Decoding Dementia: NIH’s Groundbreaking Research Pushing Toward Prevention and Cure

Dementia, encompassing complex brain disorders like Alzheimer's disease (AD) and related dementias (ADRD), poses an immense global public health challenge. These conditions progressively destroy cognitive abilities—including memory, thinking, and reasoning skills—imposing a tremendous emotional, physical, and financial toll on individuals and their care partners. Although dementia is more common in older adults, it is vital to understand that it is not a normal part of aging. Currently, an estimated 7.1 million Americans are living with Alzheimer’s symptoms, a number predicted to soar to over 13.9 million by 2060. While Alzheimer’s is the most frequently diagnosed form, many individuals experience "mixed dementia," having two or more forms simultaneously, such as Lewy body dementia (LBD) or vascular contributions to cognitive impairment and dementia (VCID). The urgent need for effective diagnostics, prevention, treatments, and care underscores the intensive efforts led by the National Institutes of Health (NIH), with the National Institute on Aging (NIA) and the National Institute of Neurological Disorders and Stroke (NINDS) driving the nation’s research strategy.

Accelerating New Avenues for Treatment and Prevention

The research landscape has seen significant advances, particularly in developing treatments for early-stage Alzheimer’s. The U.S. Food and Drug Administration (FDA) has approved specific antibodies designed to fight beta-amyloid (known as "anti-amyloid immunotherapies") to slow disease progression. Although the NIH did not directly fund the final clinical trials leading to these approvals, the therapies are built upon decades of NIH investments in fundamental research, such as studies on the amyloid protein itself and the development of Amyloid PET imaging technology.

However, the complexity of dementia—where a single diagnosis often reflects a combination of cellular and functional changes—necessitates a broad approach. The NIH is heavily investing in a precision medicine approach, which aims to find the right intervention for the right person at the right stage of the disease. As of the end of fiscal year 2024 (FY24), the NIH was funding 495 clinical trials for Alzheimer’s and related dementias, including over 225 trials testing various pharmacological and non-pharmacological interventions.

Innovative Drug Development and Repurposing

NIH investments span the entire drug development pipeline, from basic science to clinical trials. One promising development is CT1812, a small molecule drug that may treat multiple types of dementia. NIH-funded preclinical research suggests CT1812 works by displacing toxic protein aggregates—specifically beta-amyloid and alpha-synuclein—at the synapses (the communication spaces between brain cells), potentially preventing neurotoxicity. Researchers are currently recruiting participants for a Phase 2B study to evaluate CT1812’s effectiveness in improving cognitive function in people with early Alzheimer’s.

To increase efficiency, NIH is utilizing innovative trial designs and exploring drug repurposing. For instance, the newly launched PSP Platform Trial for progressive supranuclear palsy (PSP), a rare neurological disorder, allows researchers to test multiple treatments simultaneously under one research protocol. Furthermore, based on findings of abnormal electrical activity in Alzheimer’s brains, studies are evaluating whether drugs already approved for other conditions, such as the epilepsy drug levetiracetam, could be repurposed. One study found that levetiracetam might slow brain atrophy in a subgroup of individuals who do not carry the high-risk Alzheimer’s gene variant, APOE ε4, highlighting the need for precision medicine.

As of March 2025, at least 25 new drug candidates developed with NIH funding have progressed to human trials, targeting over a dozen biological processes, including inflammation, metabolic factors, and amyloid/tau biology. One of these candidates, Buntanetap, originally discovered by NIH scientists, is now in a Phase III clinical trial to assess its safety and effectiveness as a disease-modifying treatment for Alzheimer’s, Parkinson’s disease, and LBD.

Gene Therapies and Anti-Amyloid Refinement

Gene therapy represents a potentially innovative path to prevention or treatment by correcting problems with DNA. NIH research is exploring gene therapy to increase the amount of the protective protein APOE ε2 in individuals who carry the high-risk variant APOE ε4. This approach, built upon NIH-funded preclinical studies, is now being evaluated in human trials.

In parallel, NIH is funding research to refine the use of currently approved anti-amyloid immunotherapies (like lecanemab and donanemab). This includes critical trials to determine if these drugs can prevent or delay Alzheimer’s onset by treating individuals before clinical symptoms begin. The AHEAD 3-45 Study, for example, is testing lecanemab’s safety and efficacy in people with amyloid in their brain but who have not yet experienced cognitive decline, leveraging NIH-developed blood biomarker tests for screening. Research is also actively investigating Amyloid-Related Imaging Abnormalities (ARIA)—adverse events such as brain hemorrhage or edema reported during anti-amyloid trials—to understand why ARIA occurs and which patients are at highest risk, further supporting a precision medicine approach to safety.

