what are the latest major findings of dementia research

Redefining Dementia Treatment: Berkeley Scientists Unveil Promising New Breakthrough

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).

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

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

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

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

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

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

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

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

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

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

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

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New findings suggest alternative mechanisms behind Alzheimer's disease

by Emory University

New findings out of Emory University are challenging existing theories about the origins of Alzheimer's, the leading cause of dementia in the elderly worldwide. A team led by researchers at the Goizueta Brain Health Institute has found strong evidence supporting a new understanding of the mechanism behind Alzheimer's disease.

In a paper published August 9 in Cell Reports Medicine , Todd E. Golde and Yona Levites explain how the amyloid beta deposits long known to build up in the brains of Alzheimer's patients serve as a kind of scaffold for the accumulation of other proteins. Because many of these proteins have known signaling functions, their presence around the amyloid accumulations, known as plaques, could be the culprit causing brain cell damage rather than the amyloid itself.

In the brains of those who suffer from Alzheimer's, amyloids accumulate and build up into sticky plaque that disrupts brain functions and causes cognitive decline. The big unknown has been exactly how that occurs. According to the most widely adopted hypothesis, the amyloid beta buildup disrupts cell-to-cell communication and activates immune cells in a process that eventually destroys brain cells.

In the study, Golde, director of the Emory Center for Neurodegenerative Disease in the Goizueta Institute, Levites, associate professor in Emory University's School of Medicine, and their colleagues presented a new hypothesis, emphasizing a different role for amyloid beta, a simple protein that forms in all brains but normally dissolves out by natural processes.

In experiments, they used cutting-edge analytical technologies to identify and measure the level of more than 8,000 proteins in human brains with Alzheimer's, as well as similar proteins in mice. Focusing on proteins whose levels increased most dramatically, they identified more than 20 proteins that co-accumulate with amyloid beta in both the human brains with Alzheimer's and the mice. As the research continues, they suspect they'll find more.

"Once we identified these new proteins, we wanted to know whether they were merely markers of Alzheimer's or if they could actually alter the disease's deadly pathology," says Golde.

"To answer that, we focused on two proteins, midkine and pleiotrophin. Our research showed they accelerated amyloid aggregation both in the test tube and in mice. In other words, these additional proteins may play an important role in the process that leads to brain damage rather than the amyloid itself. This suggests they might be a basis for new therapies for this terrible brain affliction that's been frustratingly resistant to treatment over the years."

While the basics of Alzheimer's have been understood for more than a century, the search for a cure has been slow, often marked by repeated cycles of initially promising treatments that didn't work in trials, as well as continuing controversy over competing theories to best explain how the disease damages the brain.

As the researchers put it, "The initial notion of a purely linear amyloid cascade is now recognized as simplistic. Studies have unveiled the vast complexity of changes occurring over decades in the brains of individuals as Alzheimer's pathologies emerge."

Significantly, multiple kinds of amyloid buildup, besides amyloid beta , have been implicated in more than 30 human disorders affecting tissues and organs throughout the body. Because this new research proposes a novel process by which Alzheimer's develops, it may allow for fresh approaches to discovering treatment targets for other diseases as well.

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The New IDEAS Study is designed to evaluate the use of PET scans in diverse populations living with dementia and Alzheimer's.

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U.S. POINTER is a lifestyle intervention clinical trial to support brain health and prevent cognitive decline. Learn about study locations and eligibility.

Advancing Research Around the Globe

The Alzheimer's Association is the world's largest nonprofit funder of Alzheimer's research, currently investing more than $430 million in over 1,110 active best-of-field projects in 56 countries spanning six continents.

Our commitment to accelerating the global effort to eliminate Alzheimer's disease and other dementias is at the core of all we do.

Through our many initiatives and worldwide reach, the Alzheimer’s Association leads the charge in Alzheimer’s care, support, research and advocacy.

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Research on Alzheimer’s Disease and Related Dementias

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

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

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

Who Funds Alzheimer’s and Related Dementias Research?

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

Advances in Alzheimer's and Related Dementias Research

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

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

Challenges for the Alzheimer’s Research Community

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

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

Setting the Federal Research Agenda

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

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

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

What Is a Professional Judgment Budget?

