new research dementia alzheimer's

Appointments at Mayo Clinic

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

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

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

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

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

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

These are some of the strategies currently being studied.

Taking aim at plaques

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

Strategies aimed at beta-amyloid include:

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

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.

There is a problem with information submitted for this request. Review/update the information highlighted below and resubmit the form.

From Mayo Clinic to your inbox

Sign up for free and stay up to date on research advancements, health tips, current health topics, and expertise on managing health. Click here for an email preview.

Error Email field is required

Error Include a valid email address

To provide you with the most relevant and helpful information, and understand which information is beneficial, we may combine your email and website usage information with other information we have about you. If you are a Mayo Clinic patient, this could include protected health information. If we combine this information with your protected health information, we will treat all of that information as protected health information and will only use or disclose that information as set forth in our notice of privacy practices. You may opt-out of email communications at any time by clicking on the unsubscribe link in the e-mail.

Thank you for subscribing!

You'll soon start receiving the latest Mayo Clinic health information you requested in your inbox.

Sorry something went wrong with your subscription

Please, try again in a couple of minutes

• Treatments and research. Alzheimer's Association. https://www.alz.org/alzheimers-dementia/research_progress/treatment-horizon. Accessed March 23, 2023.
• Cummings J, et al. Alzheimer's disease drug development pipeline: 2022. Alzheimer's and Dementia. 2022; doi:10.1002/trc2.12295.
• Burns S, et al. Therapeutics of Alzheimer's disease: Recent developments. Antioxidants. 2022; doi:10.3390/antiox11122402.
• Plascencia-Villa G, et al. Lessons from antiamyloid-beta immunotherapies in Alzheimer's disease. Handbook of Clinical Neurology. 2023; doi:10.1016/B978-0-323-85555-6.00019-9.
• Brockmann R, et al. Impacts of FDA approval and Medicare restriction on antiamyloid therapies for Alzheimer's disease: Patient outcomes, healthcare costs and drug development. The Lancet Regional Health. 2023; doi:10.1016/j.lana. 2023.100467 .
• Wojtunik-Kulesza K, et al. Aducanumab — Hope or disappointment for Alzheimer's disease. International Journal of Molecular Sciences. 2023; doi:10.3390/ijms24054367.
• Can Alzheimer's disease be prevented? Alzheimer's Association. http://www.alz.org/research/science/alzheimers_prevention_and_risk.asp. Accessed March 23, 2023.
• Piscopo P, et al. A systematic review on drugs for synaptic plasticity in the treatment of dementia. Ageing Research Reviews. 2022; doi:10.1016/j.arr. 2022.101726 .
• Facile R, et al. Use of Clinical Data Interchange Standards Consortium (CDISC) standards for real-world data: Expert perspectives from a qualitative Delphi survey. JMIR Medical Informatics. 2022; doi:10.2196/30363.
• Imbimbo BP, et al. Role of monomeric amyloid-beta in cognitive performance in Alzheimer's disease: Insights from clinical trials with secretase inhibitors and monoclonal antibodies. Pharmacological Research. 2023; doi:10.1016/j.phrs. 2022.106631 .
• Conti Filho CE, et al. Advances in Alzheimer's disease's pharmacological treatment. Frontiers in Pharmacology. 2023; doi:10.3389/fphar. 2023.1101452 .
• Potter H, et al. Safety and efficacy of sargramostim (GM-CSF) in the treatment of Alzheimer's disease. Alzheimer's and Dementia. 2021; doi:10.1002/trc2.12158.
• Zhong H, et al. Effect of peroxisome proliferator-activated receptor-gamma agonists on cognitive function: A systematic review and meta-analysis. Biomedicines. 2023; doi:10.3390/biomedicines11020246.
• Grodstein F. Estrogen and cognitive function. https://www.uptodate.com/contents/search. Accessed March 23, 2023.
• Mills ZB, et al. Is hormone replacement therapy a risk factor or a therapeutic option for Alzheimer's disease? International Journal of Molecular Sciences. 2023; doi:10.3390/ijms24043205.
• Custodia A, et al. Biomarkers assessing endothelial dysfunction in Alzheimer's disease. Cells. 2023; doi:10.3390/cells12060962.
• Overview. Critical Path for Alzheimer's Disease. https://c-path.org/programs/cpad/. Accessed March 29, 2023.
• Shi M, et al. Impact of anti-amyloid-β monoclonal antibodies on the pathology and clinical profile of Alzheimer's disease: A focus on aducanumab and lecanemab. Frontiers in Aging and Neuroscience. 2022; doi:10.3389/fnagi. 2022.870517 .
• Leqembi (approval letter). Biologic License Application 761269. U.S. Food and Drug Administration. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=761269. Accessed July 7, 2023.
• Van Dyck CH, et al. Lecanemab in early Alzheimer's disease. New England Journal of Medicine. 2023; doi:10.1056/NEJMoa2212948.
• Leqembi (prescribing information). Eisai; 2023. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=761269. Accessed July 10, 2023.

Products and Services

• A Book: Mayo Clinic on Alzheimer's Disease
• Assortment of Products for Independent Living from Mayo Clinic Store
• A Book: Day to Day: Living With Dementia
• A Book: Mayo Clinic on Healthy Aging
• Give today to find Alzheimer's cures for tomorrow
• Alzheimer's sleep problems
• Alzheimer's 101
• Understanding the difference between dementia types
• Alzheimer's disease
• Alzheimer's genes
• Alzheimer's drugs
• Alzheimer's prevention: Does it exist?
• Alzheimer's stages
• Antidepressant withdrawal: Is there such a thing?
• Antidepressants and alcohol: What's the concern?
• Antidepressants and weight gain: What causes it?
• Antidepressants: Can they stop working?
• Antidepressants: Side effects
• Antidepressants: Selecting one that's right for you
• Antidepressants: Which cause the fewest sexual side effects?
• Anxiety disorders
• Atypical antidepressants
• Caregiver stress
• Clinical depression: What does that mean?
• Corticobasal degeneration (corticobasal syndrome)
• Depression and anxiety: Can I have both?
• Depression, anxiety and exercise
• What is depression? A Mayo Clinic expert explains.
• Depression in women: Understanding the gender gap
• Depression (major depressive disorder)
• Depression: Supporting a family member or friend
• Diagnosing Alzheimer's
• Did the definition of Alzheimer's disease change?
• How your brain works
• Intermittent fasting
• Lecanemab for Alzheimer's disease
• Male depression: Understanding the issues
• MAOIs and diet: Is it necessary to restrict tyramine?
• Marijuana and depression
• Mayo Clinic Minute: 3 tips to reduce your risk of Alzheimer's disease
• Mayo Clinic Minute: Alzheimer's disease risk and lifestyle
• Mayo Clinic Minute: New definition of Alzheimer's changes
• Mayo Clinic Minute: Women and Alzheimer's Disease
• Memory loss: When to seek help
• Monoamine oxidase inhibitors (MAOIs)
• Natural remedies for depression: Are they effective?
• Nervous breakdown: What does it mean?
• New Alzheimers Research
• Pain and depression: Is there a link?
• Phantosmia: What causes olfactory hallucinations?
• Positron emission tomography scan
• Posterior cortical atrophy
• Seeing inside the heart with MRI
• Selective serotonin reuptake inhibitors (SSRIs)
• Serotonin and norepinephrine reuptake inhibitors (SNRIs)
• Sundowning: Late-day confusion
• Treatment-resistant depression
• Tricyclic antidepressants and tetracyclic antidepressants
• Video: Alzheimer's drug shows early promise
• Vitamin B-12 and depression
• Young-onset Alzheimer's

Mayo Clinic does not endorse companies or products. Advertising revenue supports our not-for-profit mission.

• Opportunities

Mayo Clinic Press

Check out these best-sellers and special offers on books and newsletters from Mayo Clinic Press .

• Mayo Clinic on Incontinence - Mayo Clinic Press Mayo Clinic on Incontinence
• The Essential Diabetes Book - Mayo Clinic Press The Essential Diabetes Book
• Mayo Clinic on Hearing and Balance - Mayo Clinic Press Mayo Clinic on Hearing and Balance
• FREE Mayo Clinic Diet Assessment - Mayo Clinic Press FREE Mayo Clinic Diet Assessment
• Mayo Clinic Health Letter - FREE book - Mayo Clinic Press Mayo Clinic Health Letter - FREE book
• Alzheimer s treatments What s on the horizon

Your gift holds great power – donate today!

Make your tax-deductible gift and be a part of the cutting-edge research and care that's changing medicine.

MIT Technology Review

• Newsletters

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.

• Anne Trafton archive page

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. 

Keep Reading

Most popular, how scientists traced a mysterious covid case back to six toilets.

When wastewater surveillance turns into a hunt for a single infected individual, the ethics get tricky.

• Cassandra Willyard archive page

It’s time to retire the term “user”

The proliferation of AI means we need a new word.

• Taylor Majewski archive page

The problem with plug-in hybrids? Their drivers.

Plug-in hybrids are often sold as a transition to EVs, but new data from Europe shows we’re still underestimating the emissions they produce.

• Casey Crownhart archive page

Sam Altman says helpful agents are poised to become AI’s killer function

Open AI’s CEO says we won’t need new hardware or lots more training data to get there.

• James O'Donnell archive page

Stay connected

Get the latest updates from mit technology review.

Discover special offers, top stories, upcoming events, and more.

Thank you for submitting your email!

It looks like something went wrong.

We’re having trouble saving your preferences. Try refreshing this page and updating them one more time. If you continue to get this message, reach out to us at [email protected] with a list of newsletters you’d like to receive.

Featured Topics

Featured series.

A series of random questions answered by Harvard experts.

Explore the Gazette

Read the latest.

How do you read organization’s silence over rise of Nazism?

Got milk? Does it give you problems?

Cancer risk, wine preference, and your genes

Start of new era for alzheimer’s treatment.

Alvin Powell

Harvard Staff Writer

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?

More like this

Newly identified genetic variant protects against Alzheimer’s

Using AI to target Alzheimer’s

Excessive napping and Alzheimer’s linked in study

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.

Share this article

You might like.

Medical historians look to cultural context, work of peer publications in wrestling with case of New England Journal of Medicine

Biomolecular archaeologist looks at why most of world’s population has trouble digesting beverage that helped shape civilization

Biologist separates reality of science from the claims of profiling firms

Epic science inside a cubic millimeter of brain

Researchers publish largest-ever dataset of neural connections

Finding right mix on campus speech policies

Legal, political scholars discuss balancing personal safety, constitutional rights, academic freedom amid roiling protests, cultural shifts

Good genes are nice, but joy is better

Harvard study, almost 80 years old, has proved that embracing community helps us live longer, and be happier

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

BY CARRIE MACMILLAN July 24, 2023

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

[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.

More news from Yale Medicine

• International edition
• Australia edition
• Europe edition

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.”

• Alzheimer's
• Pharmaceuticals industry

Most viewed

Suggestions or feedback?

MIT News | Massachusetts Institute of Technology

• Machine learning
• Social justice
• Black holes
• Classes and programs

Departments

• Aeronautics and Astronautics
• Brain and Cognitive Sciences
• Architecture
• Political Science
• Mechanical Engineering

Centers, Labs, & Programs

• Abdul Latif Jameel Poverty Action Lab (J-PAL)
• Picower Institute for Learning and Memory
• Lincoln Laboratory
• School of Architecture + Planning
• School of Engineering
• School of Humanities, Arts, and Social Sciences
• Sloan School of Management
• School of Science
• MIT Schwarzman College of Computing

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

Press contact :, media download.

*Terms of Use:

Images for download on the MIT News office website are made available to non-commercial entities, press and the general public under a Creative Commons Attribution Non-Commercial No Derivatives license . You may not alter the images provided, other than to crop them to size. A credit line must be used when reproducing images; if one is not provided below, credit the images to "MIT."

Previous image Next image

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.

Share this news article on:

Press mentions, new york post.

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.

Previous item Next item

Related Links

• Li-Huei Tsai
• Department of Brain and Cognitive Sciences

Related Topics

• Neuroscience
• Alzheimer's
• Brain and cognitive sciences
• Picower Institute
• National Institutes of Health (NIH)

Related Articles

Study links gene to cognitive resilience in the elderly

Study offers an explanation for why the APOE4 gene enhances Alzheimer’s risk

Neuroscientists discover roles of gene linked to Alzheimer’s

Unique visual stimulation may be new treatment for Alzheimer’s

More mit news.

