariate Cognitive Endpoint. The results indicated that the solanezumab-treated group had greater cognitive decline on some measures relative to placebo, and that solanezumab treatment did not exert any beneficial effects on downstream biomarkers, whereas gantenerumab significantly reduced amyloid plaques, CSF total tau, and phospho-tau181 and attenuated increases in neurofilament light chain [ 53 ]. The participants were offered an open-label extension with high-dose gantenerumab because of its positive effects on imaging and other biomarkers, such as normalized CSF Aβ42, and because it reduced CSF total tau and pTau181 levels.

ALZ-801 is a prodrug of tramiprosate, a small molecule of anti-Aβ oligomers and an aggregation inhibitor [ 54 ]. The phase 3 trial APOLLOE4 (NCT04770220) is evaluating the safety and efficacy of ALZ-801 for patients with early AD and carrying the homozygous ε4 allele on the apolipoprotein E gene ( APOE4/4 ). The recruited patients are receiving 265 mg ALZ-801 or placebo twice daily for 18 months. The trial started in May 2021. The primary endpoint is ADAS-Cog scores, and the secondary endpoints are scores of the Disability Assessment for Dementia, CDR-SB, and Amsterdam-iADL. The biomarkers of interest include the hippocampal volume, as determined through MRI and based on CSF and plasma pTau181 levels. Another phase 2 trial (NCT04693520) is investigating the effects of oral ALZ-801 administered to participants with early AD who have the APOE4/4 or APOE3/4 genotype with biomarkers of core AD pathology. The study is also assessing the efficacy, safety, and tolerability of ALZ-801.

Simufilam (PTI-125) is a drug that binds to filamin, a scaffolding protein that stabilizes the interaction between soluble Aβ42 and the α7 nicotinic acetylcholine receptor [ 55 ]. Two phase 3 trials, namely RETHINK-ALZ (NCT04994483) and REFOCUS-ALZ (NCT05026177), were commenced in November 2021. Both are safety and efficacy studies of simufilam and have enrolled participants with mild-to-moderate AD. RETHINK-ALZ will randomize 750 participants with AD and CDR scores of 0.5, 1, or 2 into groups receiving either placebo or 100 mg of simufilam twice a day for 1 year (52 weeks). The coprimary outcomes of this trial are ADAS-Cog12 and ADCS-ADL scores, and the trial is set to run through October 2023. REFOCUS-ALZ will randomize 1,083 participants into groups receiving placebo or 50 or 100 mg of simufilam (1:1:1) for 76 weeks. The primary outcome measures are similar to those of the RETHINK-ALZ trial. A phase 3 trial of simufilam (NCT05575076) was started in November 2022 to assess the long-term safety and tolerability of simufilam in participants with mild-to-moderate AD. That open-label extension study is intended to assess the long-term safety and tolerability of simufilam 100 mg twice daily in patients who have completed the RETHINK-ALZ or REFOCUS-ALZ Phase 3 clinical trials. The primary outcome measure is adverse event monitoring from baseline to week 52.

Varoglutamstat (PQ912) is a glutaminyl cyclase inhibitor that reduces pGlu-Aβ generation [ 56 ]. Glutaminyl cyclase catalyzes the cyclization of an exposed glutamate at the N-terminus of Aβ, resulting in the formation of toxic pGlu-Aβ, a major component of amyloid plaques. Two ongoing phase 2 clinical trials, namely VIVA-MIND and VIVIAD, are evaluating the safety, tolerability, and efficacy of varoglutamstat in participants with MCI and mild dementia due to AD. VIVA-MIND (NCT03919162) is a phase 2A multicenter, randomized, double-blind, placebo-controlled, parallel-group study of varoglutamstat, with a stage gate to phase 2B. Phase 2A involves an adaptive dosing evaluation of three doses of varoglutamstat or placebo for ≥ 24 weeks. VIVIAD (NCT04498650) is a phase 2B, multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-finding study being conducted to evaluate the safety, tolerability, and efficacy of varoglutamstat in 259 participants with MCI and mild dementia due to AD.

ABBV-916 is a monoclonal antibody to Aβ. It recognizes N-terminal truncated Aβ modified with pyroglutamate at position 3 (N3), a form of Aβ that is aggregated into amyloid plaques. A two-stage phase 2 trial of ABBV-916 is ongoing (NCT05291234). Stage A is a multiple ascending dose study, and participants have a 25% chance of receiving placebo. Stage B is a proof-of-concept study, and participants have a 20% chance of receiving placebo. The first 6 months of the study are a double-blinded period, which is to be followed by a 2-year extension period in which all participants receive ABBV-916. Approximately 195 participants aged 50–90 years are to be enrolled at approximately 90 sites across the world. The participants are to receive intravenous doses of ABBV-916 or placebo once every 4 weeks for 24 weeks and are to be followed up for an additional 16 weeks.

CT1812 is a ligand that targets the component 1 subunit of the sigma2/progesterone membrane receptor. It functions as a negative allosteric regulator, reducing the affinity of oligomeric Aβ and interfering with Aβ-induced synaptic toxicity [ 57 ]. START(COG0203) study (NCT05531656) is a phase 2, multicenter, randomized, double-blind, placebo-controlled trial that was initiated in September 2022 for evaluating the efficacy and safety of CT1812. START is comparing the effects of CT1812 (100 or 300 mg) with those of placebo over 18 months in 540 people with MCI or mild dementia due to AD. The SHINE (COG0201) study (NCT03507790) is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, 36-week phase 2 study of two doses of CT1812 in adults with mild-to-moderate AD. The study is evaluating the safety, tolerability, pharmacokinetics, and efficacy of CT1812.

Anti-tau therapy

Table 4 summarizes the ongoing phase 2 trials of anti-tau therapy.

Bepranemab (UCB0107) is a monoclonal IgG4 antibody that targets a central tau epitope. An ongoing phase 2 trial (NCT04867616) enrolling 421 participants with prodromal or mild AD is investigating the safety, tolerability, and efficacy of bepranemab. After an 80-week double-blinded treatment period, the participants are eligible to enter a 48-week open-label extension period, in which they are to receive bepranemab treatment for 44 weeks. Subsequently, they are to participate in a safety evaluation visit 20 weeks after the last infusion. The primary outcome measure is the CDR-SB score.

JNJ-63733657 is a humanized IgG1 monoclonal antibody that targets the microtubule-binding region of tau and prevents the cell-to-cell propagation of pathogenic tau aggregates. The AUTONOMY trial (NCT04619420) is an ongoing phase 2, randomized, double-blind, placebo-controlled, parallel-group multicenter study. Participants with early AD symptoms and a positive tau PET scan are randomized to groups receiving JNJ-63733657 or placebo. This trial is enrolling 420 participants and is expected to be completed by November 2025. The primary outcome measure is clinical decline, as determined using the iADRS.

ACI-35 is a liposome-based vaccine that targets pathological conformations of phosphorylated tau. A phase 1b/2a multicenter, double-blind, randomized, placebo-controlled trial (NCT04445831) was conducted to evaluate the safety, tolerability, and immunogenicity of various doses, regimens, and combinations of tau-targeting vaccines in individuals with early AD. The vaccines tested were JACI-35.054 and ACI-35.030 at various dose levels. The findings were presented at the 2022 CTAD conference. The results indicated that participants who received ACI-35.030 exhibited a strong and sustained immune response against pathological tau proteins (pTau) and nonphosphorylated tau (ePHF), particularly in the mid- and low-dose groups. Recipients of JACI-35.054 also displayed a robust immune response against ePHF and pTau, but without a clear dose–effect relationship. The trial has been conducted across nine centers in Finland, Sweden, the Netherlands, and the United Kingdom and is expected to be completed by October 2023.

E2814 is a monoclonal IgG1 antibody that targets an HVPGG epitope in the microtubule-binding domain of tau, prevents cell-to-cell propagation, and mediates the clearance of pathogenic tau proteins. The DIAN-TU-001 (E2814) trial (NCT05269394) is a phase 2/3 multicenter, randomized, double-blind, placebo-controlled platform trial of potential disease-modifying therapies with biomarker, cognitive, and clinical endpoints. The trial is enrolling patients with dominantly inherited AD. The study design involves the use of the anti-amyloid antibody lecanemab. Some participants are receiving a matching placebo plus lecanemab, whereas others are receiving concurrent therapy with E2814 plus lecanemab.

LY3372689 is a small-molecule inhibitor of O-GlcNAcase, which promotes tau glycosylation and prevents tau aggregation [ 58 ]. A phase 2 trial (NCT05063539) was initiated in September 2021 for assessing the safety, tolerability, and efficacy of LY3372689 in 330 patients with early symptomatic AD with progressive memory changes for ≥ 6 months and who met the criterion of having a positive flortaucipir-PET scan.

BIIB080 is a tau DNA/RNA-based antisense oligonucleotide that inhibits the translation of tau mRNA into protein, thus suppressing tau expression. CELIA (NCT05399888) is an ongoing phase 2 trial that is aiming to determine whether BIIB080 can delay AD progression in comparison with placebo and to identify the most effective dose of BIIB080. In March 2019, Biogen/Ionis performed a 4-year open-label extension trial of quarterly injections for individuals who completed the randomized portion of the trial. The initial data of this trial were reported at the Alzheimer’s Association International Conference (2021), revealing no serious adverse events from the intrathecal injection of BIIB080 at either of three doses every month for 3 months or two high-dose injections 3 months apart. BIIB080 led to a dose-dependent reductions of 30%–50% in total tau and pTau181 levels in CSF.

Neuroprotectors and cognitive enhancers

Table 5 summarizes the ongoing phase 3 trials for therapies other than anti-amyloid/tau treatment.

The active metabolite of fosgonimeton (ATH-1017) is a positive modulator of hepatocyte growth factor (HGF)/MET signaling [ 59 ]. A phase 3 trial of fosgonimeton (NCT04488419) was initiated in September 2020 and is expected to be completed in February 2024. This study is evaluating the safety and efficacy of fosgonimeton in participants with mild-to-moderate AD, with double-blind, parallel-arm treatment implemented for 26 weeks. The primary outcome measure is the overall treatment effect of fosgonimeton, as measured using the Global Statistical Test, which combines cognition (ADAS-Cog) and function (ADCS-ADL) scores.

AR-1001 selectively inhibits phosphodiesterase 5 and suppresses cGMP hydrolysis, resulting in the activation of protein kinase G and the increased phosphorylation of the cAMP-responsive element-binding protein at Ser133. It can rescue long-term potentiation impairment and cognitive dysfunction in animal models of AD [ 60 ]. A phase 3 trial of AR-1001 (NCT05531526) was started in December 2022 and is estimated to be completed in December 2027. The study aims to evaluate the efficacy and safety of AR1001 in participants with early AD. The primary outcome measure is the change in the CDR-SB from baseline to week 52.

