Key Dates

Related Announcements

• December 30, 2024 - Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R21 Clinical Trial Optional). See NOFO PAR-25-331.
• December 30, 2024 - Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional). See NOFO PAR-25-332.
• January 6, 2022 - Notice of Special Interest (NOSI): Opportunities for Research in Epidemiology of Alzheimer's Disease and Alzheimer's Disease-Related Dementias (AD/ADRD) and Cognitive Resilience. See Notice NOT-AG-21-045. 
• August 25, 2021 - NIA Announces Guidance for Purchasing Identifiable Centers for Medicare and Medicaid Services (CMS) Data in Grant Applications Effective FY 2022. See Notice NOT-AG-21-055.

Issued by

National Institute on Aging (NIA)

Purpose

This Notice of Special Interest (NOSI) encourages investigator-initiated research on all aspects of cognitive epidemiology relevant to Alzheimer's disease (AD) and AD-related dementias (ADRD) and cognitive resilience, and identifies specific areas that build on current efforts supported by NIA as well as gaps and opportunities identified in the 2018 and 2021 Alzheimer’s Disease Research Summits. This NOSI is a reissue of NOT-AG-21-045. 

Applications proposing exploratory or developmental projects for which there are insufficient preliminary data as well as certain focused secondary analysis projects should consider applying to PAR-25-331. 

Applications proposing projects that already have sufficient preliminary data or a very strong and well-developed scientific premise should apply to PAR-25-332. 

Background

The etiology of AD/ADRDis complex. Ongoing cohort studies examining both AD/ADRD and cognitive aging encompass a broad array of domains including social, behavioral, environmental, cognitive, neuroimaging, biomarker, genetic, epigenetic, and other measures assessed longitudinally. These comprehensive datasets, collected from increasingly earlier stages in life, underscore the growing recognition that both risk and protective factors for AD/ADRD and cognitive aging include exposures and experiences in early and midlife, long before the appearance of any neuropathology or notable cognitive decline. Advancing our understanding of the epidemiology of both AD/ADRD and cognitive resilience is therefore likely to require the cultivation of more expansive, inclusive cohorts, enriched with diverse and representative participants and a variety of variables measured over time, capturing the dynamic interplay between policy and institutional factors, genetic predispositions, environmental influences, and individual experiences across the lifespan. Moreover, fostering greater collaboration among interdisciplinary teams is imperative to navigate the complexities inherent in identifying the etiology of these neurodegenerative conditions. Furthermore, applicants are strongly encouraged to consider sex as a biological variable, recognizing its pivotal role in shaping susceptibility to AD/ADRD and cognitive aging, and identifying differences in therapeutic efficacy and effective behavioral interventions.

Research Objectives

The following areas are of particular interest to NIA:

Augmenting existing longitudinal cohort studies

NIA supports a broad range of population-based studies to address questions related to the trajectory of AD and other aging phenotypes in diverse populations in the United States and globally. The collection and analysis of new phenotypic information from both prospective and retrospective time points, including, but not limited to: enhanced measures of cognition and function; biomarkers; -omics measures; neuroimaging; speech and language assessments, measures of oral health, and digital data on physiology, cognition, behavior, function; and environmental and occupational exposures from wearable sensors, ambient monitors, archived biospecimens and environmental samples, could broaden the impact of existing longitudinal studies. The addition of genetic data to existing or newly collected cohorts in the light of existing or novel phenotypes would allow analyses of how specific genetic variants or polygenic risk scores contribute to the risk of, or protection against, AD/ADRD and the trajectory of cognitive performance. Other emerging opportunities stem from the wider availability of electronic health records and administrative data (e.g., Centers for Medicare and Medicaid Services (CMS) Medicare claims), contextual measures capturing information about the exposome, including the social, policy, and physical environment, and the ability to collect phenotypic data online at lower cost. Additionally, incorporating environmentally well-characterized cohorts across all life stages into these studies could provide valuable insights into the role of how environmental and occupational factors interact with phenotypic and genotypic measures in the development and progression of AD/ADRD and cognitive aging outcomes.

Guidance for purchasing Identifiable CMS data in NIA grant applications can be found in NOT-AG-21-055. Note that several cohort studies are already linked to CMS claims data and therefore do not need to be purchased. A list of those Studies and Available data is accessible online. Applicants seeking to link their datasets with CMS data can apply to the NIA Data LINKAGE Program after receipt of funding.