Janabel Xia: Algorithms, dance rhythms, and the drive to succeed

Read full story →

Jonathan Byrnes, MIT Center for Transportation and Logistics senior lecturer and visionary in supply chain management, dies at 75

Researchers develop a detector for continuously monitoring toxic gases

The beauty of biology

Navigating longevity with industry leaders at MIT AgeLab PLAN Forum

Jeong Min Park earns 2024 Schmidt Science Fellowship

• More news on MIT News homepage →

Massachusetts Institute of Technology 77 Massachusetts Avenue, Cambridge, MA, USA

• Map (opens in new window)
• Events (opens in new window)
• People (opens in new window)
• Careers (opens in new window)
• Accessibility
• Social Media Hub
• MIT on Facebook
• MIT on YouTube
• MIT on Instagram

• May 18, 2024 | Discover How MIT’s SuperLimbs Help Astronauts Stand Tall on the Moon
• May 18, 2024 | Toxic Downpour: “Forever Chemicals” Rain on All Five Great Lakes
• May 18, 2024 | New UCLA Research Reveals That Practice Significantly Rewires the Brain
• May 18, 2024 | Scientists Discover Potential Opioid Replacement for Back Pain
• May 18, 2024 | Termites on Tour: How Climate Change Is Bringing Pests to Your Doorstep

Redefining Dementia Treatment: Berkeley Scientists Unveil Promising New Breakthrough

By University of California - Berkeley February 28, 2024

An illustration of a brain cell in a person with Alzheimer’s disease, showing the accumulation and clumping of tau proteins (blue squiggles) in the cytoplasm of a brain cell. Protein clumps, also known as aggregates, are thought to lead to cell death and dementia. New research suggests that such clumps may not cause brain cell death directly, but rather throw the cell’s response to stress off balance so that it never gets switched off. Credit: National Institute on Aging, National Institutes of Health

Research from UC Berkeley indicates that ongoing stress caused by protein aggregation is leading to the death of brain cells.

Numerous neurodegenerative conditions, including Alzheimer’s and Parkinson’s, involve the buildup of protein clusters, known as aggregates, within the brain. This phenomenon has prompted researchers to hypothesize that these protein masses are responsible for the death of brain cells. Despite this, efforts to develop treatments that break up and remove these tangled proteins have had little success.

But a new discovery by University of California, Berkeley , researchers suggests that the accumulation of aggregated proteins isn’t what kills brain cells. Rather, it’s the body’s failure to turn off these cells’ stress response.

In a study recently published in the journal Nature , the researchers reported that delivering a drug that forces the stress response to shut down saves cells that mimic a type of neurodegenerative disease known as early-onset dementia.

The Role of the SIFI Complex in Neurodegeneration

According to lead researcher Michael Rapé, the finding could offer clinicians another option for treatment for some neurodegenerative diseases, at least for those caused by mutations in the protein that switches off the cellular stress response. These include inherited diseases that lead to ataxia, or loss of muscle control, and early-onset dementia.

In addition, Rapé noted that other neurodegenerative diseases, including Mohr–Tranebjærg syndrome, childhood ataxia, and Leigh syndrome, are also characterized by stress responses in overdrive and have symptoms similar to those of the early onset dementia mimicked in the new study.

“We always thought that protein clumps directly kill neurons, for example by puncturing membrane structures within these cells. Yet, we now found that aggregates prevent the silencing of a stress response that cells originally mount to cope with bad proteins. The stress response is always on, and that’s what kills the cells,” said Rapé, head of the new division of molecular therapeutics in UC Berkeley’s Department of Molecular and Cell Biology and a Howard Hughes Medical Institute investigator. “We think that the same mechanisms may underlie more common pathologies that also show widespread aggregation, such as Alzheimer’s disease or frontotemporal dementia, but more work is needed to investigate the role of stress signaling in these diseases.”

Key to the discoveries by Rapé’s lab was the researchers’ finding that stress responses need to be turned off once a brain cell has successfully addressed a difficult situation. Rapé explained this finding to his son in simple terms: You not only need to clean up your room, but also turn out the light before going to bed. If you don’t turn off the light, you can’t fall asleep, but if you turn it off before you cleaned up your room, you would stumble if you had to get up in the dark.

Similarly, a cell has to clean up protein aggregates before turning off the stress response. If it doesn’t turn off the stress response, the cell will ultimately die.

“Aggregates don’t kill cells directly. They kill cells because they keep the light on,” he said. “But that means that you can treat these diseases, or at least the dozen or so neurodegenerative diseases that we found have kept their stress responses on. You treat them with an inhibitor that turns off the light. You don’t have to worry about completely getting rid of large aggregates, which changes how we think about treating neurodegenerative diseases. And most importantly, it makes this really doable.”

In their paper, Rapé and his colleagues describe a very large protein complex they discovered called SIFI (SIlencing Factor of the Integrated stress response). This machine serves two purposes: It cleans up aggregates and, afterward, turns off the stress response triggered by the aggregated proteins. The stress response controlled by SIFI is switched on to deal with specific intracellular problems — the abnormal accumulation of proteins that end up at the wrong location in the cell. If components of SIFI are mutated, the cell will accumulate protein clumps and experience an active stress response. But it is the stress response signaling that kills the cells.

“The SIFI complex would normally clear out the aggregating proteins. When there are aggregates around, SIFI is diverted from the stress response, and the signaling continues. When aggregates have been cleared — the room has been cleaned up before bedtime — then the SIFI is not diverted away anymore, and it can turn off the stress response,” he said. “Aggregates kind of hijack that natural stress response-silencing mechanism, interfere with it, stall it. And so that’s why silencing never happens when you have aggregates, and that’s why cells die.”

A future treatment, Rapé said, would likely involve the administration of a drug to turn off the stress response and a drug to keep SIFI turned on to clean up the aggregate mess.

Rapé, who is also the Dr. K. Peter Hirth Chair of Cancer Biology, studies the role of ubiquitin — a ubiquitous protein in the body that targets proteins for degradation — in regulating normal and disease processes in humans. In 2017, he discovered that a protein called UBR4 assembles a specific ubiquitin signal that was required for the elimination of proteins that tend to aggregate inside cells.

Only later did other researchers find that mutations in UBR4 are found in some inherited types of neurodegeneration. This discovery led Rapé to team up with colleagues at Stanford University to find out how UBR4 causes these diseases.

“This was a unique opportunity: We had an enzyme that makes an anti-aggregation signal, and when it’s mutated, it causes aggregation disease,” he said. “You put these two things together and you can say, ‘If you figure out how this UBR4 allows sustained cell survival, that probably tells you how aggregates kill cells.'”

They found that UBR4 is actually part of a much larger protein complex, which Rapé dubbed SIFI, and they found that this SIFI machinery was needed when a cell couldn’t sort proteins into its mitochondria. Such proteins that end up at the wrong location in cells tend to clump and, in turn, cause neurodegeneration.

“Surprisingly, though, we found that the core substrates of the SIFI complex were two proteins, one of which senses when proteins don’t make it into mitochondria. That protein detects that something is wrong, and it then activates a kinase that shuts down most of new protein synthesis as part of a stress response, giving the cell time to correct its problem with bringing proteins to the right location,” he said.

This kinase is also degraded through SIFI. A kinase is an enzyme that adds a phosphate group to another molecule, in this case, a protein, to regulate important activities in the cell. By helping degrade these two proteins, the SIFI complex turns off the stress response that is caused by clumpy proteins accumulating at the wrong location.

“That’s the very first time that we’ve seen a stress response turned off in an active manner by an enzyme — SIFI — that happens to be mutated in neurodegeneration,” Rapé said.

While investigating how SIFI can turn off the stress response at the right time — only after the room had been cleaned up — the researchers found that SIFI recognizes a short protein segment that acts as a kind of ZIP code that allows proteins or protein precursors to get into the mitochondria, where they are processed. When they are prevented from getting in, they accumulate in the cytoplasm, but SIFI homes in on that ZIP code to eliminate them. The ZIP code looks just like the light switch.

“When you have aggregates accumulating in the cytoplasm, now the ZIP code is still in the cytoplasm, and there’s a lot of it there,” he said. “And it’s the same signal as you would have in the proteins that you want to turn off. So it basically diverts the SIFI complex from the light switch back to the mess. SIFI tries to clean up the mess first, and it cannot turn off the light. And so when you have an aggregate in the cell, the light is always on. And if the light is always on, if stress signaling is always on, the cell will die. And that’s a problem.”

Implications for Treatment and Future Research

Rapé suspects that many intracellular protein aggregates characteristic of neurodegenerative diseases have similar consequences and may prevent the cell from switching off the stress response. If so, the fact that a drug can turn off the response and rescue brain cells bodes well for the development of treatments for potentially many neurodegenerative diseases.

Already, another stress response inhibitor, a drug called ISRIB discovered at UCSF in 2013, has been shown to improve memory in mice and reduce age-related cognitive decline.

“That means there is the prospect that by manipulating stress silencing, by turning off the light with chemicals, you might target other neurodegenerative diseases, as well,” he said. “At the very least, it’s another way we could help patients with these diseases. In the best possible way, I think it will change how we treat neurodegenerative diseases. That’s why this is a really important story, why I think it’s very exciting.”

Rapé, already a co-founder of two startups, Nurix Therapeutics Inc., and Lyterian Therapeutics, is now looking to develop therapies to silence the stress response while maintaining the cell’s cleanup of protein aggregates.

Reference: “Stress response silencing by an E3 ligase mutated in neurodegeneration” by Diane L. Haakonsen, Michael Heider, Andrew J. Ingersoll, Kayla Vodehnal, Samuel R. Witus, Takeshi Uenaka, Marius Wernig and Michael Rapé, 31 January 2024, Nature . DOI: 10.1038/s41586-023-06985-7

Co-authors with Rapé are postdoctoral fellows Diane Haakonsen, Michael Heider, and Samuel Witus and graduate student Andrew Ingersoll, all of UC Berkeley, and Kayla Vodehnal, Takeshi Uenaka, and Marius Wernig of Stanford. The work was supported primarily by the Stinehart–Reed Foundation and the National Institutes of Health (RF1 AG048131, T32MH020016-25).

More on SciTechDaily

Precision and Peril: Stunning New Image of Intuitive Machines Odysseus Landing on Moon

Challenging “Rule Breakers” – Children Will Confront Their Peers, but How They Do So Varies Across Cultures

Climate change and extreme weather will have complex effects on infectious disease transmission.

“Unusual” Findings Overturn Current Battery Wisdom

600 Million-Year-Old Time Capsule – New Discoveries From the Himalayas Shed Light on Earth’s Past

Billion Year Old Surface Water Found in Oceanic Plates

Beware the Splice of Life: This Killer Protein Causes Pancreatic Cancer

Reviving Ancient Skills to Solve Prehistoric Puzzles

Be the first to comment on "redefining dementia treatment: berkeley scientists unveil promising new breakthrough", leave a comment cancel reply.

Email address is optional. If provided, your email will not be published or shared.

Save my name, email, and website in this browser for the next time I comment.