BPDO-1603 is a potential cognitive-enhancing drug for AD, but its mechanism of action remains unknown [ 61 ]. A phase 3 trial of BPDO-1603 (NCT04229927) was started in February 2020 and is estimated to be completed in March 2023. The study has been undertaken to evaluate the efficacy and safety of BPDO-1603 in patients with moderate-to-severe AD. The primary outcome measures are the change in Severe Impairment Battery total scores from baseline to week 24, and CIBIC-plus total scores at week 24.

Buntanetap is a novel translational inhibitor of multiple neurotoxic proteins, including APP, tau, and α-synuclein, by enhancing the binding of the atypical iron response element in the 5′UTR regions of the mRNA of the neurotoxic proteins to iron regulatory protein 1 [ 62 ]. In February 2023, phase 2 and 3 trials (NCT05686044) were initiated to measure the efficacy and safety of three doses of buntanetap in comparison with placebo in participants with mild-to-moderate AD. The primary outcome measures are ADAS-Cog and ADCS Clinical Global Impression of Change (ADCS-CGIC) scores.

Caffeine is an adenosine receptor antagonist that has been reported to be associated with slower cognitive decline and lower cerebral amyloid accumulation [ 63 ]. A phase 3 trial of caffeine (NCT04570085) was started in March 2021 to evaluate the efficacy of 30 weeks of caffeine intake in comparison with placebo on cognitive decline in patients with mild-to-moderate AD dementia (Mini-Mental State Examination scores: 16–24). The primary outcome measure is changes in neuropsychological test battery scores between the randomized value and the value after 30 weeks of treatment.

Hydralazine may have anti-neurodegenerative effects because it activates the Nrf2 pathway, which involves more than 200 antioxidant proteins; improves mitochondrial function; and increases respiration capacity and the production of adenosine triphosphate; hydralazine also activates autophagy, which aids in the clearance of intracellular aggregates [ 64 , 65 , 66 ]. A phase 3 trial of hydralazine (NCT04842552) was started in August 2021 and is anticipated to be completed in December 2023. The study is comparing the effects of 75 mg hydralazine versus placebo in patients with mild-to-moderate AD. Various cognitive and function tests, including olfactory tests, biochemical analyses, and adverse effect monitoring, are being conducted regularly during follow-up.

KarXT (xanomeline-trospium), comprised of muscarinic agonist xanomeline and muscarinic antagonist trospium, is designed to preferentially activate muscarinic receptor in the CNS and ameliorate the peripheral muscarinic side effects. It is reported that KarXT improves cognition in patients with AD and schizophrenia [ 67 ]. A 38-week phase 3 trial comparing the effects of KarXT (NCT05511363) and placebo in participants with psychosis associated with AD dementia was started in August 2022. The trial is analyzing the time from randomization to relapse (primary outcome) as well as the time from randomization to discontinuation for any reason and the safety and tolerability of KarXT (secondary outcomes).

Metformin, a commonly prescribed antidiabetic medication, has been reported to improve cognition or mood in many neurological disorders [ 68 , 69 ]. A phase 3 trial of metformin (NCT04098666) was started in March 2021 and is anticipated to be completed in April 2026. The primary outcome measure is the total recall of the Free and Cued Selective Reminding Test at 24 months.

Nilotinib is a tyrosine kinase inhibitor that preferentially targets discoidin domain receptors and can effectively reduce the occurrence of misfolded proteins in animal models of neurodegeneration by crossing the blood–brain barrier and promoting Aβ and tau degradation [ 70 ]. A phase 3 trial (NCT05143528) was initiated in February 2022 to investigate the safety and efficacy of nilotinib BE (bioequivalent) in individuals with early AD. The primary outcome measure is changes in CDR-SB scores between baseline and week 72.

Piromelatine is a melatonin MT1/2/3 and serotonin 5-HT-1A/1D receptor agonist and was developed as a treatment for mild AD [ 71 ]. In May 2022, a randomized trial (NCT05267535) was initiated in 225 noncarriers of a specific polymorphism, and these participants with mild dementia due to AD are allocated at a ratio of 1:1 to receive piromelatine or placebo for 26 weeks. A 12-month extension involves treating the placebo group with piromelatine to assess the drug’s disease-modifying effects. The primary analysis will be conducted after the initial 26 weeks. If efficacy is not confirmed, the study is to end without the extension phase.

Semaglutide is a peptidic GLP-1 receptor agonist that may regulate the aggregation of Aβ in AD. GLP-1 receptors are involved in cognition, synaptic transmission in hippocampal neurons, and cell apoptosis; thus, they may serve as targets for exploring candidate drugs with neuroprotective and cognition-enhancing effects [ 72 ]. A phase 3 trial of semaglutide (NCT04777396) was started in May 2021 to investigate the efficacy of semaglutide in individuals with early AD. The primary outcome measure is changes in the CDR-SB score from baseline to week 104.

Tricaprilin, a semisynthetic medium-chain triglyceride, is hydrolyzed to octanoic acid after administration and is further metabolized to ketones, which serve as an alternative energy substrate for the brain [ 73 ]. Therefore, tricaprilin can be used as a ketogenic source for the management of mild-to-moderate AD. A phase 3 trial (NCT04187547) was started in June 2022 to evaluate the efficacy and safety of tricaprilin in participants with mild-to-moderate AD. The primary outcome measure is changes in ADAS-Cog scores from baseline to week 20.

Anti-neuroinflammation therapy

Masitinib, an oral tyrosine kinase inhibitor, exerts effects by inhibiting mast cell and microglia/macrophage activity, with significant CNS penetration [ 74 ]. It is currently undergoing a phase 3 trial (NCT05564169) with 600 participants, employing a randomized, double-blind, placebo-controlled, parallel-group design over 24 weeks, followed by a 24-week extension phase. Quadruple masking ensures blinding. The study aims to evaluate Masitinib as an adjunct therapy for mild to moderate AD. Estimated to conclude on December 15, 2025, the trial assesses primary outcomes through changes from baseline in ADAS-Cog-11 and ADCS-ADL scores, measuring cognitive and functional abilities, respectively.

NE3107 is an anti-inflammatory insulin sensitizer that can cross the blood–brain barrier and bind to ERK. NE3107 can selectively inhibit inflammation-driven ERK- and NF-κB-stimulated inflammatory mediators, including TNF-α, without disturbing their homeostatic functions [ 75 ]. A multicenter phase 3 trial (NCT04669028) was started in August 2021 to investigate the safety and efficacy of NE3107 at 20 mg that was orally administered twice daily versus placebo in adult participants with mild-to-moderate AD. The primary outcome measures are changes in ADAS-Cog12 and ADCS-CGIC scores from baseline to week 30 [ 76 ].

BPSD-relieving therapy

Masupirdine, a selective 5‐HT6 receptor antagonist with favorable physicochemical properties and absorption, distribution, metabolism, and excretion properties, may have beneficial effects on agitation, aggression, and psychosis in patients with moderate AD [ 77 ]. A phase 3 trial (NCT05397639) was started in November 2022 to evaluate the efficacy, safety, tolerability, and pharmacokinetics of masupirdine in comparison with placebo for treating agitation in participants with AD dementia. The primary outcome measure is the change in the score of the Cohen–Mansfield Agitation Inventory from baseline to week 12.

Nabilone is a partial agonist of cannabinoid receptor 1 (CB1) and CB2 in the brain and in peripheral tissues, and it has been reported to provide effective treatment for agitation in patients with AD [ 78 ]. A phase 3 trial (NCT04516057) was started in February 2021 to investigate whether nabilone is an effective treatment for agitation in AD patients. The primary outcome measure is agitation (Cohen–Mansfield Agitation Inventory) between baseline and week 8.

Phase 4 and repurposing trials

Table 6 summarizes ongoing phase 4 trials.

Escitalopram, a selective-serotonin reuptake inhibitor, is a commonly used antidepressant. It ameliorates cognitive impairment and could selectively attenuate phosphorylated tau accumulation in stressed rats by regulating hypothalamic–pituitary–adrenal axis activity and the insulin receptor substrate/glycogen synthase kinase-3β signaling pathway [ 79 ]. A phase 4 trial (NCT05004987) was started in February 2022 to investigate whether a reduction in depressive symptoms owing to the administration of escitalopram oxalate is associated with the normalization of AD biomarkers in CSF and inflammatory markers in the peripheral blood. The primary outcome measures are changes in CSF Aβ40 and Aβ42 levels, vascular dysfunction biomarker levels, and scores of the Montgomery–Asberg Depression Ratio Scale at week 8.

Sodium oligomannate (GV-971), a marine-derived oligosaccharide, can reconstitute the gut microbiota, reduce bacterial metabolite–driven peripheral infiltration of immune cells into the brain, inhibit amyloid-β fibril formation, and inhibit neuroinflammation in the brain, as demonstrated in animal studies [ 80 , 81 ]. A phase 4 trial (NCT05181475) was initiated in December 2021 to examine the long-term efficacy and safety of GV-971 as well as changes in blood and gut microbiota biomarkers and thereby validate its mechanism of action and establish guidance for the more rational use of drugs in clinical practice. The primary outcome measure is changes in ADAS-Cog11 scores from baseline to week 48. Another phase 4 trial was started in July 2022 and is comparing the efficacy and safety of memantine and GV-971 monotherapy and combination therapy in patients with moderate-to-severe AD. The primary outcome measure is changes in cognitive function at weeks 12, 24, 36, and 48.

Spironolactone, an aldosterone mineralocorticoid receptor antagonist, has been commonly used to treat cardiovascular diseases, including hypertension. It has anti-inflammatory effects on the peripheral tissues and central nervous system and therefore may have beneficial effects on neurological disorders [ 82 ]. A phase 4 trial (NCT04522739) was started in September 2022 to investigate whether spironolactone can be tolerated by older Black American adults with MCI and to determine its effect on memory and thinking abilities, as measured by participant performance on cognitive tests. The primary outcome measures are the number of adverse events and the attrition rate.

Published results

Among the clinical trials newly registered in the last 4 years, four articles pertaining to two trials have been published in peer-reviewed scientific journals. The characteristics of the published randomized controlled trials are summarized in Table 7 [ 43 , 53 , 83 , 84 ]. Two articles reported the results of NCT03887455 [ 43 , 84 ], and the other two reported the results of NCT01760005 [ 53 , 83 ]. The articles were published between 2018 and 2023. The results of both NCT03887455 (Clarity AD) and NCT01760005 have been discussed in the anti-amyloid section. The methodological quality of these studies is summarized in Table 8 . Both trials (NCT03887455 and NCT01760005) had a overall low risk of bias [ 43 , 53 , 83 , 84 ].

Our understanding of AD originated from clinical research, and how pathological findings are associated with clinical presentation of AD has continued to intrigue the neuroscience research community over the past century. DMTs have become the core of new drug development, and the accumulation of knowledge is leading to the evolution of diagnostic criteria and clinical outcome measurements. The view of clinical outcomes has shifted from considering them as solely determinative to considering them to be just one of the determinants. In accordance with the 2018 NIA-AA Research Framework criteria [ 25 ] or the new 2023 NIA-AA revised criteria for AD [ 26 ], the incorporation of biomarkers is necessary in clinical practice.