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

Clinical Research Into Alzheimer’s and Related Dementias

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Other Articles in This Section

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

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• Published: 18 May 2023

A WHO blueprint for action to reshape dementia research

• Rodrigo Cataldi 1 ,
• Perminder S. Sachdev   ORCID: orcid.org/0000-0002-9595-3220 2 ,
• Neerja Chowdhary 1 ,
• Katrin Seeher 1 ,
• Adam Bentvelzen 2 ,
• Vasee Moorthy 3 &
• Tarun Dua   ORCID: orcid.org/0000-0002-4269-7657 1  

Nature Aging volume  3 ,  pages 469–471 ( 2023 ) Cite this article

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The World Health Organization (WHO) blueprint for dementia research provides a roadmap to addressing the challenges in the field and reshaping our approach to dementia research. This Comment focuses on how to operationalize the drivers of research highlighted in the blueprint to make research more equitable, impactful and global.

Dementia is one of the greatest health challenges of our generation. With currently 55.2 million people affected worldwide (predicted to reach 78 million by 2030 1 ), dementia is likely to have a critical impact on healthcare systems, care infrastructure and economies. This burden is particularly severe in low- and middle-income countries (LMICs), where currently over 60% of people with dementia live and the largest increase in dementia cases is expected 1 .

International commitments to address the global dementia challenge include the 2013 G8 dementia summit 2 , the adoption of the ‘Global Action Plan on the Public Health Response to Dementia 2017–2025’ (ref. 3 ) and the Okayama Declaration of the G20 Health Ministers in 2019 (ref. 4 ). Yet, dementia research often remains uncoordinated, with disparities in funding and quality 5 . Despite some countries increasing funding for dementia research, overall investment is not proportionate to the impact and cost of dementia 5 .

Accelerating research efforts is crucial for addressing any global health challenge. The COVID-19 pandemic has shown how quickly research can advance when the international community works together. However, it has also highlighted the unequal access to biomedical advances and research infrastructure globally, as well as the need to shift our approach to research toward global public-health interests.

Notwithstanding the challenges, our knowledge about dementia has substantially increased over the past four decades and many scientific advances — although mostly seen in high-income countries (HICs) — have improved diagnosis and care for people with dementia 6 . However, there is still no cure for dementia and most countries are not acting on dementia risk reduction, despite the growing evidence in its support. A holistic approach to science is needed that focuses on all aspects of research, including basic and clinical research, and its implementation into practice and policy.

To this end, the WHO has developed a blueprint for dementia research 7 , the first WHO blueprint to focus on a noninfectious disease. The blueprint aims to support the global prioritization of dementia research and provides a coordination mechanism to facilitate timely and high-quality evidence generation, fast-track innovation, foster effective research implementation and guide resource mobilization.

The blueprint summarizes the current state of dementia research across six research themes (Fig. 1 ), highlights gaps, and outlines strategic goals and actions to address them. Addressing the gaps requires an enabling research environment that can be achieved through eight essential drivers of dementia research (Fig. 1 ) that together ensure greater efficiency, equity and impact. This Comment focuses on how these drivers of research can be operationalized by different stakeholders to foster long-term systemic changes that strengthen dementia research globally.

Reproduced with permission from ref. 7 .

Operationalizing the drivers of dementia research

Including and empowering people with lived experience to achieve impact.

Globally, people with dementia are insufficiently involved in all stages of research, ranging from priority setting, planning and development of research proposals to knowledge translation and integration in policy. Data from WHO’s Global Dementia Observatory show that in almost 50% of countries, people with dementia are not at all involved in research 1 .

The blueprint therefore calls for the mandatory inclusion and active involvement of people with dementia and their carers. Concretely, the research community in partnership with civil society should develop, for example, programs that provide training in research and science so that people can contribute in a meaningful way and create processes that account for different levels of cognitive, sensory and physical impairment or disability.

Addressing inequity and diversity

Traditionally, dementia research has been driven by and conducted in HICs. For instance, genetic data are mainly representative of populations of European origin 7 . Inequities also exist in terms of funding allocation, which negatively affects mostly women and researchers from LMICs 1 . The blueprint therefore outlines equity principles to be applied by funding bodies, regulatory authorities and the scientific community (such as fairness and equal participation in resource allocation and in representation in studies) that foster real, transparent research collaborations, decrease the power imbalance and dependence on HIC institutions, as well as increase research output and the representation of LMICs in global dementia research. Funding bodies, for example, can increase the diversity of funding streams to reflect all priority areas and actively seek submissions that address inequities and promote equal partnerships between HICs and LMICs.