Call our 24 hours, seven days a week helpline at 800.272.3900

• Professionals

• Younger/Early-Onset Alzheimer's
• Is Alzheimer's Genetic?
• Women and Alzheimer's
• Creutzfeldt-Jakob Disease
• Dementia with Lewy Bodies
• Down Syndrome & Alzheimer's
• Frontotemporal Dementia
• Huntington's Disease
• Mixed Dementia
• Normal Pressure Hydrocephalus
• Posterior Cortical Atrophy
• Parkinson's Disease Dementia
• Vascular Dementia
• Korsakoff Syndrome
• Traumatic Brain Injury (TBI)
• Know the 10 Signs
• Difference Between Alzheimer's & Dementia
• 10 Steps to Approach Memory Concerns in Others
• Medical Tests for Diagnosing Alzheimer's
• Why Get Checked?
• Visiting Your Doctor
• Life After Diagnosis
• Stages of Alzheimer's
• Earlier Diagnosis
• Part the Cloud
• Research Momentum
• Our Commitment to Research
• TrialMatch: Find a Clinical Trial
• What Are Clinical Trials?
• How Clinical Trials Work
• When Clinical Trials End
• Why Participate?
• Talk to Your Doctor
• Clinical Trials: Myths vs. Facts
• Can Alzheimer's Disease Be Prevented?
• Brain Donation
• Navigating Treatment Options
• Lecanemab Approved for Treatment of Early Alzheimer's Disease
• Aducanumab Discontinued as Alzheimer's Treatment
• Medicare Treatment Coverage
• Donanemab for Treatment of Early Alzheimer's Disease — News Pending FDA Review
• Questions for Your Doctor
• Medications for Memory, Cognition and Dementia-Related Behaviors
• Treatments for Behavior
• Treatments for Sleep Changes
• Alternative Treatments
• Facts and Figures
• Assessing Symptoms and Seeking Help
• Now is the Best Time to Talk about Alzheimer's Together
• Get Educated
• Just Diagnosed
• Sharing Your Diagnosis
• Changes in Relationships
• If You Live Alone
• Treatments and Research
• Legal Planning
• Financial Planning
• Building a Care Team
• End-of-Life Planning
• Programs and Support
• Overcoming Stigma
• Younger-Onset Alzheimer's
• Taking Care of Yourself
• Reducing Stress
• Tips for Daily Life
• Helping Family and Friends
• Leaving Your Legacy
• Live Well Online Resources
• Make a Difference
• Daily Care Plan
• Communication and Alzheimer's
• Food and Eating
• Art and Music
• Incontinence
• Dressing and Grooming
• Dental Care
• Working With the Doctor
• Medication Safety
• Accepting the Diagnosis
• Early-Stage Caregiving
• Middle-Stage Caregiving
• Late-Stage Caregiving
• Aggression and Anger
• Anxiety and Agitation
• Hallucinations
• Memory Loss and Confusion
• Sleep Issues and Sundowning
• Suspicions and Delusions
• In-Home Care
• Adult Day Centers
• Long-Term Care
• Respite Care
• Hospice Care
• Choosing Care Providers
• Finding a Memory Care-Certified Nursing Home or Assisted Living Community
• Changing Care Providers
• Working with Care Providers
• Creating Your Care Team
• Long-Distance Caregiving
• Community Resource Finder
• Be a Healthy Caregiver
• Caregiver Stress
• Caregiver Stress Check
• Caregiver Depression
• Changes to Your Relationship
• Grief and Loss as Alzheimer's Progresses
• Home Safety
• Dementia and Driving
• Technology 101
• Preparing for Emergencies
• Managing Money Online Program
• Planning for Care Costs
• Paying for Care
• Health Care Appeals for People with Alzheimer's and Other Dementias
• Social Security Disability
• Medicare Part D Benefits
• Tax Deductions and Credits
• Planning Ahead for Legal Matters
• Legal Documents
• ALZ Talks Virtual Events
• ALZNavigator™
• Veterans and Dementia
• The Knight Family Dementia Care Coordination Initiative
• Online Tools
• Asian Americans and Pacific Islanders and Alzheimer's
• Native Americans and Alzheimer's
• Black Americans and Alzheimer's
• Hispanic Americans and Alzheimer's
• LGBTQ+ Community Resources for Dementia
• Educational Programs and Dementia Care Resources
• Brain Facts
• 50 Activities
• For Parents and Teachers
• Resolving Family Conflicts
• Holiday Gift Guide for Caregivers and People Living with Dementia
• Trajectory Report
• Resource Lists
• Search Databases
• Publications
• Favorite Links
• 10 Healthy Habits for Your Brain
• Stay Physically Active
• Adopt a Healthy Diet
• Stay Mentally and Socially Active
• Online Community
• Support Groups
• Find Your Local Chapter
• Any Given Moment
• New IDEAS Study
• Bruce T. Lamb, Ph.D., Chair
• Christopher van Dyck, M.D.
• Cynthia Lemere, Ph.D.
• David Knopman, M.D.
• Lee A. Jennings, M.D. MSHS
• Karen Bell, M.D.
• Lea Grinberg, M.D., Ph.D.
• Malú Tansey, Ph.D.
• Mary Sano, Ph.D.
• Oscar Lopez, M.D.
• Suzanne Craft, Ph.D.
• RFI Amyloid PET Depletion Following Treatment
• About Our Grants
• Andrew Kiselica, Ph.D., ABPP-CN
• Arjun Masurkar, M.D., Ph.D.
• Benjamin Combs, Ph.D.
• Charles DeCarli, M.D.
• Damian Holsinger, Ph.D.
• David Soleimani-Meigooni, Ph.D.
• Donna M. Wilcock, Ph.D.
• Elizabeth Head, M.A, Ph.D.
• Fan Fan, M.D.
• Fayron Epps, Ph.D., R.N.
• Ganesh Babulal, Ph.D., OTD
• Hui Zheng, Ph.D.
• Jason D. Flatt, Ph.D., MPH
• Jennifer Manly, Ph.D.
• Joanna Jankowsky, Ph.D.
• Luis Medina, Ph.D.
• Marcello D’Amelio, Ph.D.
• Marcia N. Gordon, Ph.D.
• Margaret Pericak-Vance, Ph.D.
• María Llorens-Martín, Ph.D.
• Nancy Hodgson, Ph.D.
• Shana D. Stites, Psy.D., M.A., M.S.
• Walter Swardfager, Ph.D.
• ALZ WW-FNFP Grant
• Capacity Building in International Dementia Research Program
• ISTAART IGPCC
• Alzheimer’s Disease Strategic Fund: Endolysosomal Activity in Alzheimer’s (E2A) Grant Program
• Imaging Research in Alzheimer’s and Other Neurodegenerative Diseases
• Zenith Fellow Awards
• National Academy of Neuropsychology & Alzheimer’s Association Funding Opportunity
• Part the Cloud-Gates Partnership Grant Program: Bioenergetics and Inflammation
• Pilot Awards for Global Brain Health Leaders (Invitation Only)
• Robert W. Katzman, M.D., Clinical Research Training Scholarship
• Funded Studies
• How to Apply
• Portfolio Summaries
• Supporting Research in Health Disparities, Policy and Ethics in Alzheimer’s Disease and Dementia Research (HPE-ADRD)
• Diagnostic Criteria & Guidelines
• Annual Conference: AAIC
• Professional Society: ISTAART
• Alzheimer's & Dementia
• Alzheimer's & Dementia: DADM
• Alzheimer's & Dementia: TRCI
• International Network to Study SARS-CoV-2 Impact on Behavior and Cognition
• Alzheimer’s Association Business Consortium (AABC)
• Global Biomarker Standardization Consortium (GBSC)
• Global Alzheimer’s Association Interactive Network
• International Alzheimer's Disease Research Portfolio
• Alzheimer’s Disease Neuroimaging Initiative Private Partner Scientific Board (ADNI-PPSB)
• Research Roundtable
• About WW-ADNI
• North American ADNI
• European ADNI
• Australia ADNI
• Taiwan ADNI
• Argentina ADNI
• WW-ADNI Meetings
• Submit Study
• RFI Inclusive Language Guide
• Scientific Conferences
• AUC for Amyloid and Tau PET Imaging
• Make a Donation
• Walk to End Alzheimer's
• The Longest Day
• RivALZ to End ALZ
• Ride to End ALZ
• Tribute Pages
• Gift Options to Meet Your Goals
• Founders Society
• Fred Bernhardt
• Anjanette Kichline
• Lori A. Jacobson
• Pam and Bill Russell
• Gina Adelman
• Franz and Christa Boetsch
• Adrienne Edelstein
• For Professional Advisors
• Free Planning Guides
• Contact the Planned Giving Staff
• Workplace Giving
• Do Good to End ALZ
• Donate a Vehicle
• Donate Stock
• Donate Cryptocurrency
• Donate Gold & Sterling Silver
• Donor-Advised Funds
• Use of Funds
• Giving Societies
• Why We Advocate
• Ambassador Program
• About the Alzheimer’s Impact Movement
• Research Funding
• Improving Care
• Support for People Living With Dementia
• Public Policy Victories
• Planned Giving
• Community Educator
• Community Representative
• Support Group Facilitator or Mentor
• Faith Outreach Representative
• Early Stage Social Engagement Leaders
• Data Entry Volunteer
• Tech Support Volunteer
• Other Local Opportunities
• Visit the Program Volunteer Community to Learn More
• Become a Corporate Partner
• A Family Affair
• A Message from Elizabeth
• The Belin Family
• The Eliashar Family
• The Fremont Family
• The Freund Family
• Jeff and Randi Gillman
• Harold Matzner
• The Mendelson Family
• Patty and Arthur Newman
• The Ozer Family
• Salon Series
• No Shave November
• Other Philanthropic Activities
• Still Alice
• The Judy Fund E-blast Archive
• The Judy Fund in the News
• The Judy Fund Newsletter Archives
• Sigma Kappa Foundation
• Alpha Delta Kappa
• Parrot Heads in Paradise
• Tau Kappa Epsilon (TKE)
• Sigma Alpha Mu
• Alois Society Member Levels and Benefits
• Alois Society Member Resources
• Zenith Society
• Founder's Society
• Joel Berman
• JR and Emily Paterakis
• Legal Industry Leadership Council
• Accounting Industry Leadership Council

Find Local Resources

Let us connect you to professionals and support options near you. Please select an option below:

Use Current Location Use Map Selector

Search Alzheimer’s Association

As the largest nonprofit funder of Alzheimer's research, the Association is committed to accelerating the global progress of new treatments, preventions and, ultimately, a cure.

Information for Researchers

Research we fund, apply for a grant, find a clinical trial, efforts we lead, the first survivor of alzheimer's is out there, but we won't get there without you., learn how alzheimer’s disease affects the brain..

Take the Brain Tour

Don't just hope for a cure. Help us find one.

Keep up with alzheimer’s news and events.

• Skip to main content
• Keyboard shortcuts for audio player

• Your Health
• Treatments & Tests
• Health Inc.
• Public Health

Shots - Health News

Alzheimer's researchers are looking beyond plaques and tangles for new treatments.

Jon Hamilton

Scientists say research into Alzheimer's needs to take a broader view of how the disease affects the brain — whether that's changes in the cortex or the role of inflammation. Matt York/AP hide caption

Scientists say research into Alzheimer's needs to take a broader view of how the disease affects the brain — whether that's changes in the cortex or the role of inflammation.

The field of Alzheimer's research is branching out.

After decades of focusing on the sticky amyloid plaques and tangled tau fibers associated with the disease, brain researchers are searching for other potential causes of impaired memory and thinking.

That search is on full display this week at the Alzheimer's Association International Conference in San Diego, where sessions are exploring factors including genes, brain injury, clogged arteries and inflammation.

A group of researchers from Seattle even unveiled a highly detailed atlas showing how different types of brain cells change in Alzheimer's. The goal is to help scientists identify new approaches to treatment.

"Certainly, plaques and tangles are a hallmark," says Maria Carrillo , chief science officer of the Alzheimer's Association. "It doesn't mean plaques are the cause of cell death."

Plaques are clumps of a protein called beta-amyloid that appear in the spaces between neurons. Tangles are made up of a protein called tau that appears inside a neuron.

Both proteins tend to accumulate in the brains of people with Alzheimer's. But their role in killing brain cells is still unclear.

Carrillo says the Alzheimer's field needs to look to cancer research where a deeper understanding of the disease has led to better treatments.

The shift comes after a series of experimental drugs have succeeded in removing amyloid plaques and tau tangles from the brain, but failed to halt the disease.

The Food and Drug Administration has approved one amyloid drug, Aduhelm, but is still evaluating whether it actually helps patients.

An Alzheimer's Atlas

The study that produced the atlas is emblematic of how researchers are recalibrating.

"What we're trying to do with this study is to look at cell vulnerability early on in disease, before [people] have plaques and tangles, before they have cognitive impairment," says Dr. C. Dirk Keene , a neuropathologist at the University of Washington.

To create the atlas, Keene and a team of researches analyzed more than a million cells from 84 brains donated by people who'd signed up for Alzheimer's research projects run by the University of Washington and Kaiser Permanente Washington Research Institute.

The brains came from donors "at all different stages of disease" Keene says, "so we can pinpoint what's happening from the earliest levels all the way through to people with advanced disease."

The effort is funded by the National Institute on Aging and grew out of the federal BRAIN initiative launched by President Obama in 2013.

The atlas came from the realization that "If we want to treat diseases of an extremely complex cellular organ, you need to understand that organ much better than we do," says Ed Lein , a senior investigator at the Allen Institute for Brain Science, which played a key role in analyzing the brain tissue.

So the team spent years studying cells in healthy brains before looking at brains affected by Alzheimer's.

"We've defined what a normal adult brain looks like," Lein says, "and now we can use that knowledge and look for changes that are happening in specific kinds of cells."

