FY 2020 Director's Overview

Transformational Tools and Technologies: Building an Infrastructure for Discovery for Alzheimer's Disease and Related Dementias

Since the passage of the National Alzheimer's Project Act in 2011, NIA has used new tools and technologies to transform the research landscape. The need for new, effective interventions for AD/ADRD is urgent. Although prevalence of dementia has fallen significantly in recent decades, ⁴ AD/ADRD remains a grave public health crisis, with as many as 5.5 million Americans affected in FY 2019. ⁵ NIA's comprehensive research program on AD and related dementias spans the spectrum of discovery, from basic neuroscience through translational research and clinical application. Regular Summits on Alzheimer's disease, Alzheimer's-related dementias, and Alzheimer's Care and Services, as well as the allocation of additional funds over the past several years, have accelerated momentum in this field. The most recent Alzheimer's disease Summit was held in FY 2018, and the next Summits on Alzheimer's-Related Dementias and AD/ADRD Care and Services are planned for FY 2019 and 2020, respectively.

Over the past few years NIH has established and pursued ambitious and exciting milestones toward the ultimate goal of identifying an effective prevention or treatment intervention for AD/ADRD by 2025. A major focus at NIA has been building an infrastructure upon which we can continue to expand our research footprint, and an important feature of many of our infrastructural initiatives is the wide availability of the data they produce to qualified investigators worldwide, with stringent safeguards to protect participant privacy. Ongoing initiatives include:

• Resilience-AD, a new program bringing together experts in genomic, epigenomic, environmental, social, and behavioral science to understand why some high-risk individuals remain dementia free. Investigators are generating dense molecular profiling data on resilient individuals and applying cutting-edge network biology modeling to identify factors that promote wellness and protect against risk.
• Discovery and validation of novel AD/ADRD genes through the Alzheimer's Disease Sequencing Project (ADSP). The ADSP promotes innovative collaboration among scientists to provide genetic samples for sequencing, with the goal of identifying from multiethnic populations new genetic variants that influence risk and protection from Alzheimer's. More than 100 investigators in the United States and Europe contribute to the ADSP.
• Molecular Mechanisms of the Vascular Etiology of Alzheimer's Disease (M²OVE-AD) Initiative, exploring how metabolic and vascular risk factors influence brain aging and AD pathology and identifying blood-based markers of the disease;
• The Alzheimer's Disease Neuroimaging Initiative, a longitudinal, multicenter study to develop clinical, imaging, genetic, and biochemical biomarkers of AD/ADRD;
• The Accelerating Medicines Partnership for AD/ADRD (see Program Portrait);
• Alzheimer's Biomarker Consortium – Down Syndrome (ABC-DS), in which researchers use biomarkers to track disease progression in people with Down Syndrome, a uniquely vulnerable population at high risk for developing AD;
• Alzheimer's Disease Preclinical Efficacy Database (AlzPED), a web-based portal for housing, sharing, and mining of data related to AD preclinical therapy development; and
• Alzheimer's Clinical Trial Consortium (ACTC), to accelerate and expand trials of AD/ADRD therapies.

The additional funding has also enabled us to significantly expand the National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD), a widely-used resource that contains DNA and other biological samples used by researchers around the world. NCRAD maintains and provides scientists with access to more than 600,000 biological samples, and NIA estimates that the increased support will facilitate collection of 300,000 additional specimens in the next three years. The repository's resources have been used by more than 150 scientists and resulted in more than 500 scientific publications, and NIA anticipates that the expansion will allow a larger number and broader range of additional studies to advance.

In addition, NIA has released over 100 public solicitations for research examining multiple facets of AD/ADRD. A few recent topics include sleep disorders and circadian clock disruption in AD/ADRD; sex differences in AD/ADRD risk and treatment response; age-associated metabolic changes in AD/ADRD; and discovery of novel approaches to AD/ADRD diagnosis.