Behavioral and Lifestyle Interventions

Non-pharmacological interventions are also showing promise in reducing dementia risk factors and improving cognition. Studies indicate that managing blood pressure, using hearing aids, and personalized health coaching can reduce dementia risk in specific populations. For example, a cognitively enriched form of tai chi, which adds mental challenges to traditional physical movement, was found to be superior to the standard form in improving global cognition for people with mild cognitive impairment (MCI).

Furthermore, research links diet to dementia risk. Individuals who followed a modified Mediterranean ketogenic diet for six weeks showed improvements in risk factors, including reduced body mass index and systemic inflammation, demonstrating the effect of diet on modifiable risk factors for Alzheimer’s. These studies confirm that risk reduction strategies are not "one size fits all," noting, for example, that cognitive training provided greater protection for individuals with better access to education and health care.

Revolutionizing Diagnosis with Advanced Tools

Historically, a definitive dementia diagnosis required a post-mortem brain autopsy. Today, NIH-funded research is leading the development of newer, less invasive, and less expensive diagnostic tools, crucial for implementing treatments at the earliest, most effective disease stages.

Breakthrough Blood Biomarkers

The past year has seen significant improvements in blood tests for Alzheimer’s, notably through the measurement of a specific phosphorylated form of the tau protein known as p-tau217. A study found that the p-tau217 blood test accurately detects Alzheimer’s pathology at all stages—even before symptoms appear—performing comparably to the current gold standard spinal fluid tests.

The accuracy of a commercial blood test, PrecivityAD2, was significantly improved by combining p-tau217 detection with plasma Aβ (amyloid beta). This validated clinical tool is now reshaping how researchers detect and clinicians diagnose dementia, particularly by screening participants for anti-amyloid clinical trials. NIH is also making great strides in identifying biomarkers for related dementias, such as a new spinal fluid biomarker that may help detect amyotrophic lateral sclerosis (ALS) and frontotemporal disorders (FTD) in early stages.

AI, Speech, and Imaging Innovations

Artificial intelligence (AI) is being leveraged to spot early warning signs of dementia. NIH-funded researchers trained computer programs on electronic health records (EHRs) to predict an Alzheimer’s diagnosis with approximately 86% accuracy seven years before clinical diagnosis and 90% accuracy one year in advance. This modeling also identified sex-specific risk factors, such as osteoporosis being a warning sign for women and chest pain for men.

Subtle changes in speech are also emerging as potential markers. NIH-funded studies found that changes in speech patterns, like taking longer and more frequent pauses, are linked to an increase in the tau protein, suggesting speech markers could help health care providers diagnose Alzheimer’s or FTD earlier.

In brain imaging, innovative MRI techniques like Neurite Orientation Dispersion and Density Imaging (NODDI) and Diffusion-weighted magnetic resonance imaging (dMRI) are proving promising for detecting LBD. These tools help evaluate white matter injury and free-water changes in the brain, correlating with cognitive decline and offering new ways to track LBD progression. The progress in diagnostics is critical for primary care, where early dementia detection is often missed. NIH-supported tools, such as the rapid, culturally unbiased 5-Cog cognitive test, aim to improve screening and triple the odds of patients receiving dementia-related care within 90 days of assessment.

Understanding Risk and Protective Factors

To develop universal prevention and treatment options, NIH invests in understanding how genetic, environmental, social, and behavioral factors influence risk and resilience.

Genetics and Ancestry

Genetic factors influence at least 80% of the common late-onset Alzheimer’s cases. The strongest genetic risk factor is the APOE ε4 gene variant. Recent findings show that people with two copies of APOE ε4 (APOE ε4 homozygotes) have a 60% chance of developing Alzheimer’s by age 85, suggesting this form may share characteristics with genetically determined early-onset Alzheimer’s. Importantly, NIH research emphasizes the need to study genetic ancestry, as APOE ε4 confers different levels of risk across different populations. Researchers have identified rare gene variants associated with late-onset Alzheimer’s in people with African ancestry, underscoring the importance of tailored biomarker development for diverse populations.