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

Finding vulnerable brain cells.

At the Alzheimer's meeting, the team described changes they saw in more than 100 types of cells taken from the cortex — an area of the brain which is important to memory and thinking.

One finding was that neurons that make connections within the cortex itself were much more likely to die than those that connect to distant areas of the brain.

"What we're seeing is a profound effect on cortical circuitry that very plausibly is the reason we have cognitive decline," Lein says.

If so, a treatment designed to protect those vulnerable neurons might prevent declines in memory and thinking linked to Alzheimer's.

The team also found a proliferation of brain cells that contribute to inflammation. These included certain immune cells and a type of cell that responds to injury.

"So while the neurons are lost, the non-neuronal cells are actually increasing and changing" Lein says.

The finding supports the idea that inflammation plays an important role in Alzheimer's, and that anti-inflammatory drugs might help protect the brain.

The Seattle team hopes other scientists will use the brain cell atlas to come up with new treatments for Alzheimer's.

"We've created an open-access resource where the whole community can come and look at this data," Lein says. "They can mine it to speed up progress in the field as a whole."

Speeding up progress is one reason Kyle Travaglini , a researcher at the Allen Institute, jumped at the chance to work on the Alzheimer's project.

"My grandmother started developing Alzheimer's disease when I was just going off to college," says Travaglini, who received his PhD in 2021.

Travaglini says the atlas project is appealing because it isn't based on a preconceived idea about what causes Alzheimer's.

"It's like looking at the same disease that everyone has been looking at but in an entirely different way," he says.

A substance found in young spinal fluid helps old mice remember

Scientists look to people with Down syndrome to test Alzheimer's drugs

New class of Alzheimer's drugs showing promise in patients in early stage of disease

For decades scientists and families have been frustrated by the intractable nature of Alzheimer's disease.

Key points:

• A study showed donanemab could slow Alzheimer's disease progression by 35pc in patients in the earliest stages of the disease
• Geriatrician Michael Woodward says the medical community is excited by the results
• The donanemab study findings were similar to those of its predecessor lecanemab

As the population ages and more people develop the devastating condition, there have been no new treatments coming onto the market and for many, no hope in sight.

That was until two years ago.

In a short time, decades of research has started to come to fruition, with at least three new drugs demonstrating the first glimmers of promise.

The latest is called donanemab, with the findings of a global trial involving 1,700 patients presented at a major Alzheimer's conference in The Netherlands.

Sixteen Australians took part in the trial at eight sites in Victoria and New South Wales.

The drug, from pharmaceutical giant Eli Lilly, was able to slow Alzheimer's disease progression by 35 per cent in patients in the earliest stages of the disease.

Across the whole study, there was a 22 per cent slowdown in the disease's progress at the 18-month mark.

Michael Woodward, a geriatrician who has been involved in Alzheimer's research for decades, was at the Alzheimer's conference and said the medical community was excited by the results.

"I would regard this as the end of the beginning in Alzheimer's therapies," he said.

"The word breakthrough is used perhaps a little too often, but this is a major breakthrough.

"We now have three drugs that have been shown that can critically slow down the decline."

How does the new drug work?

Donanemab is a monoclonal antibody designed to clear the brain of amyloid plaque, which experts believe plays a role in Alzheimer's disease.

Researchers have long been trying to work out whether a protein called beta-amyloid plaque (BAP) or another protein called tau is responsible for Alzheimer's, or a combination of the two.

Those in the study were all in the early stages of Alzheimer's and aged between 60 and 85.

At the 12-month mark, the researchers said 47 per cent had no evidence of amyloid plaques, compared with 29 per cent in the placebo group.

Patients also did not need indefinite treatment, with injections being able to reduce amyloid to non-existent levels where they would not re-accumulate for many years.

Stephen Macfarlane had three patients in the study through his work with The Dementia Centre at HammondCare in Victoria.

He said the medication was the equivalent of slowing the rate of the disease by seven and a half months compared to someone who was not taking it.

"These drugs slow the progression of the disease, they don't cause people to improve," Dr Macfarlane said.

He said it was the most promising drug in two decades for Alzheimer's research.

"It's the most effective, and the safety data seems to be on a par with similar drugs," he said.

The findings show there was a risk of brain bleeding and swelling in a subset of patients, including 1.6 per cent of participants who experienced serious forms, and three who died.

"Bearing in mind that Alzheimer's disease is a fatal and otherwise untreatable illness, some degree of risk is inherent in the process," Dr Macfarlane said.

Drug follows on heels of another, lecanemab

The donanemab study findings were similar to those of its predecessor lecanemab, sold under the brand name Leqembi.

It reduced cognitive decline by 27 per cent in patients with early Alzheimer's in a study published last year.

Lou Coenen is among the Australian patients in a lecanemab trial.

This drug from Japanese drug maker Eisa is being tested in four trials that include Australian sites across 18 locations.

The 72-year-old was diagnosed with Alzheimer's about five years ago and had a family history of the disease.

"You just start feeling your thinking doesn't work quite as fast," Mr Coenen said.

"You start to wonder why."

He decided to take part in a clinical trial of lecanemab through the KaRa Institute of Neurological Diseases to help give back to the health community.

He says he does notice a difference on the medication.

It is allowing him to spend more time with his wife and family and still participate in community activities such as The Men's Shed.

"I know compared to other people this is working," he said. "But I don't have a comparative of another me that says otherwise."

On June 30 Australia's Therapeutic Goods Administration (TGA) started work to consider approving lecanemab in Australia.

This drug has shown similar results to donanemab in patients with early Alzheimer's but also comes with risks of brain swelling and bleeding in a small subset of patients.

How much will it cost?

New Alzheimer's drugs to the market are predicted to be hugely expensive for governments because of the significant time and cost they took to develop.

Leqembi is priced at about $US26,500 ($39,974) for a year's supply of infusions every two weeks but there is no potential price for donanemab yet, which will involve monthly injections.

"That's going to be a big challenge," Dr Woodward said.

"But we've got to look also at the savings. The total cost of care for Alzheimer's disease is probably closer to about $6-7 billion per year in Australia."

Dr Macfarlane said the drug would also mean Australia would need to revamp its Alzheimer's infrastructure so PET scans were more available for early diagnoses, regular hospital infusions were easier to access, and patients were diagnosed much sooner.

"We know in Australia that on average there's about a three-year delay between people first experiencing symptoms of memory loss and actually receiving a diagnosis," he said.

Biogen drug caused controversy

The drugs follow the groundbreaking but controversial release of Biogen's Aducanumab in 2021.

It is another monoclonal antibody that also works by removing the build-up of amyloid plaque proteins.

It was controversial because of the way the research was structured and the pharmaceutical company's relationship with US regulators.

In June this year the Therapeutic Goods Administration found the drug did not meet its safety and efficacy requirements for approval in Australia and Biogen withdrew its application.

Latest findings bring hope for patients

For Melbourne grandmother Jan Cody, the first sign she knew her memory was failing was when her three children met to discuss her declining mental state.

The 75-year-old had to give up her work as a psychologist, as well as cooking and driving.

"My world just shrank. There's really no medication to take," she said.

She has been involved in some Alzheimer's trials but was not eligible for donanemab.

"The slowing it down takes a long time," she said. "So one really doesn't know whether you're going to last."

"But now I do have a glimmer of hope."

• X (formerly Twitter)

Related Stories

Promising alzheimer's drug gets green light in us as australia evaluates application.

US regulators have approved the first Alzheimer's drug in two decades. And it's creating controversy

• Alzheimer's and Dementia
• Brain and Nervous System
• Diseases and Disorders
• Health Policy
• Medical Research
• Netherlands
• Pharmaceuticals
• United States

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

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

.chakra .wef-1c7l3mo{-webkit-transition:all 0.15s ease-out;transition:all 0.15s ease-out;cursor:pointer;-webkit-text-decoration:none;text-decoration:none;outline:none;color:inherit;}.chakra .wef-1c7l3mo:hover,.chakra .wef-1c7l3mo[data-hover]{-webkit-text-decoration:underline;text-decoration:underline;}.chakra .wef-1c7l3mo:focus,.chakra .wef-1c7l3mo[data-focus]{box-shadow:0 0 0 3px rgba(168,203,251,0.5);} Charlotte Edmond

.chakra .wef-9dduvl{margin-top:16px;margin-bottom:16px;line-height:1.388;font-size:1.25rem;}@media screen and (min-width:56.5rem){.chakra .wef-9dduvl{font-size:1.125rem;}} Explore and monitor how .chakra .wef-15eoq1r{margin-top:16px;margin-bottom:16px;line-height:1.388;font-size:1.25rem;color:#F7DB5E;}@media screen and (min-width:56.5rem){.chakra .wef-15eoq1r{font-size:1.125rem;}} Global Health is affecting economies, industries and global issues

.chakra .wef-1nk5u5d{margin-top:16px;margin-bottom:16px;line-height:1.388;color:#2846F8;font-size:1.25rem;}@media screen and (min-width:56.5rem){.chakra .wef-1nk5u5d{font-size:1.125rem;}} Get involved with our crowdsourced digital platform to deliver impact at scale

Stay up to date:, global health.

Listen to the article

• 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.

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 .

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.

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.

Have you read?

Here’s how exercise alters our brain chemistry – and could prevent dementia, dementia cases are expected to double in many countries over the next 30 years, these 7 simple habits could halve your risk of dementia, don't miss any update on this topic.

Create a free account and access your personalized content collection with our latest publications and analyses.

License and Republishing

World Economic Forum articles may be republished in accordance with the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International Public License, and in accordance with our Terms of Use.

The views expressed in this article are those of the author alone and not the World Economic Forum.

Related topics:

The agenda .chakra .wef-n7bacu{margin-top:16px;margin-bottom:16px;line-height:1.388;font-weight:400;} weekly.

A weekly update of the most important issues driving the global agenda

.chakra .wef-1dtnjt5{display:-webkit-box;display:-webkit-flex;display:-ms-flexbox;display:flex;-webkit-align-items:center;-webkit-box-align:center;-ms-flex-align:center;align-items:center;-webkit-flex-wrap:wrap;-ms-flex-wrap:wrap;flex-wrap:wrap;} More on Wellbeing and Mental Health .chakra .wef-nr1rr4{display:-webkit-inline-box;display:-webkit-inline-flex;display:-ms-inline-flexbox;display:inline-flex;white-space:normal;vertical-align:middle;text-transform:uppercase;font-size:0.75rem;border-radius:0.25rem;font-weight:700;-webkit-align-items:center;-webkit-box-align:center;-ms-flex-align:center;align-items:center;line-height:1.2;-webkit-letter-spacing:1.25px;-moz-letter-spacing:1.25px;-ms-letter-spacing:1.25px;letter-spacing:1.25px;background:none;padding:0px;color:#B3B3B3;-webkit-box-decoration-break:clone;box-decoration-break:clone;-webkit-box-decoration-break:clone;}@media screen and (min-width:37.5rem){.chakra .wef-nr1rr4{font-size:0.875rem;}}@media screen and (min-width:56.5rem){.chakra .wef-nr1rr4{font-size:1rem;}} See all

The fascinating link between biodiversity and mental wellbeing

Andrea Mechelli

May 15, 2024

How philanthropy is empowering India's mental health sector

Kiran Mazumdar-Shaw

May 2, 2024

From 'Quit-Tok' to proximity bias, here are 11 buzzwords from the world of hybrid work

Kate Whiting

April 17, 2024

Young people are becoming unhappier, a new report finds

Promoting healthy habit formation is key to improving public health. Here's why

Adrian Gore

April 15, 2024

What's 'biophilic design' and how can it benefit neurodivergent people?

Fatemeh Aminpour, Ilan Katz and Jennifer Skattebol

• Share full article

Advertisement

Supported by

Study Suggests Genetics as a Cause, Not Just a Risk, for Some Alzheimer’s

People with two copies of the gene variant APOE4 are almost certain to get Alzheimer’s, say researchers, who proposed a framework under which such patients could be diagnosed years before symptoms.

By Pam Belluck

Scientists are proposing a new way of understanding the genetics of Alzheimer’s that would mean that up to a fifth of patients would be considered to have a genetically caused form of the disease.

Currently, the vast majority of Alzheimer’s cases do not have a clearly identified cause. The new designation, proposed in a study published Monday, could broaden the scope of efforts to develop treatments, including gene therapy, and affect the design of clinical trials.