This review documented that in terms of the number of AD drug trials and the number of recruited participants, the majority of trials continue to focus on mechanisms involving amyloid and tau. Our 2020 report highlighted that due to the failure of early anti-amyloid trials to achieve their intended outcomes, particularly studies involving BACE inhibitors and monoclonal antibodies, some have questioned whether amyloid remains clinically relevant in AD. This shift in perspective has led to a change in the focus of research toward populations in the prodromal or preclinical stage with positive results for diagnostic biomarkers. Additionally, the validity of the amyloid hypothesis has been contested, resulting in a significant reduction in the number of anti-amyloid phase 3 trials since 2019. However, the targets of both phase 1 and phase 2 trials are diverse, with a noticeable increase in the number of phase 1 trials focusing on neuroprotection and phase 2 trials focusing on anti-neuroinflammation [ 85 ]. Since the positive outcomes in terms of slow decline in cognitive abilities in the lecanemab Clarity AD trial [ 43 ] and the donanemab trial TRAILBLAZER-ALZ [ 86 ], the impact of amyloid and consequent pathological alterations is likely to become the main focus of clinical trials. The incorporation of amyloid-related therapy either as an add-on or as a link to specific aspects of AD pathophysiology might become an important trend in clinical trials of new drugs in the future. However, despite this expansion of research areas, the scope of indications for novel anti-amyloid monoclonal antibody therapy remains limited. The mode of treatment administration and the high monitoring costs along with the need for specialized facilities and imaging scans remain challenges. Other unmet needs, such as addressing BPSD and enhancing cognitive function, necessitate pharmaceutical research. Examining drugs with diverse mechanisms necessitates thorough evaluation that extends beyond mere clinical measurements to encompass their intermediate impact on biomarkers. It is essential to investigate the potential synergy between a new drug and existing medications approved by the US FDA. This approach could even be extended to situations where adjuvant treatment, such as tau-related treatments, is provided after amyloid clearance has been achieved. Clinical trials related to AD have also exhibited a shift in focus toward the earlier stages of AD, such as MCI, or even cognitively healthy participants for developing prevention interventions.

Successful phase 3 trials such as Clarity AD (lecanemab) and EMERGE (aducanumab) have evaluated anti-amyloid treatment in mild AD (Fig.  2 ). Trials that do not target specific pathophysiologies are becoming fewer in all phases (Figs.  2 and 3 ). However, an increasing number of early-phase trials of therapies for symptoms, including cognitive enhancers and agents for relieving BPSD, are being conducted. This reflects the unmet clinical need for such therapies (Figs.  2 and 3 ). Similarly, an increasing number of phase 1 trials involving DMTs, particularly those targeting both anti-amyloid and anti-tau mechanisms, has been noted, indicating the importance of basic research (Fig.  3 ). Outcome measurement tools have also become more diverse, which has enabled meaningful improvements in AD and the efficacy of treatments to be clearly determined in clinical trials. Overall, the field of AD clinical trials is evolving, and additional promising treatments for AD are likely to be developed in the near future.

figure 2

Trends in Phase 3 trials, 2020–2023, categorized according to event-related themes in Left: Number of Phase 3 trials. Right: Percentage of Phase 3 trials. A anti-amyloid therapy, B anti-tau therapy, C neuroprotection, D anti-neuroinflammation, E cognitive enhancer, F relief of behavioral psychological symptoms of dementia, G others, U undisclosed

figure 3

Trends in Phase 1 and 2 trials, 2020–2023, categorized according to event-related themes in Left: Number of Phase 2 trials. Right: Number of Phase 1 trials; A anti-amyloid therapy, B anti-tau therapy, C neuroprotection, D anti-neuroinflammation, E cognitive enhancer, F relief of behavioral psychological symptoms of dementia, G others, U undisclosed

Availability of data and materials

Not applicable.




Cholinesterase inhibitors

  • Alzheimer disease

Alzheimer’s Disease Assessment Scale–Cognitive Subscale

Alzheimer’s Disease Cooperative Study–Activities of Daily Living Inventory–Mild Cognitive Impairment Version

Apolipoprotein gene

Amyloid precursor protein

Amyloid-related imaging abnormalities

Amyloid, tau, and neurodegeneration biomarkers

Appropriate use recommendations

Autophagic vacuoles

Beta-secretase 1

Behavioral psychological symptoms of dementia

Clinical Dementia Rating scale

Clinical Dementia Rating scale Sum of Box

Caregiver Global Impression of Change

Cerebrospinal fluid

Clinical Trial of AD

Disease-modifyung therapies

Integrated Alzheimer’s Disease Rating Scale

Immunoglobulin gamma 1

Mild cognitive impairment

Magnetic resonance imaging

Nuclear factor κB

Neurofibrillary tangles

Neuropsychiatric Inventory

Positron emission tomography



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Li-Kai Huang and Yi-Chun Kuan contributed equally to this work.

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PhD Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University, No. 291, Zhong Zheng Road, Zhonghe District, New Taipei City, Taiwan

Li-Kai Huang & Chaur-Jong Hu

Taipei Neuroscience Institute, Taipei Medical University, New Taipei City, Taiwan

Li-Kai Huang, Yi-Chun Kuan & Chaur-Jong Hu

Dementia Center and Department of Neurology, Shuang-Ho Hospital, Taipei Medical University, New Taipei City, Taiwan

Department of Neurology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

Yi-Chun Kuan & Chaur-Jong Hu

Department of Biomedical Engineering, National Taiwan University, Taipei, Taiwan

Yi-Chun Kuan

School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

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LKH and YCK: Conducted literature search, developed the study concept and design, extracted information from trials and studies, and contributed to manuscript drafting and revision. HWL: Extracted information from trials and studies and contributed to manuscript drafting and revision. CJH: Contributed to the study concept and design, interpreted the data and information, finalized and revised the manuscript, and provided overall supervision of the entire project.

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Huang, LK., Kuan, YC., Lin, HW. et al. Clinical trials of new drugs for Alzheimer disease: a 2020–2023 update. J Biomed Sci 30 , 83 (2023).

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  • Clinical trials
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new research dementia alzheimer's

Lecanemab, the New Alzheimer’s Treatment: 3 Things To Know


Yale researcher discusses the recent FDA approval of a new Alzheimer's disease treatment.

Illustration of amyloid plaques, the characteristic feature of Alzheimer’s disease, among neurons.

[Originally published January 19, 2023. Updated: July 24, 2023.]

The Food and Drug Administration (FDA) recently granted full approval to a new Alzheimer’s treatment called lecanemab, which has been shown to moderately slow cognitive and functional decline in early-stage cases of the disease.

Alzheimer’s disease is a progressive disorder that damages and destroys nerve cells in the brain. Over time, the disease leads to a gradual loss of cognitive functions, including the ability to remember, reason, use language, and recognize familiar places. It can also cause a range of behavioral changes.

In January, the FDA gave the medication an accelerated approval based on amyloid plaque clearance. Christopher van Dyck, MD , director of Yale’s Alzheimer’s Disease Research Unit, was the lead author of a study published in the Jan. 5 issue of The New England Journal of Medicine that shared results of a Phase III clinical trial of lecanemab. (Dr. van Dyck is also a paid consultant for the pharmaceutical company Eisai, which funded the trials.)

Sold under the brand name Leqembi™ and made by Eisai in partnership with Biogen Inc., the drug is delivered by an intravenous infusion every two weeks. Lecanemab works by removing a sticky protein from the brain that is believed to cause Alzheimer’s disease to advance.

“It’s very exciting because this is the first treatment in our history that shows an unequivocal slowing of decline in Alzheimer’s disease,” says Dr. van Dyck.

This is the first time in two decades that the FDA has granted full approval to a drug for Alzheimer’s, but there is also a “black box” warning on the medication—the agency’s strongest caution—because of safety concerns.

We talked more with Dr. van Dyck, who answered three questions about the new treatment.

How effective is lecanemab for Alzheimer’s disease?

In a trial that involved 1,795 participants with early-stage, symptomatic Alzheimer’s, lecanemab slowed clinical decline by 27% after 18 months of treatment compared with those who received a placebo.

“The antibody treatment selectively targets the forms of amyloid protein that are thought to be the most toxic to brain cells,” says Dr. van Dyck.

Study participants who received the treatment had a significant reduction in amyloid burden in imaging tests, usually reaching normal levels by the end of the trial. Participants also showed a 26% slowing of decline in a key secondary measure of cognitive function and a 37% slowing of decline in a measure of daily living compared to the placebo group.

“Would I like the numbers to be higher? Of course, but I don’t think this is a small effect,” says Dr. van Dyck. “These results could also indicate a starting point for bigger effects. The data appear encouraging that the longer the treatment period, the better the effect. But we’ll need more studies to determine if that’s true.”

They also beg the question about still-earlier intervention, adds Dr. van Dyck. Lecanemab is already being tested in the global AHEAD study for individuals who are still cognitively normal but at high risk of symptoms due to elevated levels of brain amyloid.

Yale currently has the largest number of participants in the AHEAD study, which is funded by the National Institutes of Health (NIH) and Eisai and is enrolling participants as young as 55. “We may see a larger benefit if we intervene before significant brain damage has occurred,” he says.

Is lecanemab safe?

The most common side effect (26.4% of participants vs. 7.4% in the placebo group) of the treatment is an infusion-related reaction, which may include transient symptoms, such as flushing, chills, fever, rash, and body aches. The majority (96%) of these reactions were mild to moderate, and 75% happened after the first dose.

“We can medicate those individuals in advance if we find they have those side effects repeatedly,” says Dr. van Dyck. “We can use medications such as diphenhydramine or acetaminophen. But this is generally not an issue.”

Another potential side effect associated with lecanemab was amyloid-related imaging abnormalities with edema, or fluid formation on the brain. This occurred in 12.6% of trial participants compared to 1.7% in the placebo group. “It’s usually asymptomatic when it occurs, but we can detect it on MRI scans. We often don’t stop dosing if we see it, unless there are symptoms, in which case we would pause infusions until it fully resolves,” Dr. van Dyck says.

It’s important to note that the studies with lecanemab show substantially lower rates of this side effect than do published trials of other, similar drugs such as aducanumab—they're at about a third of the rate, explains Dr. van Dyck. “So, for drugs in this class, I think lecanemab has a favorable safety profile,” he says.

Lastly, 17.3% of trial participants experienced amyloid-related imaging abnormalities with brain bleeding compared to 9% in the placebo group.

“Most of the time we're really talking about microhemorrhages that are in the order of millimeters,” says Dr. van Dyck. “People with Alzheimer's disease are more prone to these events because of the amyloid deposits in their blood vessels, but a catastrophic bleed is quite rare.”

The medication’s label includes warnings about brain swelling and bleeding and that people with a gene mutation that increases their risk of Alzheimer’s disease are at greater risk of brain swelling on the treatment. The label also cautions against taking blood thinners while on the medication.