To promote diversity and inclusion of populations and communities who are traditionally less likely to participate in dementia research or are rarely covered by scientific studies (for example, epidemiological research), funders and research institutions can develop equity monitoring systems to ensure better representativeness and a fair distribution of resources.

Sustainable, adequate and equitable funding

Dementia research has been chronically underfunded and unevenly distributed. Of the 50 organizations and institutions that received the most grants for dementia research in 2019, 41 were in the USA, 6 in the UK and 3 in Canada 8 . This discrepancy also results in research collaborations being predominantly established with other HIC institutions 8 .

To address this imbalance, funding agencies can strategically allocate resources to LMICs towards building research capacity and infrastructure, and support the perennial development and training of a research workforce. The extent to which funders implement such recommendations can be monitored by measuring the proportion of awards being allocated to collaborations between HICs and LMICs in the design and execution of studies, as well as to researchers with geographical, gender and background underrepresentation.

The duration and continuity of funding are also crucial. Given the chronic and often slowly progressive nature of dementia, continuous funding must be provided for comprehensive longitudinal research, which is often costly. This can be facilitated by increased advocacy for resource allocation to dementia research, as well as the establishment of collaborations between funders to jointly develop funding calls. Funding agencies should strive to achieve a better balance by including underresearched aspects of dementia, such as conditions other than Alzheimer’s disease or dementia in highly vulnerable or marginalized populations.

Improving access to science, data and materials

Access to scientific knowledge, data and materials is limited in many parts of the world, with international restrictions interfering with the ability to share biosamples. Simultaneously, a lack of international standards, regulations and incentives can also hinder the ability to share materials and data. Moreover, insufficient researcher time, lack of funding, inadequate storage infrastructure and the fact that funders do not fully mandate open access to data 9 further hamper routine data sharing and global access to science.

To facilitate scientific data sharing and collaboration, governments can review existing laws and regulations concerning data sharing and protection or develop new ones, and funding agencies can promote the responsible and ethical use of data by mandating data sharing or providing incentives to do so within existing regulations.

Access to science has often been pay-walled by publishers, which creates barriers — especially in low-income settings. Recent efforts to make scientific literature more accessible through open-access publishing are encouraging, and the exemption from payment of open-access publishing fees to scientists from low-resource countries can substantially help to develop and foster scientific enterprise in LMICs.

Building capacity across different settings

Research career pathways are often insecure in dementia, owing to scarce funding and support. As a result, promising researchers (particularly women and junior researchers) may seek alternative careers, which cause a ‘brain drain’ and a reduction in research capacity 10 .

To address this, the blueprint calls for long-term strategies to invest in and build research capacity across all income settings. For instance, the academic sector should provide researchers in disciplines that are relevant to dementia research and related areas (such as aging, noncommunicable diseases and mental health) with training and resources in basic science, epidemiology, cognitive assessment, ethical research practice and dementia care, particularly in areas and settings where skills are lacking. This will strengthen capacity and broaden the pool of scientists working on dementia, and lead to a greater impact in areas such as epidemiology, disease mechanisms and risk reduction.

The career paths of female researchers also require increased attention, with academic institutions fostering their development and ensuring a fair representation in professorship and management positions. Likewise, junior researchers experience uncertainties regarding their career development. Addressing this issue requires the relevant government sectors to jointly develop strategies to provide more tenure-track positions, instead of short-term development grants and temporary positions.

Technology to provide benefits

Often considered a new determinant of health 11 , digital technologies have tremendous potential to improve the quality and reach of healthcare. Wearable devices and smartphones, for example, can collect large amounts of continuous real-time data that can be integrated and harmonized by big-data technology at different scales. However, 37% of the world’s population is still offline 12 , hampering the access to potential health benefits for many populations.