It could also mean that hundreds of thousands of people in the United States alone could, if they chose, receive a diagnosis of Alzheimer’s before developing any symptoms of cognitive decline, although there currently are no treatments for people at that stage.

The new classification would make this type of Alzheimer’s one of the most common genetic disorders in the world, medical experts said.

“This reconceptualization that we’re proposing affects not a small minority of people,” said Dr. Juan Fortea, an author of the study and the director of the Sant Pau Memory Unit in Barcelona, Spain. “Sometimes we say that we don’t know the cause of Alzheimer’s disease,” but, he said, this would mean that about 15 to 20 percent of cases “can be tracked back to a cause, and the cause is in the genes.”

The idea involves a gene variant called APOE4. Scientists have long known that inheriting one copy of the variant increases the risk of developing Alzheimer’s, and that people with two copies, inherited from each parent, have vastly increased risk.

The new study , published in the journal Nature Medicine, analyzed data from over 500 people with two copies of APOE4, a significantly larger pool than in previous studies. The researchers found that almost all of those patients developed the biological pathology of Alzheimer’s, and the authors say that two copies of APOE4 should now be considered a cause of Alzheimer’s — not simply a risk factor.

The patients also developed Alzheimer’s pathology relatively young, the study found. By age 55, over 95 percent had biological markers associated with the disease. By 65, almost all had abnormal levels of a protein called amyloid that forms plaques in the brain, a hallmark of Alzheimer’s. And many started developing symptoms of cognitive decline at age 65, younger than most people without the APOE4 variant.

“The critical thing is that these individuals are often symptomatic 10 years earlier than other forms of Alzheimer’s disease,” said Dr. Reisa Sperling, a neurologist at Mass General Brigham in Boston and an author of the study.

She added, “By the time they are picked up and clinically diagnosed, because they’re often younger, they have more pathology.”

People with two copies, known as APOE4 homozygotes, make up 2 to 3 percent of the general population, but are an estimated 15 to 20 percent of people with Alzheimer’s dementia, experts said. People with one copy make up about 15 to 25 percent of the general population, and about 50 percent of Alzheimer’s dementia patients.

The most common variant is called APOE3, which seems to have a neutral effect on Alzheimer’s risk. About 75 percent of the general population has one copy of APOE3, and more than half of the general population has two copies.

Alzheimer’s experts not involved in the study said classifying the two-copy condition as genetically determined Alzheimer’s could have significant implications, including encouraging drug development beyond the field’s recent major focus on treatments that target and reduce amyloid.

Dr. Samuel Gandy, an Alzheimer’s researcher at Mount Sinai in New York, who was not involved in the study, said that patients with two copies of APOE4 faced much higher safety risks from anti-amyloid drugs.

When the Food and Drug Administration approved the anti-amyloid drug Leqembi last year, it required a black-box warning on the label saying that the medication can cause “serious and life-threatening events” such as swelling and bleeding in the brain, especially for people with two copies of APOE4. Some treatment centers decided not to offer Leqembi, an intravenous infusion, to such patients.

Dr. Gandy and other experts said that classifying these patients as having a distinct genetic form of Alzheimer’s would galvanize interest in developing drugs that are safe and effective for them and add urgency to current efforts to prevent cognitive decline in people who do not yet have symptoms.

“Rather than say we have nothing for you, let’s look for a trial,” Dr. Gandy said, adding that such patients should be included in trials at younger ages, given how early their pathology starts.

Besides trying to develop drugs, some researchers are exploring gene editing to transform APOE4 into a variant called APOE2, which appears to protect against Alzheimer’s. Another gene-therapy approach being studied involves injecting APOE2 into patients’ brains.

The new study had some limitations, including a lack of diversity that might make the findings less generalizable. Most patients in the study had European ancestry. While two copies of APOE4 also greatly increase Alzheimer’s risk in other ethnicities, the risk levels differ, said Dr. Michael Greicius, a neurologist at Stanford University School of Medicine who was not involved in the research.

“One important argument against their interpretation is that the risk of Alzheimer’s disease in APOE4 homozygotes varies substantially across different genetic ancestries,” said Dr. Greicius, who cowrote a study that found that white people with two copies of APOE4 had 13 times the risk of white people with two copies of APOE3, while Black people with two copies of APOE4 had 6.5 times the risk of Black people with two copies of APOE3.

“This has critical implications when counseling patients about their ancestry-informed genetic risk for Alzheimer’s disease,” he said, “and it also speaks to some yet-to-be-discovered genetics and biology that presumably drive this massive difference in risk.”

Under the current genetic understanding of Alzheimer’s, less than 2 percent of cases are considered genetically caused. Some of those patients inherited a mutation in one of three genes and can develop symptoms as early as their 30s or 40s. Others are people with Down syndrome, who have three copies of a chromosome containing a protein that often leads to what is called Down syndrome-associated Alzheimer’s disease .

Dr. Sperling said the genetic alterations in those cases are believed to fuel buildup of amyloid, while APOE4 is believed to interfere with clearing amyloid buildup.

Under the researchers’ proposal, having one copy of APOE4 would continue to be considered a risk factor, not enough to cause Alzheimer’s, Dr. Fortea said. It is unusual for diseases to follow that genetic pattern, called “semidominance,” with two copies of a variant causing the disease, but one copy only increasing risk, experts said.

The new recommendation will prompt questions about whether people should get tested to determine if they have the APOE4 variant.

Dr. Greicius said that until there were treatments for people with two copies of APOE4 or trials of therapies to prevent them from developing dementia, “My recommendation is if you don’t have symptoms, you should definitely not figure out your APOE status.”

He added, “It will only cause grief at this point.”

Finding ways to help these patients cannot come soon enough, Dr. Sperling said, adding, “These individuals are desperate, they’ve seen it in both of their parents often and really need therapies.”

Pam Belluck is a health and science reporter, covering a range of subjects, including reproductive health, long Covid, brain science, neurological disorders, mental health and genetics. More about Pam Belluck

The Fight Against Alzheimer’s Disease

Alzheimer’s is the most common form of dementia, but much remains unknown about this daunting disease..

How is Alzheimer’s diagnosed? What causes Alzheimer’s? We answered some common questions .

A study suggests that genetics can be a cause of Alzheimer’s , not just a risk, raising the prospect of diagnosis years before symptoms appear.

Determining whether someone has Alzheimer’s usually requires an extended diagnostic process . But new criteria could lead to a diagnosis on the basis of a simple blood test .

The F.D.A. has given full approval to the Alzheimer’s drug Leqembi. Here is what to know about i t.

Alzheimer’s can make communicating difficult. We asked experts for tips on how to talk to someone with the disease .

Research Offers New Ideas for Treating Alzheimer’s

“out-of-the-clump,” mitochondrial, and other theories offer hope on alzheimer’s..

Posted May 17, 2024 | Reviewed by Tyler Woods

• What Is Dementia?
• Find counselling to help with dementia
• The need for a new "out-of-the-clump" way of thinking about AD is emerging as a top priority in brain science.
• In Alzheimer’s, the brain’s immune system fails to differentiate between bacteria and brain cells.
• Probiotics may not only support a healthier gut, but a healthier brain as well.
• For the elderly, in particular those with cognitive impairment, good oral hygiene is essential.

Dementia refers to an array of symptoms characterized by failing short-term memory , confused thinking, and a decline in language skills. Of all the dementias, Alzheimer’s disease (AD) constitutes approximately 60 to 80 percent of cases.

Two drugs, Lecanemab and Donanemab, have been hailed as part of a new class of monoclonal antibody (MOA) drugs that could mark a turning point for Alzheimer’s (AZ) drug research. These drugs are incredibly expensive and carry risks of brain microbleeds and swelling. More importantly, they do not cure or even halt the disease, they delay it by about six months on average. At least 98 unique compounds tested in Phase 2 or 3 trials that pursued the various MOA classes have failed over the years. Howard Chertow, of McGill University, commented, “They’re not a home run.”

Personally, I think they’re more like a strike-out, in view of the fact that most neuroscientists and the drug companies employed by them may be looking in the wrong places in the wrong way.

In 2006, a research paper published in the highly regarded journal Nature asserted that the development of Alzheimer’s is caused by the formation in the brain of abnormally high levels of the naturally occurring protein beta-amyloid that clumps together to form plaques and the intracellular accumulations of neurofibrillary tangles of tau protein that disrupt cell function.

In 2023, a critical review in the journal Brain , collaboratively written by scientists from Denmark, the U.S., Italy, and Australia, stated that “Despite the importance of amyloid in the definition of Alzheimer's disease, we argue that the data point to Aβ playing a minor aetiological role.” They further asserted that the search for more effective ways to treat Alzheimer’s should involve more than amyloid as the single causative agent.

I propose to discuss the currently leading "out-of-the-clump" research, a term coined by Donald Weaver of the University of Toronto, that may eventually usher in new and better ways of dealing with Alzheimer’s.

One of the most auspicious of these novel directions comes from the above-mentioned Weaver, who found that significant resemblances between bacterial membranes and brain cell membranes exist. Beta-amyloid erroneously mistakes the brain cells for invading bacteria and attacks them. These brain cells gradually decay, ultimately leading to dementia. According to Weaver, Alzheimer’s is an autoimmune disease.

If this theory gains traction in the scientific world, treatments that are effective in autoimmune diseases such as celiac disease, Crohn’s disease, diabetes type 1, eczema, etc. may prove successful in the treatment of Alzheimer’s.

In addition to this autoimmune theory of Alzheimer’s, many other new and varied theories are appearing. John Mamo of Curtin University in Australia, demonstrated already in 2021 that the liver also makes amyloid protein.

It follows that finding ways to either prevent the liver from manufacturing the amyloid protein or destroying it before it enters the circulation ought to be explored.

A recent study from Portugal suggests that Alzheimer’s is a disease of the mitochondria . Mitochondria are tiny organelles (similar to organs like the heart or liver but much smaller inside cells) that generate most of the chemical energy required to power the cell's functions. The authors of this study reported positive outcomes in Alzheimer’s with animals fed a diet rich in antioxidants.

This is good news because we are in familiar territory here. We have known for a long time that antioxidants scavenge free radicals from the body cells and prevent or reduce the damage caused by oxidation. Of course, further research is necessary before it is proven that antioxidants in humans can lessen the risk of developing Alzheimer’s or benefit people in the early stages of Alzheimer’s. However, the consumption of antioxidants like vitamins A, C, and E, the minerals copper, zinc, and selenium, as well as nuts, fruits and vegetables, pecans, blueberries, and dark chocolate, seems well-proven to benefit the health of everyone, at any stage of life.

Scientists from the University of Bern, Switzerland, contend that Alzheimer’s is the end result of a brain infection, particularly with bacteria from the mouth. Since our hands and fingers swarm with viruses and bacteria, a recent paper that advanced the hypothesis that nose picking could play a role in increasing the risk of developing Alzheimer’s makes much sense. Digging around our noses is encouraging all those little critters to hop on the olfactory nerve train and take a vacation in our brains.

Recent research has focussed on probiotics as potentially beneficial in preventing the development or slowing the progression of Alzheimer’s. Probiotics are foods or supplements that contain live microorganisms that help to maintain or improve a diverse microflora in the gut. A systematic review of the literature on the effect of probiotics on Alzheimer’s by scientists from Malaysia in conjunction with researchers from Baghdad in 2022 write, “Probiotics are known to be one of the best preventative measures against cognitive decline in AD. Numerous in vivo trials and recent clinical trials have proven the effectiveness of selected bacterial strains in slowing down the progression of AD. It is proven that probiotics modulate the inflammatory process, counteract [with] oxidative stress , and modify gut microbiota.”

This and many other academic papers present robust evidence on the role of probiotics in alleviating the progression of Alzheimer’s.

As opposed to drugs, probiotics are readily available in foods such as yogurt, buttermilk, sauerkraut, pickles, and many others.

If we are going to make significant advances in the prevention and treatment of Alzheimer’s, we urgently require new approaches outside the old amyloid plaque box. Here I reviewed a number of such studies that promise to make a difference in the near future.

Understanding the condition, its origins, and effective strategies for prevention should be a top priority of our healthcare system.

Lee, Y. R., Ong, L., Gold, M., Kalali, A., & Sarkar, J. (2022). Alzheimer’s disease: key insights from two decades of clinical trial failures. Journal of Alzheimer's Disease, 87(1), 83-100.

Van Dyck, C. H., Swanson, C. J., Aisen, P., Bateman, R. J., Chen, C., Gee, M., ... & Iwatsubo, T. (2023). Lecanemab in early Alzheimer’s disease. New England Journal of Medicine, 388(1), 9-21.