Enabling precision medicine for AD/ADRD through deep phenotyping

Enabling precision-medicine for AD/ADRD through deep phenotyping, including advanced artificial intelligence and machine learning (AI/ML) analysis techniques, presents new opportunities for understanding the multifaceted behavioral, social, environmental, and molecular determinants of AD/ADRD risk and cognitive resilience. This NOSI invites applications that will enhance the potential of community-based cohort studies to enable precision medicine for AD/ADRD by, for example: expanding the types of cross-sectional and longitudinal ante- and post-mortem-biospecimen data collection needed to generate multiple layers of “omics” data; integrating multiple “omics” data layers through AI/ML driven data analysis techniques to uncover nuanced molecular insights into AD/ADRD; incorporating dense molecular endophenotyping (e.g., genomic, epigenomic, proteomic, metabolomic, and microbiomic); collecting nontraditional data modalities using wearable sensors and mobile-health technologies (sometimes referred to as digital phenotyping); and embedding biomarkers of environmental exposure and geocodes. The large-scale multidimensional data generated and synthesized with the above approaches, combined with AI/ML-driven analysis techniques, could serve as the basis for future systems biology and gene-environment studies as well as the development of a new taxonomy for AD/ADRD prevention.

Enhancing the power of multiethnic cohort studies

The multi-factorial etiology and heterogeneity of AD/ADRD may reveal itself in racial or ethnic differences in overall AD/ADRD risk and in putative risk or protective factors or in the progression of neuropathology and cognitive decline. Although multi-ethnic cohorts can be very informative, well-powered cohort studies are needed to identify specific risk or protective factors that vary between (sub)populations in the United States and globally. These cohorts may also benefit from the addition of measures that may help us better identify the determinants of both disease risk and cognitive resilience, including behavioral, social, structural and environmental/occupational factors, that often pattern with race/ethnicity, such as education, quality of care, social vulnerability, and access to financial instruments like loans or insurance. The 2018 and 2021 Alzheimer’s Disease Research Summits include a recommendation to establish new cohorts and/or expand existing cohorts for intense endophenotyping that are sufficiently powered to analyze the effects of gender and race/ethnic differences.

Exploring trends in the risk of AD/ADRD and their explanation via risk and protective factors in multiple populations in the United States and globally

Recent research in well-characterized cohorts suggests the age-specific risk of AD/ADRD may be declining in some populations and increasing in others. The answer to the trend question has clear implications for public health and policy. Trend data also provide a potentially powerful way to test whether putative risk or protective factors are truly causal. For example, educational attainment appears to be protective against AD/ADRD, whereas both cardiovascular disease (CVD) and female sex may confer additional risk. But the reasons for these observed patterns are not yet clear. The risk posed by female sex status, for example, may reflect sex differences affecting the disease process, which may include differences in the trajectory of hormonal changes with age or in the sex chromosome, or difference in behavioral and social risk or protective factors that pattern with gender such as educational attainment or all of these. Comparisons between cohorts differing in these factors over time will be informative and may require sophisticated analyses or meta-analyses and replication plans.

Collecting and sequencing DNA samples from well-characterized cases and controls

Research conducted by investigators from the Alzheimer’s Disease Sequencing Project (ADSP) and others has demonstrated the value of whole-genome and whole-exome sequencing in the detection of genetic variants that may modify AD risk or protection. The sequencing of more genomes of well-characterized cases and controls as well as family-based cohorts from large multiply-affected families will accelerate gene discovery for target identification efforts and accelerate the progress of the drug development pipeline. Well-characterized subjects from various sample sets are especially needed to augment statistical power in understudied and underrepresented populations including those from low- and middle-income countries (LMICs). Applicants interested in this line of research should be aware of current and emerging NIH guidance with respect to sharing genomic data and are expected to facilitate rapid data-sharing according to existing ADSP and NIA policies, which include providing all types of data to the ADSP NIAGADS/dbGaP database or the AD Knowledge Portal.

Electronic archiving of cohort studies and linkage to administrative data

Although NIH encourages broad and inclusive data-sharing for large studies, electronic archiving of data from many longitudinal cohorts is either incomplete or relies on data infrastructure that is vulnerable to research-funding lapses. The current NIH Strategic Plan for Data Science focuses on enhancing the discoverability and usability of data sets, developing appropriate analysis tools, and providing special opportunities for collaboration between epidemiologists and survey scientists on the one hand, and computer and data scientists on the other – one example being the ScHARe resource provided by NIMHD. In addition to a wealth of information relevant to cognitive epidemiology that is trapped in non-digitized or obsolete formats, there are other highly relevant data sets and biospecimen collections that have never been publicly shared or linked to administrative datasets such as those from US federal agencies such as the Census Bureau, Environmental Protection Agency, Centers for Disease Control, National Aeronautics and Space Administration, National Oceanic and Atmospheric Administration, and the United States Geological Survey (among others), as well as surveys where the greater availability of paradata and metadata would benefit researchers. Linkages to administrative data from other countries is also encouraged where allowed. NIA welcomes all applications that will make more data available for use by the research community as expeditiously as possible, and likewise encourage dissemination efforts that enhance the Findability, Accessibility, Interoperability, and Reuse of these data to examine how these exogenous factors influence the etiology of AD/ADRD across the life course using an exposomics framework.