When will lecanemab be available for Alzheimer’s disease treatment?

Eisai set the price for Leqembi at $26,500 per year, and it has reportedly been largely unavailable while FDA full approval was pending. That may change now that Medicare has said it will cover 80% of the cost.

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The headquarters of Lilly, the maker of donanemab, in Indianapolis

New Alzheimer’s drug slows cognitive decline by 35%, trial results show

Donanemab is second drug in a year to succeed in trials in what could be ‘beginning of the end’ of disease

A new Alzheimer’s drug slowed cognitive decline by 35%, according to late-stage trial results, raising the prospect of a second effective treatment for the disease.

Donanemab met all goals of the trial and slowed progression of the condition by 35% to 36% compared with a placebo in 1,182 people with early-stage Alzheimer’s, the drugmaker Lilly said.

It comes after trial results published last year showed that lecanemab , made by Eisai and Biogen, reduced the rate of cognitive decline by 27% in patients with early Alzheimer’s.

“This could be the beginning of the end of Alzheimer’s disease,” said Dr Richard Oakley, the associate director of research at the Alzheimer’s Society in the UK. “After 20 years with no new Alzheimer’s drugs, we now have two potential new drugs in just 12 months – and for the first time, drugs that seem to slow the progression of disease.”

Maria Carrillo, the chief science officer of the Alzheimer’s Association in the US, also hailed donanemab’s trial results. “These are the strongest phase 3 data for an Alzheimer’s treatment to date,” she said.

Alzheimer’s is the most common cause of dementia, one of the world’s biggest health threats. The number of people living with dementia globally is forecast to nearly triple to 153 million by 2050, and experts have said it presents a rapidly growing threat to future health and social care systems in every community, country and continent.

In patients on donanemab, 47% showed no signs of the disease progressing after a year, according to a statement issued by Lilly . That compared to 29% on a placebo.

The drug resulted in 40% less decline in the ability to perform activities of daily living, the company said. Patients on donanemab also experienced a 39% lower risk of progressing to the next stage of disease compared to those on a placebo.

However, the company also reported side-effects.

Brain swelling occurred in 24% of those on donanemab, with 6.1% experiencing symptoms, Lilly said. Brain bleeding occurred in 31.4% of the donanemab group and 13.6% of the placebo group.

Lilly also said the incidence of serious brain swelling in the donanemab study was 1.6%, including two deaths attributed to the condition and a third death after an incident of serious brain swelling.

“The treatment effect is modest, as is the case for many first-generation drugs, and there are risks of serious side-effects that need to be fully scrutinised before donenemab can be marketed and used,” said Dr Susan Kohlhaas, the executive director of research and partnerships at Alzheimer’s Research UK.

But she said the results were still “incredibly encouraging” and represented “another hugely significant moment for dementia research”.

“We’re now on the cusp of a first generation of treatments for Alzheimer’s disease, something that many thought impossible only a decade ago,” she added. “People should be really encouraged by this news, which is yet more proof that research can take us ever closer towards a cure.”

Lilly said it planned to apply for approval from the US Food and Drug Administration next month, and with regulators in other countries shortly thereafter.

“At face value, these data look positive, but we need to see the full dataset,” said Dr Liz Coulthard, an associate professor in dementia neurology at the University of Bristol.

“Donanemab seems to help people with early Alzheimer’s retain cognitive function for longer – and this effect looks to be clinically meaningful. Donanemab might help people live well with Alzheimer’s for longer. If approved alongside lecanemab, this potentially brings a choice of treatments for patients.”

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New breakthroughs on Alzheimer’s

MIT scientists have pinpointed the first brain cells to show signs of neurodegeneration in the disorder and identified a peptide that holds potential as a treatment.

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scan of a human brain with some neurons highlighted in green

Neuronal hyperactivity and the gradual loss of neuron function are key features of Alzheimer’s disease. Now researchers led by Li-Huei Tsai, director of MIT’s Picower Institute for Learning and Memory, have identified the cells most susceptible to this damage, suggesting a good target for treatment. Even more exciting, Tsai and her colleagues have found a way to reverse neurodegeneration and other symptoms by interfering with an enzyme that is typically overactive in the brains of Alzheimer’s patients. 

In one study , the researchers used single-­cell RNA sequencing to distinguish two populations of neurons in the mammillary bodies, a pair of structures in the hypothalamus that play a role in memory and are affected early in the disease. Previous work by Tsai’s lab found that they had the highest density of amyloid beta plaques, abnormal clumps of protein that are thought to cause many Alzheimer’s symptoms. 

The researchers found that neurons in the lateral mammillary body showed much more hyperactivity and degeneration than those in the larger medial mamillary body. They also found that this damage led to memory impairments in mice and that they could reverse those impairments with a drug used to treat epilepsy.

In the other study , the researchers treated mice with a peptide that blocks a hyperactive version of an enzyme called CDK5, which plays an important role in development of the central nervous system. They found dramatic reductions in neurodegeneration and DNA damage in the brain, and the mice got better at tasks such as learning to navigate a water maze.

CDK5 is activated by a smaller protein known as P35, allowing it to add a phosphate molecule to its targets. However, in Alzheimer’s and other neurodegenerative diseases, P35 breaks down into a smaller protein called P25, which allows CDK5 to phosphorylate other molecules—including the Tau protein, leading to the Tau tangles that are another characteristic of Alzheimer’s.

Pharmaceutical companies have tried to target P25 with small-molecule drugs, but these drugs also interfere with other essential enzymes. The MIT team instead used a peptide—a string of amino acids, in this case a sequence matching that of a CDK5 segment that is critical to binding P25.

In tests on neurons in a lab dish, the researchers found that treatment with the peptide moderately reduced CDK5 activity. But in a mouse model that has hyperactive CDK5, they saw myriad beneficial effects, including reductions in DNA damage, neural inflammation, and neuron loss. 

The treatment also produced dramatic improvements in a different mouse model of Alzheimer’s, which has a mutant form of the Tau protein. Tsai hypothesizes that the peptide might confer resilience to cognitive impairment in the brains of people with Tau tangles.

“We found that the effect of this peptide is just remarkable,” she says. “We saw wonderful effects in terms of reducing neurodegeneration and neuroinflammatory responses, and even rescuing behavior deficits.”

The researchers hope the peptide could eventually be used as a treatment not only for Alzheimer’s but for frontotemporal dementia, HIV-induced dementia, diabetes-­linked cognitive impairment, and other conditions. 

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Recent breakthroughs in Alzheimer’s research provide hope for patients

While there is no cure, researchers say a newly approved drug, advanced testing, and increasing knowledge about the disease may improve patients’ lives..

Lori Weiss, 65, a retired teacher, has early onset Alzheimer’s disease. She is enrolled in a drug clinical trial and is hopeful about recent progress in disease research.

A few years ago, Lori Weiss, a high school math and engineering teacher, noticed it was taking her longer to do her lesson plans and grading. She also repeatedly needed to ask for help using spreadsheets she’d once mastered and she struggled to answer her students’ questions.

The symptoms were all too familiar to Weiss. Not only had she cared for her grandfather with Alzheimer’s disease when she was a teenager, she’d also watched her mother slowly lose her memory to the disease for nearly two decades. She had aunts, uncles, and a cousin as well who were diagnosed with the neurological disorder, which gradually steals a person’s memory and cognitive abilities.

“It’s rampant in my family,” Weiss says.

Weiss decided to speak with her primary care physician, who referred her to a neurologist for testing. In 2020, at the age of 62, Weiss was diagnosed with mild cognitive impairment. Two years after that, a PET scan revealed amyloid plaques, a buildup of toxic proteins in the brain that disrupt neural function and are a hallmark of Alzheimer’s disease.

Soon, Weiss began to lose her sense of direction, which prompted fears that she might be forced into a full-time care facility at a young age.

“Losing my freedom was just more than I could handle,” she says. Around that time, a friend saw a TV advertisement for a clinical trial for a drug that would attempt to slow progression of the disease using manmade monoclonal antibodies to attack and remove the amyloid plaques in the brain.

“I don’t even think that I thought twice about” enrolling in the trial, says Weiss, who has been receiving monthly infusions of the drug, called donanemab , near her home in Portland, Oregon, for about a year. “I just said, ‘Yeah, sign me up!’”

Although donanemab is not approved by the Food and Drug Administration (FDA), it uses a similar approach to the drug lecanemab, which received accelerated FDA approval on Jan. 6, and which showed biological and clinical benefits for patients in trials. In November, drugmaker Eli Lilly and Company announced promising results for donanemab, but last week, the FDA denied the company’s request for accelerated approval, saying it needed more data for participants receiving the drug for at least 12 months.

Nonetheless, this recent progress has given people like Weiss hope that previous generations have not had.

“Alzheimer’s research is getting to a place where cancer research was maybe 30, 40 years ago.” Anton Porsteinsson, MD, University of Rochester Medical Center in New York

Participating in the clinical trial “has had a huge impact,” Weiss says. “It’s given me the drive to do things while I can; it’s given me the desire to talk to more people about getting treatment, getting diagnosed early, and getting in drug trials.”

Weiss says that since she’s begun taking donanemab, she’s regained her sense of direction and has not noticed significant cognitive decline. For her, even the hope that the trial has given her has made all the difference.

“For my husband and I, it’s totally changed our lives. Instead of living in fear … we treat each day like it’s Valentine’s Day,” Weiss says. Getting diagnosed early has “given me so much more life. [I thought] getting the disease was a death sentence for me, but I’m taking a water painting class, I’m in a walking group and a music group. I thrive on my relationships with my Alzheimer’s friends and other friends, and I’m connected with my family. I feel like I’m living my life. It’s so much better than I imagined.”

Lori Weiss, 65, with her husband, Kevin Weiss, 60, at Rockaway Beach in Oregon.

And while Alzheimer’s researchers are careful to emphasize that they are still a long way from a cure, many say the hope is not a false one. The field has had several breakthroughs in recent years, from identifying easier and cheaper ways to diagnose the disease early to better understanding how individuals with the disease might require a variety of interventions.

“Alzheimer’s research is getting to a place where cancer research was maybe 30, 40 years ago,” says Anton Porsteinsson, MD, director of the Alzheimer’s Disease Care, Research and Education Program at the University of Rochester Medical Center in New York. “I think we’re at a point where we’re going to see a logarithmic increase in discovery.”

Fighting a complex disease

Alzheimer’s disease, which was discovered in 1906 and is now the seventh leading cause of death in the United States, has long boggled the scientific community. Though research over the decades has identified characteristics of the disease — such as the presence of amyloid plaques between neurons and the buildup, known as tangles, of another toxic protein, tau, inside neurons — questions remain about what causes the disease and how best to treat it in a clinically meaningful way.

