Preventing and Treating Alzheimer’s Disease and Related Dementias

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

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

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

NIH-funded trials of drug candidates

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

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

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

Behavioral and lifestyle interventions

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

Examples of progress in 2023 include:

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

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

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

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

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

Enhancing diversity and inclusion in clinical trials

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

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

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

Updates on drug discovery and development

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

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

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

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