To achieve substantial global progress and eliminate the ‘digital divide’ both within and between HICs and LMICs, and across gender and socioeconomic lines, governments, funders and the private sector must invest in technological health infrastructure where it is currently lacking and ensure that innovations are applied and scaled to the benefit of societies and the elimination of health inequity. Similarly, legal frameworks regulating the access, use and protection of personal data need to be developed and regularly reviewed.

Across all income settings, infrastructure should be developed, and training provided to apply approaches grounded in data and enable the application of artificial intelligence such as machine-learning and deep-learning to dementia research. Open-source and offline software should be developed through public–private partnerships to support digitally disadvantaged groups, while an increase in capacity and investment takes place.

Knowledge translation and implementation

The time gap between evidence generation and its implementation in clinical practice is often too long 13 . Similarly, the translation and uptake of evidence into policy is also hampered owing to lack of awareness from policy-makers and communication between the various sectors 7 .

The blueprint therefore emphasizes the need for increased efforts and dedicated resources to disseminate research evidence to relevant stakeholders in a timely manner. It is also key to specifically strengthen the field of implementation science through long-term strategic investment and requirements for grant proposals to include implementation strategies, either into policy or practice, when relevant.

Often, knowledge, skills and infrastructure that are required for dementia research and implementation may not be present in all settings. To address this, the research community can share expertise by building strong international networks, shared databases and platforms that link diverse researchers, facilitate multidisciplinary collaboration and ensure that research findings can be implemented in diverse settings at local, national and international levels.

Strengthening of regulatory frameworks

Regulatory frameworks for drug development and clinical trials are sometimes seen as barriers to research progress. However, a strong, well-formulated and transparent regulatory environment is a key driver of research and an important enabler of collaboration and successful research implementation. Complexity and a lack of transparency in regulatory environments, combined with divergent international norms and standards, may create barriers that will hinder the establishment of collaborations and slow down the implementation of innovations 7 .

This warrants the creation of ethically sound guidelines by regulatory agencies that anticipate the evidence and requirements necessary for regulatory review and policy development, to fast-track life-changing scientific advances. This would be further facilitated by international harmonization of norms and standards and international agreements for the establishment of worldwide collaborations.

The next steps in implementing the drivers of research

All stakeholders have a role in operationalizing these interconnected drivers of dementia research and making research an integral part of the public health response to dementia, fully recognizing the wide societal impact of dementia with consequences that span well beyond the healthcare and social care sectors.

As outlined here, national and international research agencies and funding bodies should use this blueprint to inform their funding streams and research efforts. Civil society can support advocacy efforts that align with this blueprint, aiming to create a more equitable, efficient and collaborative research landscape. Researchers can also contribute by addressing the identified research gaps. Adopting this comprehensive approach will contribute positively to the promotion and protection of overall brain health. The WHO will use its convening power to bring together stakeholders, including regulatory bodies, funders and the scientific community, to advance the actions outlined in the blueprint.

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Acknowledgements

The WHO gratefully acknowledges the financial support of Gates Ventures for the development of the WHO blueprint for dementia research. The authors alone are responsible for the views expressed in this article and they do not necessarily represent the views, decisions or policies of the institutions with which they are affiliated.

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Rodrigo Cataldi, Neerja Chowdhary, Katrin Seeher & Tarun Dua

Centre for Healthy Brain Ageing, University of New South Wales, Sydney, New South Wales, Australia

Perminder S. Sachdev & Adam Bentvelzen

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R.C., P.S.S., N.C., K.S. and T.D. developed the initial concept of this Comment. R.C., P.S.S., N.C., K.S., A.B., V.M. and T.D. contributed to discussing the content, and writing, reviewing and/or editing of the Comment.

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Cataldi, R., Sachdev, P.S., Chowdhary, N. et al. A WHO blueprint for action to reshape dementia research. Nat Aging 3 , 469–471 (2023). https://doi.org/10.1038/s43587-023-00381-6

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Advances in Alzheimer's Disease & Related Dementias Research

NIA is the primary Federal agency supporting and conducting Alzheimer’s disease research. The Institute also supports much work on cognitive health and related dementias. Below is a listing of some of the most significant NIA-supported research findings about cognitive health, Alzheimer’s disease, and related dementias from the last ten years. Advances such as these continue to push researchers ever closer to one day discovering how we may effectively prevent and treat dementia.

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