“It’s a complex disease. It’s not just a single molecule that’s gone awry. It’s not an infection that has a viral particle,” says Ronald C. Petersen, MD, PhD, director of the Mayo Clinic Alzheimer’s Disease Research Center in Rochester, Minnesota. “We’ve defined it by the presence of amyloid , neuritic plaques , and neurofibrillary tangles , but that’s just the tip of the iceberg.”

Many researchers now believe that the precursors to developing Alzheimer’s begin to accumulate in the brain 10 or more years before symptoms begin to show.

Alzheimer’s disease progression affects the brain much like a forest fire, with many factors affecting how it spreads, says Rudolph E. Tanzi, PhD, director of the Genetics and Aging Research Unit at Massachusetts General Hospital in Boston.

Amyloid plaques and tau tangles can build up over years, at some point triggering an inflammatory response that can quickly destroy brain cells. These conditions can be influenced by a range of factors, from genetic predisposition to environmental exposures to lifestyle, he explains.

That’s why the solution to treating — or ideally, preventing — Alzheimer’s disease will likely require a combination of interventions, Petersen says.

One important part of the puzzle — and a part that has been the focus of much pharmaceutical development — is targeting the amyloid plaques.

This approach has been controversial. In 2021, the FDA granted accelerated approval to the anti-amyloid drug aducanumab, sold as Aduhelm, despite objections from an advisory committee and outcry from the scientific community that the lack of clinical benefit made the drug’s high cost, initially set at $56,000 a year and later reduced to $28,000 a year, unjustifiable. A Congressional investigation found numerous flaws and irregularities in the process the FDA used when approving the drug.

Lecanemab, on the other hand, has been met with more optimism in the Alzheimer’s research community because its clinical trials demonstrated an actual clinical benefit to patients early in the disease progression.

“The field is feeling that, finally, we have a drug that didn’t have the controversy aducanumab had,” Petersen says. “It looks like it does what it’s supposed to do biologically [and] this looks like it could be meaningful for patients.”

In clinical trials , lecanemab showed a modest but tangible decrease in cognitive decline (of 27%) over 18 months in Alzheimer’s patients who were early in the disease’s progression, compared with patients who were given a placebo. Though it’s far from a cure, experts say it could give patients months of retaining memory and cognition that they might otherwise lose, a prospect that could be meaningful for patients and their families who have no other options.

But this drug, too, has stirred some controversy because of its high price tag and potentially deadly side effects, including swelling and bleeding in the brain. The pharmaceutical company Eisai has priced lecanemab, sold as Leqembi, at $26,000 a year, and the Centers for Medicare and Medicaid Services has yet to decide if it will cover the drug.

“It’s very expensive,” Tanzi says, explaining that patients who take the drug will also need several MRIs to check for brain bleeds on top of the cost of the infusions. “There is a health care disparity this could create; those who want to remove amyloid can pay out of pocket [but] the average person can’t afford that. The wealthy can protect themselves.”

Equity starting in research

The high costs of treatment could also exacerbate existing racial disparities when it comes to Alzheimer’s outcomes. Although Black Americans are about twice as likely as White Americans to have Alzheimer’s, and Hispanics are about 1.5 times as likely to have it, White people make up a disproportionate majority of clinical trial participants and non-White people report greater barriers to diagnosis and access to care, according to the Alzheimer’s Association .

“Most of the research operations are either based at large academic institutions or private professional research sites,” Porsteinsson explains about pharmaceutical company trials. “The temptation [for researchers] is to go where the treatment is ‘easiest’; where you’ve recruited before.”

In its clinical trial recruitment for lecanemab, the University of Rochester succeeded in increasing the representation of Hispanic participants, but struggled to include a representative number of Black patients.

“We can’t just wait until the brain deteriorates.” Rudolph E. Tanzi, PhD, Massachusetts General Hospital in Boston

“If we want to go after historically underrepresented groups in research, first we need to recognize they’re underrepresented for a reason,” Porsteinsson says. “There might have been a poor experience with researchers coming [into their community], doing a study [the researchers] needed, and then basically leaving. There isn’t an ongoing commitment.”

He says that if Alzheimer’s treatments are going to be meaningful to all people affected by the disease, it will take a concerted effort to include more diversity in clinical trial participants, not only in race and ethnicity, but in health status and inclusion of people with comorbidities. Often, trials tend to select for the healthiest patients possible, he explains.

“[We must] secure making our research more representative of the American population,” Porsteinsson says. “It’s going to take an investment in infrastructure and it’s going to take an investment of time.”

A stage set for discovery

Alzheimer’s disease already affects more than six million people living in the United States, and that number is projected to grow to 13 million by 2050. It’s also an incredibly financially costly disease, with an economic impact of $321 billion in health care costs in 2022, expected to rise to $1 trillion by 2050, according to the Alzheimer’s Association. That prospect prompted the U.S. Congress to approve an additional $226 million to the National Institutes of Health for Alzheimer’s research in December, bringing the annual federal funding outlay to more than $3.7 billion .

Experts say it is not in vain. Research efforts, particularly those at teaching hospitals, have helped unlock mysteries about the genetic underpinnings of the disease, ways to identify biomarkers in the blood that can more easily diagnose the disease in its earliest states, and complex treatment approaches that use lifestyle interventions and a combination of drug therapies.

Tanzi believes that the future of Alzheimer’s treatment and prevention will be similar to current management of heart disease and diabetes. It could mean more regular screenings and early interventions, such as taking anti-amyloid drugs and incorporating lifestyle and diet changes before the disease gets out of control. And for those already diagnosed, it means using a combination of therapies that target different aspects of the disease, such as neuroinflammation and plaque buildup.

“We can’t just wait until the brain deteriorates,” he says.

With the current momentum, Porsteinsson hopes that young and aspiring physician-scientists will be inspired to join the field and continue the research for generations to come.

“What many medical students and young doctors have historically been hesitant about is that dementia is very nebulous, there is a lot of gray there. … They felt things were pretty bleak, too uncertain, and there was too little you could offer,” he says. “Now, I think we are at the dawn of a very different era.”

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Research on Alzheimer’s Disease and Related Dementias

Breadth of NIH-supported research on Alzheimer’s and related dementias

Alzheimer’s disease and related dementias are a series of complex brain disorders that affect millions of Americans and many more people worldwide. These disorders have an enormous impact on individuals and their families, long-term care facilities, health care providers, health care systems and infrastructure, and the communities in which we all live. As the economic, social, and personal costs of these diseases climb, the research community is working to discover solutions that will improve the lives of those with dementia, their caregivers, and their communities.

The federal government’s Alzheimer’s and related dementias research strategy focuses on engaging a cross-disciplinary team of geneticists, epidemiologists, gerontologists, behavioral scientists, disease and structural biologists, pharmacologists, clinical researchers, and others to bring the greatest and most diverse expertise to the field. This includes training new generations of researchers and clinician-scientists and engaging in innovative partnerships with private industry, nonprofit groups, and more to foster collaboration and broaden access to research resources and data.

Critically, the government’s research strategy includes the search to find treatment and prevention strategies, as well as interventions, services, and supports to improve quality of life for those already living with these diseases and their families.

Who Funds Alzheimer’s and Related Dementias Research?

The National Institutes of Health (NIH) is made up of Institutes, Centers, and Offices that conduct and fund research into all aspects of human health. The National Institute on Aging (NIA) leads NIH’s efforts in clinical, behavioral, and social research in Alzheimer’s and related dementias through efforts aimed at finding ways to treat and ultimately prevent the disorder. NIA collaborates closely with the National Institute of Neurological Disorders and Stroke (NINDS), which manages a research portfolio targeting Alzheimer’s-related dementias. While some of this research takes place in NIH laboratories, the vast majority of NIH support is provided through a competitive grants process to institutions and small businesses across the country. Other federal agencies support a range of activities focused on public health and community programs.

Advances in Alzheimer's and Related Dementias Research

As the nation’s biomedical research agency, NIH supports research ranging from basic biology to drug development and from clinical studies to evaluating public health outcomes. Within the past several decades, researchers have made great strides toward better understanding what causes Alzheimer’s and related dementias and discovering approaches that may prevent, diagnose, and treat them. Some highlights of these efforts include:

  • Drug discovery and drug repurposing. Thanks to the substantial investment in Alzheimer’s and related dementias research over the past decade, NIH has increased drug discovery significantly. Of the many compounds in NIH-supported drug development programs for Alzheimer’s and related dementias, 18 new dementia drug candidates have now matured through the pipeline, from discovery in the lab all the way through preclinical development, to reach the stage of human testing. NIA currently supports more than 60 clinical trials testing drug candidates that target many different aspects of the disease. Several of these drug candidates are intended to stop or slow the disease process rather than only treat symptoms. For example, some target amyloid plaques and tau tangles in new ways. Researchers are also exploring multiple ways to repurpose drugs for the potential treatment of dementia, including FDA-approved drugs used to treat epilepsy and diabetes.
  • Early detection and diagnosis. Researchers have made significant progress in developing, testing, and validating biomarkers that detect signs of the disease process. For example, in addition to PET scans that detect abnormal beta-amyloid plaques and tau tangles in the brain, NIH-supported scientists have developed the first commercial blood test for Alzheimer’s. This test and others in development can not only help support diagnosis but also be used to screen volunteers for research studies. Other discoveries are leading to the development of potential biomarkers for other dementias. These include the detection of abnormal TDP-43 protein, found in frontotemporal dementias, and a cerebrospinal fluid test to help diagnose Lewy body dementia and Parkinson’s disease. Researchers are also studying behavioral and social indicators, including problems with paying bills and a combined decline in memory and walking speed, that may be early signs of these diseases. Other early markers are also under study.
  • Risks factors, genetics, and disease pathways. NIH’s research investments to identify the biological mechanisms that lead to Alzheimer’s and related dementias are fundamental for the discovery of potential drugs that target them. There are many biological pathways that scientists can target with investigational drugs. For example, several recent studies have further revealed how components of the immune system, brain inflammation, vascular disease, and possibly viruses and bacteria — including the many tiny organisms that live in the digestive system, known as the gut microbiome — contribute to the development of these diseases. Scientists are also exploring genetic variations that may contribute to or prevent disease. Recent research has revealed that the genetic risk for Alzheimer’s differs between ethnic and racial groups, highlighting the need for more diversity in genetic research studies. Scientists are also discovering genetic variants that may help protect against Alzheimer’s. Other studies are identifying the genetic underpinnings of related dementias, including new gene variants linked to the development of Lewy body dementia.
  • Population studies and precision medicine. By studying large, diverse groups of people, researchers are identifying which genes, behaviors, and lifestyle choices are linked with dementia. Population studies have shown that sedentary behavior, low socioeconomic status, low level of education, and living in a poor neighborhood may increase the risk of developing dementia. These observational discoveries, along with knowledge of genetic and other factors, can be used to advance the development of methods for diagnosis, prevention, and treatment at an individualized level.
  • Health disparities and dementia risk. NIH-funded researchers are examining the biological, social, and environmental factors that contribute to the higher prevalence of dementia in Hispanic Americans and Black Americans compared with other White Americans. Since dementia is also underdiagnosed in these populations, researchers are studying approaches to improve diagnoses in underserved communities. NIH is also investing in strategies to increase diversity in research study participants.
  • Lifestyle interventions. Researchers are investigating interventions around exercise, healthy eating, cognitive training, preventive health care, and management of chronic conditions, such as high blood pressure, that — if made early in life — may be able to prevent or delay disease symptoms. Emerging areas of study include interventions to enhance cognitive reserve — the mind’s ability to cope with the effects of aging — and interventions to potentially compensate for premature cognitive decline and dementia linked to adverse exposures in early life, such as abuse and malnutrition. NIA currently supports more than 150 trials testing behavioral and lifestyle interventions.
  • Dementia care and caregiver support. NIH has significantly expanded research on how to improve dementia care and support for care partners. Researchers are investigating new dementia care models and strategies to equip family caregivers with tools and knowledge to manage the challenges of caring for a loved one with dementia. Studies are also underway to examine ways to improve quality of life for people with dementia and their caregivers. Other studies aim to understand the costs and challenges of dementia, including lost wages and paying for long-term care. NIA currently supports more than 200 studies on dementia care and caregiving.
  • Infrastructure development. NIH is continually investing in research infrastructure to advance Alzheimer’s and related dementias research. Efforts in this area include launching a consortium for Alzheimer’s clinical trials, a collaboratory to test interventions to improve care of people with dementia in real-world settings, research efforts to validate cognitive tests in a primary care setting, and centralized data-sharing platforms and other technologies.