Romanenko, M., Kholin, V., Koliada, A., & Vaiserman, A. (2021). Nutrition, gut microbiota, and Alzheimer's disease. Frontiers in psychiatry, 12, 712673

Prater, K. E., Green, K. J., Smith, C. L., ... & Jayadev, S. (2023). Human microglia show unique transcriptional changes in Alzheimer’s disease. Nature Aging, 3(7), 894-907.

Thomas R. Verny, M.D. , the author of eight books, including The Embodied Mind , has taught at Harvard University, University of Toronto, York University, and St. Mary’s University of Minnesota. His podcast, Pushing Boundaries , may be viewed on Youtube or listened to on Spotify and many other platforms.

• Find a Therapist
• Find a Treatment Center
• Find a Psychiatrist
• Find a Support Group
• Find Online Therapy
• International
• New Zealand
• South Africa
• Switzerland
• Asperger's
• Bipolar Disorder
• Chronic Pain
• Eating Disorders
• Passive Aggression
• Personality
• Goal Setting
• Positive Psychology
• Stopping Smoking
• Low Sexual Desire
• Relationships
• Child Development
• Self Tests NEW
• Therapy Center
• Diagnosis Dictionary
• Types of Therapy

At any moment, someone’s aggravating behavior or our own bad luck can set us off on an emotional spiral that threatens to derail our entire day. Here’s how we can face our triggers with less reactivity so that we can get on with our lives.

• Emotional Intelligence
• Gaslighting
• Affective Forecasting
• Neuroscience

• U.S. Department of Health & Human Services

• Virtual Tour
• Staff Directory
• En Español

You are here

Nih research matters.

May 14, 2024

Study defines major genetic form of Alzheimer’s disease

At a glance.

• In a study of people primarily of European descent, those with two copies of a certain gene,  APOE4 , predictably began to develop the underlying abnormalities of Alzheimer’s disease as early as age 55.
• While other populations still need to be studied, the findings suggest a newly defined genetic form of Alzheimer’s disease, with implications for future research, diagnosis, and treatment.

A small portion of early-onset Alzheimer’s disease (AD) cases are known to be genetically determined. These include early-onset autosomal dominant AD and Down syndrome-associated AD. In these conditions, almost everyone with the associated gene variants will develop the disease. Symptoms typically begin between 40 and 60 years of age. Clinical, pathological, and biomarker changes follow a predictable sequence.

Most AD cases, however, occur later in life. Genetics alone does not determine whether someone will get late-onset AD. But genetic variations can affect the risk of developing it. One of the strongest genetic risk factors for people of European descent is a variant of the APOE gene, called APOE4 . People who carry two APOE4 copies, called APOE4 homozygotes, have been estimated to have a 60% chance of developing AD dementia by age 85. While APOE4  homozygotes account for only about 2% of the overall population, they make up a larger share of AD cases—an estimated 15%.

A team of researchers led by Drs. Juan Fortea and Victor Montal at the Sant Pau Research Institute in Barcelona set out to study APOE4 homozygotes in more detail. They examined data from the NIH-funded National Alzheimer’s Coordinating Center on postmortem brain pathology from more than 3,200 people with different versions of the APOE gene. The people were largely of European descent. The team complemented this with data on clinical, pathological, and AD biomarkers from five clinical studies totaling more than 10,000 people. Results of the study, which was funded in part by NIH, appeared in Nature Medicine on May 6, 2024.

Almost all of the APOE4 homozygotes in the postmortem dataset had AD brain pathology from age 55 on, compared with about half of those without APOE4 . APOE4 homozygotes also consistently had high levels of AD biomarkers starting at age 55. By age 65, almost all had abnormal levels of one AD biomarker, amyloid beta, in their cerebrospinal fluid. Three quarters had detectable amyloid on brain imaging.

APOE4 homozygotes began experiencing AD symptoms around 65 years of age, on average. Mild cognitive impairment diagnosis occurred around age 72 on average, dementia diagnosis around age 74, and death around age 77. All these happened 7 to 10 years earlier than in people without APOE4 .

The age of symptom onset was also less variable and more predictable in APOE4 homozygotes than in people without APOE4 . The variability in age of symptom onset in homozygotes was comparable to that seen in other genetic forms of AD. Changes in biomarker levels with age followed a consistent sequence in APOE4 homozygotes as well. This, too, resembled what occurs in the known genetic forms of AD. APOE4 homozygotes did not have distinctive biomarker levels among people who had already developed dementia.

These findings suggest that, for the population studied, AD in APOE4 homozygotes shares key characteristics with other genetically determined forms of AD. Thus, AD in these individuals could also be considered genetically determined.

“These data represent a reconceptualization of the disease or what it means to be homozygous for the APOE4 gene,” Fortea says.

The findings suggest the need for future research into diagnosis and treatment strategies specific to APOE4 homozygotes. Currently, NIH funds studies on potential treatments for people who carry two copies of the APOE4 gene. APOE4 homozygote risk also needs to be studied in populations not of European descent. NIH is actively working to increase the diversity of studies on Alzheimer’s disease and related dementias.

—by Brian Doctrow, Ph.D.

*Editor's Note: The bullets were edited after publication to add that the study was done in people primarily of European descent and clarify that it was preclinical AD that could be detected as early as age 55.

Related Links

• Research in Context: Diagnosing dementia
• Alzheimer’s Tied to Cholesterol, Abnormal Nerve Insulation
• Common Drug May Have Potential for Treating Alzheimer’s Disease
• Study Reveals How APOE4 Gene May Increase Risk for Dementia
• Alzheimer’s Gene Contributes to Blood-Brain Barrier Breakdown
• Alzheimer's Disease Genetics Fact Sheet
• Alzheimer’s Causes and Risk Factors

References:  APOE4 homozygozity represents a distinct genetic form of Alzheimer's disease. Fortea J, Pegueroles J, Alcolea D, Belbin O, Dols-Icardo O, Vaqué-Alcázar L, Videla L, Gispert JD, Suárez-Calvet M, Johnson SC, Sperling R, Bejanin A, Lleó A, Montal V. Nat Med . 2024 May 6. doi: 10.1038/s41591-024-02931-w. Online ahead of print. PMID: 38710950.

Funding:  NIH’s National Institute on Aging (NIA), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and National Center for Advancing Translational Sciences (NCATS); Carlos III Health Institute; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas; Department de Salut de la Generalitat de Catalunya; Fundación Tatiana Pérez de Guzmán el Bueno; Horizon 2020; La Caixa Foundation; Alzheimer’s Association; Jerome Lejeune Foundation.

Connect with Us

• More Social Media from NIH

• Election 2024
• Entertainment
• Newsletters
• Photography
• Personal Finance
• AP Investigations
• AP Buyline Personal Finance
• AP Buyline Shopping
• Press Releases
• Israel-Hamas War
• Russia-Ukraine War
• Global elections
• Asia Pacific
• Latin America
• Middle East
• Election Results
• Delegate Tracker
• AP & Elections
• Auto Racing
• 2024 Paris Olympic Games
• Movie reviews
• Book reviews
• Personal finance
• Financial Markets
• Business Highlights
• Financial wellness
• Artificial Intelligence
• Social Media

A gene long thought to just raise the risk for Alzheimer’s may cause some cases

FILE - A section of a human brain with Alzheimer’s disease is displayed at the Museum of Neuroanatomy at the University at Buffalo, in Buffalo, N.Y., Oct. 7, 2003. A long-feared gene appears to do more than raise people’s risk of Alzheimer’s: Inheriting two copies can cause the mind-robbing disease, according to research published in the journal Nature Medicine on Monday, May 6, 2024. (AP Photo/David Duprey, File)

• Copy Link copied

WASHINGTON (AP) — For the first time, researchers have identified a genetic form of late-in-life Alzheimer’s disease — in people who inherit two copies of a worrisome gene.

Scientists have long known a gene called APOE4 is one of many things that can increase people’s risk for Alzheimer’s, including simply getting older. The vast majority of Alzheimer’s cases occur after age 65. But research published Monday suggests that for people who carry not one but two copies of the gene, it’s more than a risk factor, it’s an underlying cause of the mind-robbing disease.

The findings mark a distinction with “profound implications,” said Dr. Juan Fortea, who led the study the Sant Pau Research Institute in Barcelona, Spain.

Among them: Symptoms can begin seven to 10 years sooner than in other older adults who develop Alzheimer’s.

An estimated 15% of Alzheimer’s patients carry two copies of APOE4, meaning those cases “can be tracked back to a cause and the cause is in the genes,” Fortea said. Until now, genetic forms of Alzheimer’s were thought to be only types that strike at much younger ages and account for less than 1% of all cases.

Scientists say the research makes it critical to develop treatments that target the APOE4 gene. Some doctors won’t offer the only drug that has been shown to modestly slow the disease, Leqembi, to people with the gene pair because they’re especially prone to a dangerous side effect, said Dr. Reisa Sperling, a study coauthor at Harvard-affiliated Brigham and Women’s Hospital in Boston.

Sperling hunts ways to prevent or at least delay Alzheimer’s and “this data for me says wow, what an important group to be able to go after before they become symptomatic.”

But the news doesn’t mean people should race for a gene test. “It’s important not to scare everyone who has a family history” of Alzheimer’s because this gene duo isn’t behind most cases, she told The Associated Press.

HOW DO GENETICS AFFECT ALZHEIMER’S?

More than 6 million Americans, and millions more worldwide, have Alzheimer’s. A handful of genes are known to cause rare “early-onset” forms, mutations passed through families that trigger symptoms unusually young, by age 50. Some cases also are linked to Down syndrome.

But Alzheimer’s most commonly strikes after 65, especially in the late 70s to 80s, and the APOE gene – which also affects how the body handles fats -- was long known to play some role. There are three main varieties. Most people carry the APOE3 variant that appears to neither increase nor decrease Alzheimer’s risk. Some carry APOE2, which provides some protection against Alzheimer’s.

APOE4 has long been labeled the biggest genetic risk factor for late-in-life Alzheimer’s, with two copies risker than one. About 2% of the global population is estimated to have inherited a copy from each parent.

RESEARCH POINTS TO A CAUSE FOR A SUBSET OF ALZHEIMER’S

To better understand the gene’s role, Fortea’s team used data from 3,297 brains donated for research and from over 10,000 people in U.S. and European Alzheimer’s studies. They examined symptoms and early hallmarks of Alzheimer’s such as sticky amyloid in the brain.

People with two APOE4 copies were accumulating more amyloid at age 55 than those with just one copy or the “neutral” APOE3 gene variety, they reported in the journal Nature Medicine. By age 65, brain scans showed significant plaque buildup in nearly three-quarters of those double carriers – who also were more likely to have initial Alzheimer’s symptoms around that age rather than in the 70s or 80s.

Fortea said the disease’s underlying biology was remarkably similar to young inherited types.

It appears more like “a familial form of Alzheimer’s,” said Dr. Eliezer Masliah of the National Institute on Aging. “It is not just a risk factor.”

Importantly, not everyone with two APOE4 genes develops Alzheimer’s symptoms and researchers need to learn why, Sperling cautioned.

“It’s not quite destiny,” she said.

HOW THE NEW FINDINGS MAY AFFECT ALZHEIMER’S RESEARCH AND TREATMENT

The drug Leqembi works by clearing away some sticky amyloid but Sperling said it’s not clear if carriers of two APOE4 genes benefit because they have such a high risk of a side effect from the drug – dangerous brain swelling and bleeding. One research question is whether they’d do better starting such drugs sooner than other people.

Masliah said other research aims to develop gene therapy or drugs to specifically target APOE4. He said it’s also crucial to understand APOE4’s effects in diverse populations since it’s been studied mostly in white people of European ancestry.

As for gene tests, for now they’re typically used only to evaluate if someone’s a candidate for Leqembi or for people enrolling in Alzheimer’s research – especially studies of possible ways to prevent the disease. Sperling said the people most likely to carry two APOE4 genes had parents who both got Alzheimer’s relatively early, in their 60s rather than 80s.

The Associated Press Health and Science Department receives support from the Howard Hughes Medical Institute’s Science and Educational Media Group. The AP is solely responsible for all content.

The vicious cycle of protein clumping in Alzheimer's disease and normal aging

Buck researchers uncover connections and suggestions for interventions to improve both.