Building on Basic Science

An understanding of aging processes at their most fundamental level is a necessary foundation for discovery of new preventive interventions and cures. For this reason, investment in research on the basic biology of aging is a high priority for NIA. Currently, a particularly promising avenue of research involves cellular senescence, a process in which cells lose function, including the ability to divide and replicate, but have the ability to secrete molecules that can damage neighboring cells. Investigators found that when treated with senolytics, or compounds that selectively remove senescent cells, mice who had previously been injected with damaging senescent cells regained physical function. Senolytics also extended lifespan and health span in naturally-aging mice. Investigators also found that clearing senescent cells from the brain preserved cognition in a mouse model of Alzheimer's disease. If these findings can be translated to humans, they may result in a major step toward delaying disease and disability in older people.

The establishment of the trans-NIH GeroScience Interest Group (GSIG) to facilitate discovery on the common risks and mechanisms behind age-related diseases and conditions has invigorated the field of basic geroscience. See the Division of Aging Biology description below for more information about this initiative.

Technological advances are facilitating research at the most fundamental levels. For example, development of a new approach to brain imaging in laboratory animals and humans has led to the discovery that the brain has its own previously unidentified waste-drainage system consisting of the glymphatic system (a clearance pathway through the brain tissue) and brain lymphatic system, which connects directly to the lymphatic vessels. These findings have spurred a reassessment of a number of basic assumptions in the field of neuroimmunology, but also opened new avenues for discovery, particularly with respect to AD/ADRD. NIA has solicited, and currently supports, research projects on the glymphatic and lymphatic system in aging and disease. These studies will be active in FY 2020.

NIA also supports an extensive portfolio of basic behavioral and social research. The Institute leads the trans-NIH Science of Behavior Change (SOBC) initiative, which seeks to promote basic research on the initiation, personalization, and maintenance of behavior change, with application to increasing adherence to treatment and prevention strategies, and to avoiding behaviors that threaten health. This groundbreaking program will celebrate 10 active years in 2019; in 2018, the SOBC initiative was the subject of a special issue of the journal Behaviour Research and Therapy. In addition, NIA is currently soliciting applications to continue its successful program of infrastructure support for development of high-priority areas of behavioral and social research relevant to aging. If meritorious applications are received, NIA expects to fund additional awards in FY 2019; these will be active in FY 2020.

Exploring the Next Frontier

As we close out the second decade of the 21st century, collaboration and cooperation are increasingly critical to expanded discovery. Within its AD/ADRD portfolio, NIA collaborates with a number of organizations and agencies on everything from rapid, precise identification of risk and protective genes to development of large-scale clinical trials. NIA also makes data generated through our scientific initiatives broadly available to qualified researchers worldwide.

The NIA-supported Health and Retirement Study (HRS) provides another example of data-sharing and collaboration on a global scale. Over 30 countries across five continents have designed surveys to be comparable with the HRS, facilitating cross-national comparisons across a wide variety of parameters. In 2018, the HRS implemented a Harmonized Cognitive Assessment Protocol (HCAP) to measure and understand dementia risk. Local versions of the HCAP are being implemented in England, continental Europe, India, Mexico, China, and South Africa, and several other countries have expressed interest. This new tool provides the research community with rich data to study the prevalence, predictors, outcomes, and future trends in cognitive functioning and dementia on a global scale, with national comparisons providing potential clues to causative factors and targets for intervention.

NIA is also preparing for the future through the establishment and support of a diverse and talented biomedical workforce. NIA supports training awards for both individuals and institutions, including some awards specifically for training in research relevant to AD/ADRD. The NIH Intramural Research Program offers training for promising scientists from high school through the postdoctoral years. The Paul B. Beeson Emerging Leaders Career Development Awards foster the careers of exceptionally talented clinical investigators who are pursuing academic leadership in aging and geriatrics. The Butler-Williams Program is a week-long "boot camp" for emerging investigators in aging, including those who specialize in topics relevant to aging of special populations, which provides intensive instruction on securing grants and the application process at NIA. Finally, the Grants for Early Medical and Surgical Specialists' Transition to Aging Research program awards small grants to enable early stage physician-scientists to get a "foot in the door" in research related to aging in their clinical specialty area.

To learn more about the NIA and its scientific priorities, see the NIA website. ⁶