Challenges for the Alzheimer’s Research Community

Even with the progress that we’ve made, there’s still a lot of work to do before we can find treatment and prevention strategies for the millions of people affected by Alzheimer’s and related dementias. These devastating diseases are highly complex conditions caused by an interplay of genetic, lifestyle, and environmental factors. They usually develop gradually — changes in the brain take place over years and even decades, long before the first symptoms appear. This complexity presents challenges to the discovery and development of new drugs and other prevention and treatment approaches.

Researchers believe Alzheimer’s and related dementias will likely require multiple treatments customized to individuals. We also know that as the older population continues to grow — aging remains the most important risk factor for dementia — we will see increased numbers of people living with these diseases. That’s why thousands of researchers around the country are working on this issue.

Setting the Federal Research Agenda

NIH takes a collaborative, methodical approach to reviewing progress, identifying gaps, and setting the future agenda for research into Alzheimer’s and related dementias. NIH funding in this area is guided by gaps and opportunities identified in research summits , which alternate yearly to focus on Alzheimer’s, Alzheimer’s-related dementias, or dementia care and services. Smaller, focused workshops are held more frequently on specific aspects of this research.

NIH outlines its Alzheimer’s research efforts in the NIH AD/ADRD Research Implementation Milestones , a research framework detailing specific steps and success criteria toward achieving the goals of the National Plan to Address Alzheimer’s Disease . The milestones also showcase funding initiatives, accomplishments, and highlights of progress toward accomplishing the National Plan goals.

NIH’s research progress is highlighted in the annual Alzheimer’s and related dementias professional judgment budget , which is submitted to Congress each year.

What Is a Professional Judgment Budget?

Each year NIH submits a professional judgment budget that estimates the additional funding needed to advance NIH-supported research into the treatment and prevention of Alzheimer’s and related dementias. The report also summarizes progress and promising research opportunities. Only two other areas of biomedical research — cancer and HIV/AIDS — follow a similar process designed to accelerate research discovery. This approach is often referred to as a “bypass budget” because of its direct transmission to the President and then to Congress without modification through the traditional federal budget process.

Clinical Research Into Alzheimer’s and Related Dementias

No major advance in Alzheimer’s and related dementias treatment, prevention, or care will be possible without robust clinical research. Clinical research includes studies that involve people so scientists can learn more about disease progression, how behavior and lifestyle factors may affect health, and the safety and effectiveness of an intervention. Advances made through clinical research rely on the volunteers who participate in these types of studies. NIA is working on multiple initiatives to enhance recruitment and retention of diverse populations in clinical research. View some of those resources below.

NIA-funded clinical research includes both observational studies through which researchers gather important information, and clinical trials in which researchers test interventions to treat or prevent disease, improve care and caregiver support, and enhance quality of life for people living with dementia. NIA is currently funding more than 400 active clinical trials .

NIA also funds more than 30 Alzheimer’s Disease Research Centers across the country. Scientists at these centers conduct clinical research to improve diagnosis and care for people with dementia and their families, and to find a treatment or increase prevention.

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Find More Resources on Alzheimer’s Research

Explore the resources on this website and linked below to find more information from federal government agencies.

View professional judgment budgets for Alzheimer’s and related dementias from NIH, including yearly updates on research progress.

Browse this database to learn more about research implementation plans and progress toward the goal of treating or preventing Alzheimer’s and related dementias.

Search this repository of resources to support the recruitment and retention of participants into clinical trials and studies on Alzheimer’s disease and related dementias.

Learn about the data sharing policies, considerations, resources, and guidance available to support researchers in safely and efficiently sharing data from their studies.

Visit IADRP to search a database of categorized research across public and private sources.

Learn about NIA's efforts toward the National Plan and NIH annual summits that shape research priorities.

View a list of all active NIA-funded clinical trials, including drug trials, intervention studies, and care and caregiver interventions.

Search for NIA-supported clinical research tools, datasets, samples, visualization tools, and more for Alzheimer’s and related dementias research.

Read the National Strategy for Recruitment and Participation in Alzheimer’s and Related Dementias Research and get resources to support study recruitment.

Read about the National Institute of Neurological Disorders and Stroke’s research into Alzheimer’s disease-related dementias.

Search NIH-funded research in Alzheimer’s and related dementias.

Other Articles in This Section

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Questions? Contact the ADEAR Center

The Alzheimer’s & related Dementias Education & Referral (ADEAR) Center is a service of the National Institute on Aging at the National Institutes of Health. Call 800-438-4380 or email [email protected] to talk with an information specialist.

This content is provided by the National Institute on Aging (NIA), part of the National Institutes of Health. NIA scientists and other experts review this content to ensure it is accurate and up to date.

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January 30, 2024

Research in Context: Diagnosing dementia

Detecting brain diseases early.

Until recently, a diagnosis of dementia might help explain cognitive decline, but there were no available treatments. In the last several years, the first drugs to slow the progression of Alzheimer’s have reached the market. This special Research in Context feature explores approaches to the diagnosis of Alzheimer’s and other dementias and the development of strategies to try to prevent their progression.

Elderly father with adult son and grandson out for a walk in the park.

Diseases that degrade the mind strike at the very heart of our humanity. Unfortunately, such diseases aren’t rare. Strokes, infections, and chronic conditions like diabetes can all cause lasting damage to the brain. And more than 6 million Americans are living with Alzheimer’s disease and other dementias—a number that is expected to rise over the coming decades.

Dementia is a loss of thinking, remembering, and reasoning skills that affects everyday life. The risk for developing dementia increases sharply with age, but dementia is not part of the healthy aging process.

“When [older] people start to have memory problems, cognitive problems, it’s due to a disease. It’s not a normal consequence of aging,” explains Dr. Michael Weiner, a dementia researcher at the University of California, San Francisco.

While there are several different forms of dementia, Alzheimer’s disease is the most common. Until recently, a diagnosis of dementia might help explain cognitive decline, but there were no treatments available to change the course of the disease. However, the last several years have brought a major change, as the first drugs that can slow the progression of Alzheimer’s have reached the market.

NIH-funded researchers are now drawing on decades of advances in detecting the changes that lead to Alzheimer’s and other dementias to develop strategies to try to prevent or slow their progression.

“There’s really consistent evidence that the process of Alzheimer’s disease in the brain begins at least a decade before symptoms appear—maybe even two decades,” explains Dr. Reisa Sperling, an Alzheimer’s disease researcher at Harvard Medical School. The same appears to be true for many other dementias. “But that’s a glass-half-full situation, because it means we can potentially detect the disease before there is irreversible damage.”

Seeing damage in the brain

Brain image of woman showing large red areas.

Some types of damage to the brain, like from a stroke, are relatively easy to pick out with a CT scan in the emergency department. But the brain changes associated with dementia start at the molecular level and get worse slowly. In the past, this made them difficult to detect.

For example, until fairly recently, Alzheimer’s disease could only be confirmed after death. Characteristic damage to the brain could be seen during an autopsy. This damage includes abnormal clumps, called plaques, of a protein called amyloid-beta. It also involves bundles of fibers, or tangles, formed by another protein called tau.

Together, these harmful substances are thought to gum up the activity of neurons—the brain cells that convey chemical and electrical messages to create thoughts. This is associated with a progressive worsening of the cognitive symptoms of Alzheimer's disease.

“Traditionally, the diagnosis of Alzheimer’s disease in patients was based on the clinical symptoms of dementia,” explains Dr. Eliezer Masliah, an aging expert at NIH.

In the early 2000s, biomarkers to diagnose Alzheimer’s disease in living people first became available for research. Broadly, a biomarker is any measurable characteristic that can reliably help diagnose disease. Biomarkers may include molecules found in blood tests, results from imaging exams, or other characteristics.

For Alzheimer’s disease, a breakthrough came with positron emission tomography, or PET scans. This imaging technique could pinpoint the buildup of amyloid-beta in the brain. “That’s currently the gold standard for Alzheimer’s diagnosis,” Weiner notes.

NIH-funded research has continued to build on this advance. For example, a recent study found that using PET to image tau in the brain was even better at predicting future brain degeneration than measuring amyloid-beta. PET imaging of tau may also aid future clinical trials.

PET scans, however, are extremely expensive and require exposure to radiation. Other tests have become available that don’t require brain imaging. One type measures amyloid-beta levels in the cerebrospinal fluid, or CSF, instead. Though less expensive than PET scans, these tests require a lumbar puncture—the insertion of a needle into the spinal canal. This procedure must be done by a specialist, typically takes 30 to 60 minutes, and not everyone can have one.

Building on the promise of these methods, researchers have been working to develop quicker and easier tests for biomarkers of Alzheimer’s disease. Blood tests would be ideal. “The advantages of a blood test are that it’s easy to obtain, it’s very fast, and it’s much cheaper,” Masliah says.

Such tests have the potential to greatly widen access to early diagnosis and treatment for Alzheimer’s disease. “Most people with Alzheimer’s disease are cared for by general practitioners, not specialty clinics,” Sperling explains. “If these blood tests are accurate, people who aren’t Alzheimer’s specialists could use them to figure out how best to care for patients.”

Better tests for Alzheimer’s

Immunofluorescence image of purple clusters around loose light blue clusters.

The most obvious target for an Alzheimer’s blood test is amyloid-beta. Dysfunctional forms of this protein can build up in the brain long before damage to neurons occurs. Studies have found that these abnormal proteins can also make their way into the bloodstream.