It has long been known that a hallmark of Alzheimer's disease, and most other neurodegenerative diseases, is the clumping together of insoluble protein aggregates in the brain. During normal disease-free aging, there is also an accumulation of insoluble proteins.

To date, approaches to treatments for Alzheimer's disease have not addressed the contribution of protein insolubility as a general phenomenon, instead focusing on one or two insoluble proteins. Buck researchers have recently completed a systematic study in worms that paints an intricate picture of the connections between insoluble proteins in neurodegenerative diseases and aging. Furthermore, the work demonstrated an intervention that could reverse the toxic effects of the aggregates by boosting mitochondrial health.

"Based on our discoveries, targeting insoluble proteins could provide a strategy for the prevention and treatment of a variety of age-related diseases," said Edward Anderton, PhD, a postdoctoral fellow in Gordon Lithgow's lab and co-first author of a study that appears in the May 16 issue of the journal GeroScience .

"Our study shows how maintaining healthy mitochondria can combat protein clumping linked to both aging and Alzheimer's," said Manish Chamoli, PhD, a research scientist in Gordon Lithgow's and Julie Andersen's lab, and co-first author of the study. "By boosting mitochondrial health, we can potentially slow down or reverse these harmful effects, offering new ways to treat both aging and age-related diseases."

Results support the geroscience hypothesis

The strong link between insoluble proteins promoting normal aging and diseases also builds a case for the bigger picture of how aging and age-related diseases occur. "We would argue that this work really supports the geroscience hypothesis that there is a common pathway to Alzheimer's disease and aging itself," said Buck Professor Gordon Lithgow. PhD, Vice President of Academic Affairs and the senior author of the study. "Aging is driving the disease, but the factors that put you on the track toward the disease actually occur very early."

The fact that the team found a core insoluble proteome enriched with numerous proteins that had not been considered before creates new targets for exploration, said Lithgow. "In some ways it raises the flag about whether we should be thinking about what Alzheimer's looks like in very young people," he said.

Beyond amyloid and tau

The focus of most research on Alzheimer's disease to date has been targeting accumulations of two proteins: amyloid beta and tau. But there are actually thousands of other proteins in these insoluble aggregations, said Anderton, and their role in Alzheimer's disease was unknown. Additionally, he added, their lab and others' have observed that during the normal disease-free aging process there is also an accumulation of insoluble proteins. These insoluble proteins from aged animals, when mixed with amyloid beta in the test tube, accelerate the aggregation of the amyloid.

What was the connection between the accumulation aggregates Alzheimer's and disease-free aging, the team wondered. Focusing on the amyloid beta protein, they used a strain of the microscopic worm Caenorhabditis elegans, long been used in aging studies, that has been engineered to produce human amyloid protein.

Anderton said the team suspected they might see that amyloid beta is driving some level of insolubility in other proteins. "What we found is that amyloid beta causes a massive amount of insolubility, even in a very young animal," said Anderton. They found that there is a subset of proteins that seem to be very vulnerable to becoming insoluble, either by adding amyloid beta or during the normal aging process. They called that vulnerable subset the "core insoluble proteome."

The team went on to demonstrate that the core insoluble proteome is full of proteins that have already been linked to different neurodegenerative diseases in addition to Alzheimer's disease, including Parkinson's disease, Huntington's disease and prion disease.

"Our paper shows that amyloid could be acting as a driver of this normal aging aggregation," said Anderton. "Now we've got clear evidence, I think for the first time, that both amyloid and aging are affecting the same proteins in a similar way. It's quite possibly a vicious cycle where aging is driving insolubility and amyloid beta is also driving insolubility, and they're just making each other worse."

The amyloid protein is very toxic to the worms and the team wanted to find a way to reverse that toxicity. "Since hundreds of mitochondrial proteins become insoluble both during aging and after expressing amyloid beta, we thought if we can boost the mitochondrial protein quality using a compound, then maybe we can reverse some of the negative effects of amyloid beta," said Anderton. That's exactly what they found, using Urolithin A, a natural gut metabolite produced when we eat raspberries, walnuts, and pomegranates which is known to improve mitochondrial function: it significantly delayed the toxic effects of amyloid beta.

"Something that was glaringly obvious from our dataset is that the importance of mitochondria keeps coming up," said Anderton. A takeaway, the authors say, is the reminder that the health of mitochondria is critical to overall health. "Mitochondria have a strong link with aging. They've got a strong link with amyloid beta," he said. "I think ours is one of the few studies that shows that insolubility and aggregation of those proteins might be the link between the two."

"Because the mitochondria are so central to all of this, one way to break the vicious cycle of decline is to replace damaged mitochondria with new mitochondria," said Lithgow. "And how do you do that? You exercise and follow a healthy diet."

• Alzheimer's Research
• Healthy Aging
• Chronic Illness
• Diseases and Conditions
• Alzheimer's
• Huntington's Disease
• Protein structure
• Molecular biology
• Personalized medicine

Story Source:

Materials provided by Buck Institute for Research on Aging . Note: Content may be edited for style and length.

Journal Reference :

• Edward Anderton, Manish Chamoli, Dipa Bhaumik, Christina D. King, Xueshu Xie, Anna Foulger, Julie K. Andersen, Birgit Schilling, Gordon J. Lithgow. Amyloid β accelerates age-related proteome-wide protein insolubility . GeroScience , 2024; DOI: 10.1007/s11357-024-01169-1

Cite This Page :

Explore More

• High-Efficiency Photonic Integrated Circuit
• Life Expectancy May Increase by 5 Years by 2050
• Toward a Successful Vaccine for HIV
• Highly Efficient Thermoelectric Materials
• Toward Human Brain Gene Therapy
• Whale Families Learn Each Other's Vocal Style
• AI Can Answer Complex Physics Questions
• Otters Use Tools to Survive a Changing World
• Monogamy in Mice: Newly Evolved Type of Cell
• Sustainable Electronics, Doped With Air

Trending Topics

Strange & offbeat.

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

• View all journals
• Explore content
• About the journal
• Publish with us
• Sign up for alerts
• Published: 06 May 2024

APOE4 homozygozity represents a distinct genetic form of Alzheimer’s disease

• Juan Fortea   ORCID: orcid.org/0000-0002-1340-638X 1 , 2 , 3   na1 ,
• Jordi Pegueroles   ORCID: orcid.org/0000-0002-3554-2446 1 , 2 ,
• Daniel Alcolea   ORCID: orcid.org/0000-0002-3819-3245 1 , 2 ,
• Olivia Belbin   ORCID: orcid.org/0000-0002-6109-6371 1 , 2 ,
• Oriol Dols-Icardo   ORCID: orcid.org/0000-0003-2656-8748 1 , 2 ,
• Lídia Vaqué-Alcázar 1 , 4 ,
• Laura Videla   ORCID: orcid.org/0000-0002-9748-8465 1 , 2 , 3 ,
• Juan Domingo Gispert 5 , 6 , 7 , 8 , 9 ,
• Marc Suárez-Calvet   ORCID: orcid.org/0000-0002-2993-569X 5 , 6 , 7 , 8 , 9 ,
• Sterling C. Johnson   ORCID: orcid.org/0000-0002-8501-545X 10 ,
• Reisa Sperling   ORCID: orcid.org/0000-0003-1535-6133 11 ,
• Alexandre Bejanin   ORCID: orcid.org/0000-0002-9958-0951 1 , 2 ,
• Alberto Lleó   ORCID: orcid.org/0000-0002-2568-5478 1 , 2 &
• Víctor Montal   ORCID: orcid.org/0000-0002-5714-9282 1 , 2 , 12   na1  

Nature Medicine ( 2024 ) Cite this article

17k Accesses

4487 Altmetric

Metrics details

• Alzheimer's disease
• Predictive markers

This study aimed to evaluate the impact of APOE4 homozygosity on Alzheimer’s disease (AD) by examining its clinical, pathological and biomarker changes to see whether APOE4 homozygotes constitute a distinct, genetically determined form of AD. Data from the National Alzheimer’s Coordinating Center and five large cohorts with AD biomarkers were analyzed. The analysis included 3,297 individuals for the pathological study and 10,039 for the clinical study. Findings revealed that almost all APOE4 homozygotes exhibited AD pathology and had significantly higher levels of AD biomarkers from age 55 compared to APOE3 homozygotes. By age 65, nearly all had abnormal amyloid levels in cerebrospinal fluid, and 75% had positive amyloid scans, with the prevalence of these markers increasing with age, indicating near-full penetrance of AD biology in APOE4 homozygotes. The age of symptom onset was earlier in APOE4 homozygotes at 65.1, with a narrower 95% prediction interval than APOE3 homozygotes. The predictability of symptom onset and the sequence of biomarker changes in APOE4 homozygotes mirrored those in autosomal dominant AD and Down syndrome. However, in the dementia stage, there were no differences in amyloid or tau positron emission tomography across haplotypes, despite earlier clinical and biomarker changes. The study concludes that APOE4 homozygotes represent a genetic form of AD, suggesting the need for individualized prevention strategies, clinical trials and treatments.

This is a preview of subscription content, access via your institution

Access options

Access Nature and 54 other Nature Portfolio journals

Get Nature+, our best-value online-access subscription

24,99 € / 30 days

cancel any time

Subscribe to this journal

Receive 12 print issues and online access

195,33 € per year

only 16,28 € per issue

Buy this article

• Purchase on Springer Link
• Instant access to full article PDF

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

APOE4/4 is linked to damaging lipid droplets in Alzheimer’s disease microglia

Dynamics of cognitive variability with age and its genetic underpinning in NIHR BioResource Genes and Cognition cohort participants

The Amyloid-β Pathway in Alzheimer’s Disease

Data availability.

Access to tabular data from ADNI ( https://adni.loni.usc.edu/ ), OASIS ( https://oasis-brains.org/ ), A4 ( https://ida.loni.usc.edu/collaboration/access/appLicense.jsp ) and NACC ( https://naccdata.org/ ) can be requested online, as publicly available databases. All requests will be reviewed by each studyʼs scientific board. Concrete inquiries to access the WRAP ( https://wrap.wisc.edu/data-requests-2/ ) and ALFA + ( https://www.barcelonabeta.org/en/alfa-study/about-the-alfa-study ) cohort data can be directed to each study team for concept approval and feasibility consultation. Requests will be reviewed to verify whether the request is subject to any intellectual property.

Code availability

All statistical analyses and raw figures were generated using R (v.4.2.2). We used the open-sourced R packages of ggplot2 (v.3.4.3), dplyr (v.1.1.3), ggstream (v.0.1.0), ggpubr (v.0.6), ggstatsplot (v.0.12), Rmisc (v.1.5.1), survival (v.3.5), survminer (v.0.4.9), gtsummary (v.1.7), epitools (v.0.5) and statsExpression (v.1.5.1). Rscripts to replicate our findings can be found at https://gitlab.com/vmontalb/apoe4-asdad (ref. 32 ). For neuroimaging analyses, we used Free Surfer (v.6.0) and ANTs (v.2.4.0).

Bellenguez, C. et al. New insights into the genetic etiology of Alzheimer’s disease and related dementias. Nat. Genet. 54 , 412–436 (2022).

Article   CAS   PubMed   PubMed Central   Google Scholar  

Frisoni, G. B. et al. The probabilistic model of Alzheimer disease: the amyloid hypothesis revised. Nat. Rev. Neurosci. 23 , 53–66 (2022).

Article   CAS   PubMed   Google Scholar  

Bateman R. J. et al. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N. Engl. J. Med. 367 , 795–804 (2012).

Genin, E. et al. APOE and Alzheimer disease: a major gene with semidominant inheritance. Mol. Psychiatry 16 , 903–907 (2011).

Fortea, J. et al. Alzheimer’s disease associated with Down syndrome: a genetic form of dementia. Lancet Neurol. 20 , 930–942 (2021).

Fortea, J. et al. Clinical and biomarker changes of Alzheimer’s disease in adults with Down syndrome: a cross-sectional study. Lancet 395 , 1988–1997 (2020).

Jansen, W. J. et al. Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis. JAMA 313 , 1924–1938 (2015).

Article   PubMed   PubMed Central   Google Scholar  

Saddiki H. et al. Age and the association between apolipoprotein E genotype and Alzheimer disease: a cerebrospinal fluid biomarker-based case-control study. PLoS Med. https://doi.org/10.1371/JOURNAL.PMED.1003289 (2020).

Jack, C. R. et al. NIA‐AA Research Framework: toward a biological definition of Alzheimer’s disease. Alzheimer’s Dement. 14 , 535–562 (2018).