Conversely, researchers have identified rare gene variants that provide protection. For example, the APOE ε3-Christchurch (APOE3Ch) variant was associated with a delayed onset of cognitive impairment in a family with a very high prevalence of Alzheimer’s. Furthermore, a man genetically predisposed to early-onset Alzheimer’s remained cognitively healthy decades longer than expected. Genetic analysis revealed he carried nine protective variants his relatives lacked, suggesting that resilience is influenced by a combination of factors.

Lifestyle, Social Factors, and Sex Differences

NIH studies continue to affirm that healthy lifestyles—including not smoking, being physically active, limiting alcohol, and maintaining a healthy diet—are linked to better cognitive function. An unfavorable social environment, marked by economic instability or low education, is linked to increased dementia risk, though healthy lifestyles can offer some protection. Smoking was identified as the lifestyle factor most closely linked to cognitive decline in middle-aged and older European adults.

NIH research is also characterizing sex-based differences in dementia risk. While women make up roughly two-thirds of individuals diagnosed with Alzheimer’s, and although men experience steeper declines in brain volume and cognitive performance once amyloid pathology appears, women’s memory networks may have less effective compensatory mechanisms, potentially explaining an accelerated cognitive decline trajectory in women.

Identifying Core Biological Pathways

NIH research is uncovering diverse molecular, cellular, and systemic processes—or biological pathways—involved in dementia progression.

Active research focuses on vascular contributions to cognitive impairment and dementia (VCID), investigating the strong links between vascular disease, cardiac disease, and cognitive decline. Research has shown that small clumps of beta-amyloid can damage arterial walls in the brain by triggering molecular pathways that reduce energy production and cause cell death.

Another key area is brain metabolism, or energy production. Researchers found that abnormal beta-amyloid and tau increase the activity of a protein called IDO1 in astrocytes (cells that support neurons), reducing the astrocytes’ ability to provide energy to neurons. Reducing IDO1 activity reversed this dysfunction, suggesting it may be a valuable therapeutic target.

Furthermore, the APOE gene and the immune system interaction are a robust area of study. NIH-funded scientists determined that the APOE ε4 risk variant promotes lipid buildup in immune cells found in the brain, called microglia. Blocking the APOE protein from binding to a receptor on the surface of microglia in mouse models reduced beta-amyloid plaques and associated symptoms. These findings suggest that targeting the immune system, particularly microglia, could potentially slow or halt dementia progression.

Advancing Care and Caregiving Research

In addition to searching for cures, NIH funds extensive research to improve comprehensive care and support for those living with dementia and their care partners. Researchers have developed computational models to help predict the need for nursing home care among community-dwelling older adults with dementia, using factors like age, general health, and driving status.

Studies also highlight disparities in dementia care, finding that expenditures are higher for Black and Hispanic Medicare beneficiaries compared to White beneficiaries. Moreover, the monetary value of informal (unpaid) caregiving is estimated to be significantly higher for Hispanic ($44,656 annually) and Black ($37,508 annually) caregivers compared to White caregivers ($25,121 annually).

Finally, NIH-funded research is characterizing lucid episodes—periods of mental clarity reported by family members of individuals with severe dementia. Caregivers often describe these as positive "blips" in a negative journey. Researchers have identified four types of lucid episodes, often precipitated by external stimuli like family visits. Understanding these episodes is critical for improving ongoing care and developing a more nuanced understanding of the neurobiology of dementia.

Strengthening the Research Infrastructure

To accelerate discoveries, NIH is bolstering the research enterprise through robust data sharing, innovative resources, and workforce development. The NIH’s Center for Alzheimer’s and Related Dementias (CARD), a collaboration between NIA and NINDS, is a centralized hub working to bridge basic, preclinical, and clinical research. CARD develops resources like specialized stem cell lines (iPSCs) representing various genetic variants and ancestral backgrounds to enable global research collaborations.

Crucially, NIH is embracing artificial intelligence and machine learning (ML). Tools like FAIRkit use AI to automate data harmonization—the process of integrating data from various sources into a unified dataset—while CARD.AI is an advanced tool designed to answer biomedical research questions related to neurodegenerative disorders.

NIH also supports extensive workforce development programs, from high school and undergraduate training to comprehensive programs like IMPACT-AD, which has trained over 150 participants, including early-stage investigators, in conducting dementia clinical trials.

These sustained and increasing investments, guided by decades of research and spurred by the National Plan to Address Alzheimer’s Disease, continue to advance our collective understanding of dementia’s complexity—from its risk factors and underlying biology to new avenues for treatment and compassionate care. NIH remains committed to leveraging these achievements to bring us closer to preventing and treating dementia for all people.