An NIH-funded research team recently developed a test that could detect clumps of amyloid-beta in the bloodstream. It could distinguish these clumps from other types of amyloid that aren’t thought to harm the brain. The test proved better at predicting the later development of Alzheimer’s dementia than other more invasive tests.

Another candidate for a blood-based biomarker of Alzheimer’s is tau. Tau tangles in the brain are thought to occur later in Alzheimer’s disease, but blood tests for some forms of tau have shown promise for early detection. One type of tau, called p-tau-217, for example, has recently shown especially strong results.

Two recent NIH-funded studies found that blood tests for p-tau-217 identified, with about 90% accuracy, people with Alzheimer’s-related changes in the brain that were later verified by PET imaging.

Another class of promising biomarkers for Alzheimer’s are molecules that get released when neurons and other types of brain cells are damaged. Some of these molecules aren’t unique to Alzheimer’s and so might also be used for early diagnoses of different types of dementia.

Tests for other dementias

Gloved hand holding a test tube with brain images in background

Other types of dementia may be rarer than Alzheimer’s but no less devastating. Potential biomarkers for the early detection of other forms of dementia include a protein called α-synuclein. This may be able to help diagnose Lewy body dementia, as well as Parkinson’s disease, which can also affect the brain. 

Researchers have also been studying potential biomarkers for a group of disorders that have some similarities to Alzheimer’s, collectively known as frontotemporal disorders, or FTD. These rose in the public consciousness in 2023, when the family of actor Bruce Willis revealed his diagnosis.

Unlike Alzheimer’s, FTD tends to occur most often in those under the age of 65 and starts with behavior or language changes. But like Alzheimer’s, FTD can be difficult to diagnose before symptoms develop—and sometimes even afterward—especially in people with no family history of the disease.

Recently, NIH-funded researchers showed that blood tests for a protein called neurofilament light chain, or NfL, hold promise for early detection of FTD and related conditions, such as amyotrophic lateral sclerosis, or ALS. NfL is one of the proteins released when nerve cells in the brain or body are damaged.

“NfL won’t ever, on its own, be a diagnostic biomarker for any of the neurodegenerative diseases,” explains Dr. Tania Gendron, an FTD researcher at the Mayo Clinic. “However, there are some diseases, like FTD or ALS, that have symptoms that might be mimicked by other diseases that are not neurodegenerative. So what NfL could do is help facilitate a diagnosis by ruling out or ruling in neuronal injury.”

Gendron and her collaborators found that, among people who carried a genetic risk factor for FTD, NfL levels in the blood were higher in those who later developed symptoms compared with those who didn’t. Higher levels of NfL in blood samples taken at the start of the study were also associated with faster cognitive decline.

Having a test to catch FTD early would enable testing of treatments that aim to halt the disease before it causes substantial damage. But while NfL can detect neural damage, it can’t tell what molecular mechanisms set off that process. Many different genetic factors can affect FTD, and these will likely require different treatment strategies.

“We believe it's ideal to stop the molecular underpinnings of FTD as early as possible in its tracks,” Gendron explains. “It’s like one domino hits another domino, and then it just becomes chaos, like a snowball going down a mountain. So if you could halt the first key molecular events that trigger the disease, then you’d be better able to, hopefully, prevent worsening of that disease.”

Improving diversity, improving accuracy

Senior man with his eyes closed embracing a woman while standing in nursing home.

Several blood tests for Alzheimer’s disease have already received a type of certification called CLIA, which means the test reliably measures what it claims to measure. To date, none have been approved by the Food and Drug Administration for guiding treatment. But the tests that have reached the CLIA stage are already being adopted by memory clinics and large, ongoing treatment studies, Sperling explains.

For example, Sperling’s team has been running large NIH-funded clinical trials of drugs to prevent the progression of Alzheimer’s disease. As imaging biomarkers have become more widespread, they’ve pushed the timeline for intervention earlier and earlier—from full-blown Alzheimer’s disease to its precursor, called mild cognitive impairment, and finally to people without any symptoms of cognitive decline.

For one of their ongoing studies, called AHEAD, “the first step for screening is now a blood test,” Sperling says. “In terms of therapeutics that target amyloid buildup, treating earlier is better, probably even before symptoms develop. And the blood-based biomarkers are pretty good at finding people at that early stage of amyloid buildup.”

One roadblock has been that such blood tests haven’t been widely tested in diverse populations, Weiner explains. In the past, biomarker tests for dementia have largely enrolled people from white, well-educated, relatively wealthy groups. “But these tests should be validated in populations that really look like America,” Weiner says.

The relationship between amyloid PET levels and dementia outcomes, for example, appears to vary across different populations. “We don’t really understand the relationship of amyloid PET to Alzheimer’s pathology in the Black population very well,” Weiner notes. That could lead to sub-optimal treatment for many patients.

For almost 20 years, Weiner and his team have been running a large NIH-funded study to improve biomarkers for Alzheimer’s disease. In the last year, they’ve doubled participation among people from underrepresented groups.

“Underrepresented means Black, Latino, Asian/Pacific Islander, but also anyone with 12 years of education or less. And people from rural areas are also considered underrepresented,” he adds. His team hopes to eventually have more than half of their participants come from underrepresented groups. Having diversity during a test’s validation greatly increases its likelihood of being useful across populations.

Sperling’s group is also working to diversify their study participants. They noticed that many people from communities of color weren’t meeting the amyloid PET criteria for study participation, regardless of their symptoms. So this year, they started a new study that uses blood tests to explore what happens in the brains of people who have low levels of amyloid on PET scans but are at risk for developing dementia in the future.

The team hopes to find patterns in blood tests that will help inform future prevention strategies. “I think we’re getting closer to precision medicine,” Sperling says. “If amyloid is not the main contributor to Alzheimer’s symptoms in some communities, then we’ll need other drugs.”

Reliable, early biomarkers will also allow for the testing of strategies that may sound like science fiction today, such as anti-Alzheimer’s vaccines, Sperling explains. “That’s the future—that’s the way you’d be able to get preventive treatment to millions, or tens or hundreds of millions of people who need it.”

“What’s happening with biomarkers in Alzheimer’s disease is a real breakthrough; it has completely transformed the field,” Masliah says. “But I can’t stress enough the importance of people participating in these studies. All these breakthroughs have been not only due to the great work that the researchers are doing, but to the people who are volunteering to take part.”

Learn about joining a study of Alzheimer’s disease .

—by Sharon Reynolds

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References:  Prospective longitudinal atrophy in Alzheimer's disease correlates with the intensity and topography of baseline tau-PET.  La Joie R, Visani AV, Baker SL, Brown JA, Bourakova V, Cha J, Chaudhary K, Edwards L, Iaccarino L, Janabi M, Lesman-Segev OH, Miller ZA, Perry DC, O'Neil JP, Pham J, Rojas JC, Rosen HJ, Seeley WW, Tsai RM, Miller BL, Jagust WJ, Rabinovici GD.  Sci Transl Med . 2020 Jan 1;12(524). pii: eaau5732. doi: 10.1126/scitranslmed.aau5732. PMID:31894103. SOBA: Development and testing of a soluble oligomer binding assay for detection of amyloidogenic toxic oligomers.  Shea D, Colasurdo E, Smith A, Paschall C, Jayadev S, Keene CD, Galasko D, Ko A, Li G, Peskind E, Daggett V.  Proc Natl Acad Sci U S A . 2022 Dec 13;119(50):e2213157119. doi: 10.1073/pnas.2213157119. Epub 2022 Dec 9. PMID: 36490316. Discriminative accuracy of plasma phospho-tau217 for Alzheimer disease vs other neurodegenerative disorders.  Palmqvist S, Janelidze S, Quiroz YT, Zetterberg H, Lopera F, Stomrud E, Su Y, Chen Y, Serrano GE, Leuzy A, Mattsson-Carlgren N, Strandberg O, Smith R, Villegas A, Sepulveda-Falla D, Chai X, Proctor NK, Beach TG, Blennow K, Dage JL, Reiman EM, Hansson O.  JAMA . 2020 Jul 28. doi: 10.1001/jama.2020.12134. Online ahead of print. PMID: 32722745. Blood plasma phosphorylated-tau isoforms track CNS change in Alzheimer's disease.  Barthélemy NR, Horie K, Sato C, Bateman RJ.  J Exp Med . 2020 Nov 2;217(11):e20200861. doi: 10.1084/jem.20200861. PMID: 32725127. Comprehensive cross-sectional and longitudinal analyses of plasma neurofilament light across FTD spectrum disorders . Gendron TF, Heckman MG, White LJ, Veire AM, Pedraza O, Burch AR, Bozoki AC, Dickerson BC, Domoto-Reilly K, Foroud T, Forsberg LK, Galasko DR, Ghoshal N, Graff-Radford NR, Grossman M, Heuer HW, Huey ED, Hsiung GR, Irwin DJ, Kaufer DI, Leger GC, Litvan I, Masdeu JC, Mendez MF, Onyike CU, Pascual B, Ritter A, Roberson ED, Rojas JC, Tartaglia MC, Wszolek ZK, Rosen H, Boeve BF, Boxer AL; ALLFTD consortium, Petrucelli L.  Cell Reports Medicine . 2022 Apr 19;3(4):100607. doi: 10.1016/j.xcrm.2022.100607. eCollection 2022 Apr 19. PMID: 35492244. A multicentre validation study of the diagnostic value of plasma neurofilament light.  Ashton NJ, Janelidze S, Al Khleifat A, Leuzy A, van der Ende EL, Karikari TK, Benedet AL, Pascoal TA, Lleó A, Parnetti L, Galimberti D, Bonanni L, Pilotto A, Padovani A, Lycke J, Novakova L, Axelsson M, Velayudhan L, Rabinovici GD, Miller B, Pariante C, Nikkheslat N, Resnick SM, Thambisetty M, Schöll M, Fernández-Eulate G, Gil-Bea FJ, López de Munain A, Al-Chalabi A, Rosa-Neto P, Strydom A, Svenningsson P, Stomrud E, Santillo A, Aarsland D, van Swieten JC, Palmqvist S, Zetterberg H, Blennow K, Hye A, Hansson O.  Nat Commun.  2021 Jun 7;12(1):3400. doi: 10.1038/s41467-021-23620-z. PMID: 34099648.

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  • 12 February 2024

Early dementia diagnosis: blood proteins reveal at-risk people

  • Miryam Naddaf

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Coloured CT scan of a coronal section through the brain of a patient with Alzheimer's disease.

A computed-tomography scan of a brain affected by Alzheimer’s disease, the most common cause of dementia. Credit: Vsevolod Zviryk/Science Photo Library

An analysis of around 1,500 blood proteins has identified biomarkers that can be used to predict the risk of developing dementia up to 15 years before diagnosis.

The findings, reported today in Nature Aging 1 , are a step towards a tool that scientists have been in search of for decades: blood tests that can detect Alzheimer’s disease and other forms of dementia at a very early, pre-symptomatic stage.

Researchers screened blood samples from more than 50,000 healthy adults in the UK Biobank, 1,417 of whom developed dementia in a 14-year period.