Article   Google Scholar  

Beekly, D. L. et al. The National Alzheimer’s Coordinating Center (NACC) Database: an Alzheimer disease database. Alzheimer Dis. Assoc. Disord. 18 , 270–277 (2004).

PubMed   Google Scholar  

Montine, T. J. et al. National Institute on Aging–Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: a practical approach. Acta Neuropathol. 123 , 1–11 (2012).

Reiman, E. M. et al. Exceptionally low likelihood of Alzheimer’s dementia in APOE2 homozygotes from a 5,000-person neuropathological study. Nat. Commun. 11 , 1–11 (2020).

Iulita M. F. et al. Association of Alzheimer disease with life expectancy in people with Down syndrome. JAMA Netw. Open https://doi.org/10.1001/JAMANETWORKOPEN.2022.12910 (2022).

Corder, E. H. et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261 , 921–923 (1993).

Fortea, J., Quiroz, Y. T. & Ryan, N. S. Lessons from Down syndrome and autosomal dominant Alzheimer’s disease. Lancet Neurol. 22 , 5–6 (2023).

Therriault, J. et al. Frequency of biologically defined Alzheimer’s disease in relation to age, sex, APOE ε4, and cognitive impairment. Neurology 96 , e975–e985 (2021).

Betthauser, T. J. et al. Multi-method investigation of factors influencing amyloid onset and impairment in three cohorts. Brain 145 , 4065–4079 (2022).

Snellman, A. et al. APOE ε4 gene dose effect on imaging and blood biomarkers of neuroinflammation and beta-amyloid in cognitively unimpaired elderly. Alzheimers Res. Ther. 15 , 71 (2023).

Ghisays, V. et al. Brain imaging measurements of fibrillar amyloid-β burden, paired helical filament tau burden, and atrophy in cognitively unimpaired persons with two, one, and no copies of the APOE ε4 allele. Alzheimers Dement. 16 , 598–609 (2020).

Mehta, R. I. & Schneider, J. A. What is ‘Alzheimer’s disease’? The neuropathological heterogeneity of clinically defined Alzheimer’s dementia. Curr. Opin. Neurol. 34 , 237–245 (2021).

van der Lee, S. J. et al. The effect of APOE and other common genetic variants on the onset of Alzheimer’s disease and dementia: a community-based cohort study. Lancet Neurol. 17 , 434–444 (2018).

Belloy, M. E., Napolioni, V. & Greicius, M. D. A quarter century of APOE and Alzheimera’s disease: progress to date and the path forward. Neuron 101 , 820–838 (2019).

Belloy, M. E. et al. APOE genotype and Alzheimer disease risk across age, sex, and population ancestry. JAMA Neurol. 80 , 1284–1294 (2023).

Jack, C. R. et al. Long-term associations between amyloid positron emission tomography, sex, apolipoprotein E and incident dementia and mortality among individuals without dementia: hazard ratios and absolute risk. Brain Commun. 4 , fcac017 (2022).

Morris, J. C. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology 43 , 2412–2414 (1993).

Weiner, M. W. et al. The Alzheimer’s Disease Neuroimaging Initiative 3: continued innovation for clinical trial improvement. Alzheimer’s Dement. 13 , 561–571 (2017).

Sperling R. A. et al. The A4 Study: stopping AD before symptoms begin? Sci. Transl. Med. https://doi.org/10.1126/scitranslmed.3007941 (2014).

Molinuevo, J. L. et al. The ALFA project: a research platform to identify early pathophysiological features of Alzheimer’s disease. Alzheimer’s Dement.: Transl. Res. Clin. Interventions 2 , 82–92 (2016).

Johnson, S. C. et al. The Wisconsin Registry for Alzheimer’s Prevention: a review of findings and current directions. Alzheimer’s Dement.: Diagnosis, Assess. Dis. Monit. 10 , 130–142 (2018).

Google Scholar  

LaMontagne P. J. et al. OASIS-3: longitudinal neuroimaging, clinical and cognitive dataset for normal aging and Alzheimer disease. Preprint at MedRxiv https://doi.org/10.1101/2019.12.13.19014902 (2019).

La Joie, R. et al. Multisite study of the relationships between antemortem [ 11 C]PIB-PET Centiloid values and postmortem measures of Alzheimer’s disease neuropathology. Alzheimers Dement. 15 , 205–216 (2019).

Montal, V. APOE4-ASDAD. GitLab https://gitlab.com/vmontalb/apoe4-asdad (2024).

Download references

Acknowledgements

We acknowledge the contributions of several consortia that provided data for this study. We extend our appreciation to the NACC, the Alzheimer’s Disease Neuroimaging Initiative, The A4 Study, the ALFA Study, the Wisconsin Register for Alzheimer’s Prevention and the OASIS3 Project. Without their dedication to advancing Alzheimer’s disease research and their commitment to data sharing, this study would not have been possible. We also thank all the participants and investigators involved in these consortia for their tireless efforts and invaluable contributions to the field. We also thank the institutions that funded this study, the Fondo de Investigaciones Sanitario, Carlos III Health Institute, the Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas and the Generalitat de Catalunya and La Caixa Foundation, as well as the NIH, Horizon 2020 and the Alzheimer’s Association, which was crucial for this research. Funding: National Institute on Aging. This study was supported by the Fondo de Investigaciones Sanitario, Carlos III Health Institute (INT21/00073, PI20/01473 and PI23/01786 to J.F., CP20/00038, PI22/00307 to A.B., PI22/00456 to M.S.-C., PI18/00435 to D.A., PI20/01330 to A.L.) and the Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas Program 1, partly jointly funded by Fondo Europeo de Desarrollo Regional, Unión Europea, Una Manera de Hacer Europa. This work was also supported by the National Institutes of Health grants (R01 AG056850; R21 AG056974, R01 AG061566, R01 AG081394 and R61AG066543 to J.F., S10 OD025245, P30 AG062715, U54 HD090256, UL1 TR002373, P01 AG036694 and P50 AG005134 to R.S.; R01 AG027161, R01 AG021155, R01 AG037639, R01 AG054059; P50 AG033514 and P30 AG062715 to S.J.) and ADNI (U01 AG024904), the Department de Salut de la Generalitat de Catalunya, Pla Estratègic de Recerca I Innovació en Salut (SLT006/17/00119 to J.F.; SLT002/16/00408 to A.L.) and the A4 Study (R01 AG063689, U24 AG057437 to R.A.S). It was also supported by Fundación Tatiana Pérez de Guzmán el Bueno (IIBSP-DOW-2020-151 o J.F.) and Horizon 2020–Research and Innovation Framework Programme from the European Union (H2020-SC1-BHC-2018-2020 to J.F.; 948677 and 847648 to M.S.-C.). La Caixa Foundation (LCF/PR/GN17/50300004 to M.S.-C.) and EIT Digital (Grant 2021 to J.D.G.) also supported this work. The Alzheimer Association also participated in the funding of this work (AARG-22-923680 to A.B.) and A4/LEARN Study AA15-338729 to R.A.S.). O.D.-I. receives funding from the Alzheimer’s Association (AARF-22-924456) and the Jerome Lejeune Foundation postdoctoral fellowship.

Author information

These authors contributed equally: Juan Fortea, Víctor Montal.

Authors and Affiliations

Sant Pau Memory Unit, Hospital de la Santa Creu i Sant Pau - Biomedical Research Institute Sant Pau, Barcelona, Spain

Juan Fortea, Jordi Pegueroles, Daniel Alcolea, Olivia Belbin, Oriol Dols-Icardo, Lídia Vaqué-Alcázar, Laura Videla, Alexandre Bejanin, Alberto Lleó & Víctor Montal

Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas. CIBERNED, Barcelona, Spain

Juan Fortea, Jordi Pegueroles, Daniel Alcolea, Olivia Belbin, Oriol Dols-Icardo, Laura Videla, Alexandre Bejanin, Alberto Lleó & Víctor Montal

Barcelona Down Medical Center, Fundació Catalana Síndrome de Down, Barcelona, Spain

Juan Fortea & Laura Videla

Department of Medicine, Faculty of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, Barcelona, Spain

Lídia Vaqué-Alcázar

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

Juan Domingo Gispert & Marc Suárez-Calvet

Neurosciences Programme, IMIM - Hospital del Mar Medical Research Institute, Barcelona, Spain

Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain

Centro de Investigación Biomédica en Red Bioingeniería, Biomateriales y Nanomedicina. Instituto de Salud carlos III, Madrid, Spain

Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain

Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA

Sterling C. Johnson

Brigham and Women’s Hospital Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

Reisa Sperling

Barcelona Supercomputing Center, Barcelona, Spain

Víctor Montal

You can also search for this author in PubMed   Google Scholar

Contributions

J.F. and V.M. conceptualized the research project and drafted the initial manuscript. V.M., J.P. and J.F. conducted data analysis, interpreted statistical findings and created visual representations of the data. O.B. and O.D.-I. provided valuable insights into the genetics of APOE. L.V., A.B. and L.V.-A. meticulously reviewed and edited the manuscript for clarity, accuracy and coherence. J.D.G., M.S.-C., S.J. and R.S. played pivotal roles in data acquisition and securing funding. A.L. and D.A. contributed to the study design, offering guidance and feedback on statistical analyses, and provided critical review of the paper. All authors carefully reviewed the manuscript, offering pertinent feedback that enhanced the study’s quality, and ultimately approved the final version.

Corresponding authors

Correspondence to Juan Fortea or Víctor Montal .

Ethics declarations

Competing interests.

S.C.J. has served at scientific advisory boards for ALZPath, Enigma and Roche Diagnostics. M.S.-C. has given lectures in symposia sponsored by Almirall, Eli Lilly, Novo Nordisk, Roche Diagnostics and Roche Farma, received consultancy fees (paid to the institution) from Roche Diagnostics and served on advisory boards of Roche Diagnostics and Grifols. He was granted a project and is a site investigator of a clinical trial (funded to the institution) by Roche Diagnostics. In-kind support for research (to the institution) was received from ADx Neurosciences, Alamar Biosciences, Avid Radiopharmaceuticals, Eli Lilly, Fujirebio, Janssen Research & Development and Roche Diagnostics. J.D.G. has served as consultant for Roche Diagnostics, receives research funding from Hoffmann–La Roche, Roche Diagnostics and GE Healthcare, has given lectures in symposia sponsored by Biogen, Philips Nederlands, Esteve and Life Molecular Imaging and serves on an advisory board for Prothena Biosciences. R.S. has received personal consulting fees from Abbvie, AC Immune, Acumen, Alector, Bristol Myers Squibb, Janssen, Genentech, Ionis and Vaxxinity outside the submitted work. O.B. reported receiving personal fees from Adx NeuroSciences outside the submitted work. D.A. reported receiving personal fees for advisory board services and/or speaker honoraria from Fujirebio-Europe, Roche, Nutricia, Krka Farmacéutica and Esteve, outside the submitted work. A.L. has served as a consultant or on advisory boards for Almirall, Fujirebio-Europe, Grifols, Eisai, Lilly, Novartis, Roche, Biogen and Nutricia, outside the submitted work. J.F. reported receiving personal fees for service on the advisory boards, adjudication committees or speaker honoraria from AC Immune, Adamed, Alzheon, Biogen, Eisai, Esteve, Fujirebio, Ionis, Laboratorios Carnot, Life Molecular Imaging, Lilly, Lundbeck, Perha, Roche and outside the submitted work. O.B., D.A., A.L. and J.F. report holding a patent for markers of synaptopathy in neurodegenerative disease (licensed to Adx, EPI8382175.0). The remaining authors declare no competing interests.

Peer review

Peer review information.

Nature Medicine thanks Naoyuki Sato, Yadong Huang and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Jerome Staal, in collaboration with the Nature Medicine team.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary information.

Supplementary Methods, Results, Bibliography, Figs. 1–7 and Tables 1–3.

Reporting Summary

Supplementary code.

This code is also available in the GitLab repository.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Cite this article.

Fortea, J., Pegueroles, J., Alcolea, D. et al. APOE4 homozygozity represents a distinct genetic form of Alzheimer’s disease. Nat Med (2024). https://doi.org/10.1038/s41591-024-02931-w

Download citation

Received : 03 November 2023

Accepted : 19 March 2024

Published : 06 May 2024

DOI : https://doi.org/10.1038/s41591-024-02931-w

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

Quick links

• Explore articles by subject
• Guide to authors
• Editorial policies

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.