The NIA Data LINKAGE Program can offer existing and new Studies a secure virtual environment to link their data with CMS records capturing participant Medicare and Medicaid utilization and health data. The LINKAGE program can serve as a platform to share linked datasets across multiple studies with appropriate permissions. The secure virtual environment of the LINKAGE program provides increased access to matched study data with low risk of inappropriate disclosure.

Harmonizing complex data sets relevant to AD/ADRD

There have been substantial efforts at NIH to develop brief, reliable measures (e.g., PROMIS®, NIH Toolbox®, and Mobile Toolbox) as well as recommendations for the use of off-the-shelf phenotypic measures (e.g., PhenX) in large epidemiological studies. The Gateway to Global Aging data has also created harmonized data files which are comprised of variables representing a subset of the original survey data from the HRS International Family of Studies and have been defined to be as comparable as possible across different studies. These data cover a wide range of topics including wealth, retirement, pension, health care, family, caregiving, and the environmental exposome.  NIA also supports several population-representative, demographically diverse educational cohort studies such as Add Health, EdSHARe, Wisconsin Longitudinal Study, Project Talent, and NLSY-79. These studies provide a resource for scholars seeking to elucidate how education and other social factors impact health disparities and health outcomes, including AD/ADRD, over the life course. Nevertheless, more work is needed to create crosswalks between these measures and those that have been historically used in cohort studies. The need for harmonization across these platforms is particularly acute in studies that include longitudinal clinical, neuroimaging, genetic and genomic, and biomarker data that are costly to obtain. Coordination and harmonization of data from existing cohort studies with the Alzheimer’s Disease Neuroimaging Initiative (ADNI), the Accelerating Medicines Partnership (AMP) effort for AD/ADRD, datasets available in the Gateway to Global Aging data, the AD Knowledge Portal and the ADSP (among others) are also welcome.

Harmonizing dementia assessment, additional data collection, and analysis to enhance cross-national comparisons

As important as harmonization is to the study of dementia trends and the risk and protective factors (against dementia) that differ between cohorts, more work is needed on the harmonization of dementia-assessment methods that could inform cross-national comparisons. This requires more than simple translation of instruments, since even the best ones may not operate equivalently in low- and middle-income countries (LMICs) where literacy rates and levels of educational attainment are much lower. Recent work done within the HRS International Family of Studies and the Harmonized Cognitive Assessment Protocol (HCAP), which is a sub-study within the HRS in the US and within some of the studies in the HRS International Family of Studies, has included the collection of cognitive data that can be used to compare dementia prevalence cross-nationally. This data has also facilitated secondary data analyses that help illuminate how different policy, institutional, social, and cultural factors influence AD and ADRD-related outcomes cross-nationally.

Applications to use or extend these approaches or develop new approaches to harmonize dementia assessments suitable for cross-national comparisons and feasible both in clinical and field settings, are encouraged, including harmonization of HCAP data and/or developing crosswalks between HCAP and non-HCAP data. Evaluations of the quality of HCAP and non-HCAP data related to the assessment of dementia are also encouraged. In addition, applications proposing the collection of data in LMIC using the HRS/HCAP framework are encouraged, as well as analysis of international HRS/HCAP data to identify risk and protective factors for dementia and illuminate causal mechanisms.

Application and Submission Information

This notice applies to due dates on or after March 11, 2025 and subsequent receipt dates through November 17, 2027.

Submit applications for this initiative using one of the following notice of funding opportunity (NOFO) or any reissues of these announcements through the expiration date of this notice.

• PAR-25-331 - Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R21 Clinical Trial Optional)
• PAR-25-332 - Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional)

All instructions in the How to Apply - Application Guide and the notice of funding opportunity used for submission must be followed, with the following additions:

• For funding consideration, applicants must include “NOT-AG-24-042” (without quotation marks) in the Agency Routing Identifier field (box 4B) of the SF424 R&R form. Applications without this information in box 4B will not be considered for this initiative.

Applications nonresponsive to terms of this NOSI will not be considered for the NOSI initiative.

Inquiries

Please direct all inquiries to the contacts in Section VII of the listed notice of funding opportunity with the following additions/substitutions:

Dallas W. Anderson, Ph.D.
Division of Neuroscience
National Institute on Aging (NIA)
Telephone: 301-402-6693
Email: [email protected]

Minki Chatterji, Ph.D.
Division of Behavioral and Social Research
National Institute on Aging (NIA)
Telephone: 301-435-0998
Email: [email protected]