They found that high blood levels of four proteins — GFAP, NEFL, GDF15 and LTBP2 — were strongly associated with dementia.

“Studies such as this are required if we are to intervene with disease-modifying therapies at the very earliest stage of dementia,” said Amanda Heslegrave, a neuroscientist at University College London, in a statement to the Science Media Centre in London.

Late diagnosis

According to the World Health Organization, more than 55 million people worldwide currently live with dementia.

People are often diagnosed only when they notice memory problems or other symptoms. At that point, the disease might have been progressing for years. “Once we diagnose it, it’s almost too late,” says study co-author Jian-Feng Feng, a computational biologist at Fudan University in Shanghai, China. “And it’s impossible to reverse it.”

new research dementia alzheimer's

Dementia risk linked to blood-protein imbalance in middle age

By screening 1,463 proteins in blood samples from 52,645 people, the authors found that increased levels of GFAP, NEFL, GDF15 and LTBP2 were associated with dementia and Alzheimer’s disease. For some participants who developed dementia, blood levels of these proteins were outside normal ranges more than ten years before symptom onset.

GFAP, a protein that provides structural support to nerve cells called astrocytes, has already been proposed as a diagnostic marker for Alzheimer’s disease 2 , as has GDF15 .

The latest study finds that people with high levels of GFAP in their blood are more than twice as likely as people with normal levels to develop dementia, and are nearly three times as likely to develop Alzheimer’s.

The authors used machine learning to design predictive algorithms, combining levels of the four protein biomarkers with demographic factors such as age, sex, education level and family history. They trained the model on information from two-thirds of the study participants, and tested its performance using data from the remaining 17,549 people.

The model predicted the incidence of three subtypes of dementia, including Alzheimer’s disease, with about 90% accuracy, using data from more than ten years before participants were officially diagnosed.

The authors say their findings could be used to develop blood tests that identify people at risk of developing dementia. Other researchers caution that the new biomarkers need further validation before being used as clinical screening tools.

The study “needs to be replicated and biomarkers that enable us not only to screen for disease risk but also to differentiate between diseases should be a priority”, said Heslegrave.


Guo, Y. et al. Nature Aging (2024).

Article   Google Scholar  

Shir, D. et al. Alzheimers Dement. 14 , e12291 (2022).

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Team develops highly accurate universal diagnostic blood test for Alzheimer's disease and mild cognitive impairment

by Hong Kong University of Science and Technology

Highly accurate universal diagnostic blood test for Alzheimer's disease and mild cognitive impairment

An HKUST-led international research collaboration has achieved a significant milestone in Alzheimer's disease (AD) diagnosis and management. The team has developed a cutting-edge blood test for the early detection of AD and mild cognitive impairment (MCI), surpassing remarkable accuracy rates of over 96% and 87% respectively.

Notably, this blood test is applicable across ethnic populations, providing a global solution to the diagnosis and management of AD. The work was recently published in Alzheimer's & Dementia . The research team was led by Prof. Nancy Ip, President and the Morningside Professor of Life Science at the Hong Kong University of Science and Technology (HKUST), and Director of the Hong Kong Center for Neurodegenerative Diseases (HKCeND).

AD affects more than 50 million people worldwide. A major hallmark of the disease is the accumulation of toxic amyloid beta (Aβ) in the brain, leading to the dysfunction and loss of brain cells, resulting in progressive memory loss, cognitive decline, and difficulties in daily tasks and communication.

The recent approval of the AD drug Lecanemab offers new hope by targeting MCI or mild AD-related dementia with elevated Aβ in the brain. However, the majority of individuals with these conditions are undiagnosed and untreated, largely due to the challenges in making an early diagnosis.

Currently, elevated Aβ can only be measured through costly brain imaging or invasive procedures. Additionally, disease diagnosis heavily relies on clinical observation of symptoms that typically appear 10–20 years after disease onset, by which time the disease has progressed to an advanced stage and is difficult to treat.

Therefore, the development of a simple blood test that accurately identifies individuals with MCI and mild AD, while also detecting elevated Aβ in the brain, would be a game-changer for AD diagnosis and treatment strategies.

Prof. Ip and her team at HKUST have recently developed a blood test for the early detection of AD and MCI with exceptionally high accuracy. In a multinational study involving individuals of Chinese and European descent, the international research team demonstrated the robust performance of the blood test in distinguishing individuals with AD and MCI from cognitively normal people, as well as its ability to detect brain amyloid pathology. These findings also highlight the applicability of the test across diverse ethnic and regional boundaries, showcasing its potential for global impact.

Unlike existing blood assays that mainly focus on a single biomarker analysis to reveal brain pathology, the HKUST-developed blood test simultaneously measures the levels of 21 proteins (as shown in the graphic above), thus revealing the alterations in multiple crucial biological pathways, and achieving more accurate classification of AD and MCI as well as close monitoring of disease progression.

This comprehensive AD profile for each individual opens the door for the future development of tailored treatment approaches for individual patients, known as precision medicine, which can revolutionize the field of AD diagnosis and management.

Highly accurate universal diagnostic blood test for Alzheimer's disease and mild cognitive impairment

"Our blood test heralds a new era of simple, effective, and less invasive diagnostics, and by expanding the scope of our research to include diverse populations, we have taken a crucial step towards making our test a universally applicable tool for AD diagnosis," remarked Prof. Ip.

"Our test can also be used to screen suitable individuals for specific drug treatments in clinical studies , and closely monitor disease progression and drug responses. In the future, it may also facilitate the development of personalized treatments, by shedding light on the molecular underpinnings of AD that vary from person to person and between ethnicities."

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  8. Large-scale study of brain proteins uncovers new clues to Alzheimer's

    Through a large-scale analysis of tissue samples, NIA-funded researchers have discovered new disease-related changes in the brains of people who had died with Alzheimer's disease. The study results, published in Nature Neuroscience, underscore the key role proteins may play in disease progression.

  9. Clinical trials of new drugs for Alzheimer disease: a 2020-2023 update

    Alzheimer's disease (AD) is the leading cause of dementia, presenting a significant unmet medical need worldwide. The pathogenesis of AD involves various pathophysiological events, including the accumulation of amyloid and tau, neuro-inflammation, and neuronal injury. Clinical trials focusing on new drugs for AD were documented in 2020, but subsequent developments have emerged since then.

  10. Lecanemab, the New Alzheimer's Treatment: 3 Things To Know

    [Originally published January 19, 2023. Updated: July 24, 2023.] The Food and Drug Administration (FDA) recently granted full approval to a new Alzheimer's treatment called lecanemab, which has been shown to moderately slow cognitive and functional decline in early-stage cases of the disease.. Alzheimer's disease is a progressive disorder that damages and destroys nerve cells in the brain.

  11. New Alzheimer's drug slows cognitive decline by 35%, trial results show

    A new Alzheimer's drug slowed cognitive decline by 35%, according to late-stage trial results, raising the prospect of a second effective treatment for the disease. Donanemab met all goals of ...

  12. Alzheimer's & Dementia Research

    Alzheimer's and dementia research - find the latest information on research funding, grants, clinical trials and global research news.

  13. New breakthroughs on Alzheimer's

    June 27, 2023. A pair of structures in the hypothalamus called the mammillary bodies (highlighted in green) are among the first brain regions to show neurodegeneration in Alzheimer's disease ...

  14. Recent breakthroughs in Alzheimer's research provide hope for ...

    Lori Weiss, 65, a retired teacher, has early onset Alzheimer's disease. She is enrolled in a drug clinical trial and is hopeful about recent progress in disease research. Courtesy of Lori Weiss. A few years ago, Lori Weiss, a high school math and engineering teacher, noticed it was taking her longer to do her lesson plans and grading.

  15. Research on Alzheimer's Disease and Related Dementias

    Of the many compounds in NIH-supported drug development programs for Alzheimer's and related dementias, 18 new dementia drug candidates have now matured through the pipeline, from discovery in the lab all the way through preclinical development, to reach the stage of human testing.

  16. New genetic therapy holds promise for ALS and frontotemporal dementia

    It may also hold opportunities for treating more common forms of dementia, such as Alzheimer's disease. The new treatment, dubbed CTx1000, targets pathological build-ups of the protein TDP-43 in ...

  17. New drug donanemab is 'a turning point in the fight against Alzheimer's'

    Full results about the Alzheimer's disease drug donanemab have been released today, supporting earlier trial results that suggested the breakthrough drug may slow down the progression of the disease.. Dr Richard Oakley, Associate Director of Research and Innovation at Alzheimer's Society, said: "Dementia is the biggest killer in the UK and over 60% of people living with dementia are ...

  18. Alzheimer's Research News -- ScienceDaily

    Read the latest research on Alzheimer's disease. Learn about Alzheimer's symptoms such as memory loss and senile dementia. Find out about Alzheimer's stages, causes and new treatments.

  19. Research in Context: Diagnosing dementia

    Until recently, a diagnosis of dementia might help explain cognitive decline, but there were no available treatments. In the last several years, the first drugs to slow the progression of Alzheimer's have reached the market. This special Research in Context feature explores approaches to the diagnosis of Alzheimer's and other dementias and ...

  20. Early dementia diagnosis: blood proteins reveal at-risk people

    The model predicted the incidence of three subtypes of dementia, including Alzheimer's disease, with about 90% accuracy, using data from more than ten years before participants were officially ...

  21. A new Alzheimer's drug has been approved. But should you take it?

    July 15, 2021 By Andrew E. Budson, MD, Contributor; Editorial Advisory Board Member, Harvard Health Publishing On June 7, 2021, the FDA granted accelerated approval to aducanumab (brand name Aduhelm), the first drug in 18 years for Alzheimer's disease.

  22. Dementia research news

    Dementia research updates Learn about the most recent news in the wider dementia research community. News Tag: News. Alzheimer's Society respond to FDA decision on Alzheimer's drug lecanemab The Food and Drug Administration has today approved lecanemab, a new drug for Alzheimer's disease, for use across the US. Read more News Tag: News.

  23. Scientists discover new cause of Alzheimer's, vascular dementia

    Researchers have discovered a new avenue of cell death in Alzheimer's disease and vascular dementia. A new study, led by scientists at Oregon Health & Science University and published in the ...

  24. Dementia: Researchers link the stress response to brain cell death

    Alzheimer's / Dementia. Share this article. New research suggests the body's inability to turn off the stress response is linked to brain cell death in neurodegenerative diseases like Alzheimer's ...

  25. Researcher finds help for Alzheimer's-associated agitation with new FDA

    Earlier this year, brexpiprazole became the first FDA-approved treatment of agitation-associated Alzheimer's dementia. Of the 6.7 million people 65 and older in the US with Alzheimer's dementia ...

  26. Team develops highly accurate universal diagnostic blood test for

    An HKUST-led international research collaboration has achieved a significant milestone in Alzheimer's disease (AD) diagnosis and management. The team has developed a cutting-edge blood test for ...