Mechanistic Investigations into ADRD Multiple Etiology Dementias (R01 - Clinical Trial Not Allowed) | PAR 24 147

Opportunity Information: Apply for PAR 24 147

Mechanistic Investigations into ADRD Multiple Etiology Dementias (R01 - Clinical Trial Not Allowed) is an NIH research grant opportunity (PAR-24-147) focused on Alzheimer’s disease and related dementias (ADRD) where more than one disease process is contributing to decline. The central goal is to fund mechanistic, hypothesis-driven studies that explain how interactions between at least two co-occurring brain pathologies make neurodegeneration worse and lead to more severe or different clinical outcomes than a single pathology alone. In practical terms, the program is looking for work that moves beyond simply documenting that mixed pathologies co-exist, and instead digs into the cellular and molecular reasons those pathologies amplify damage when they appear together.

A key requirement is that proposed projects must include a minimum of two relevant co-pathologies. Examples named in the announcement include tau, alpha-synuclein, TDP-43, TMEM106B-related biology, and vascular contributions, but applicants can incorporate other well-justified co-pathologies as appropriate. Risk factors and co-morbidities are optional additions, meaning investigators may include elements such as genetic risk, metabolic disease, inflammation, cerebrovascular risk, or other clinical co-conditions if they strengthen the mechanistic story. The emphasis remains on how multiple etiologic processes intersect to drive disease biology and shape phenotypes.

The scientific scope prioritizes studies that examine how co-pathologies interact in specific cells and circuits over time, rather than treating the brain as a uniform tissue. Projects are encouraged to look across brain regions and disease stages, and to focus on proximate cell populations where interacting pathologies might realistically influence one another (for example, within the same neuron, within neuron-glia neighborhoods, or along connected networks). The NOFO also highlights the importance of intracellular dynamics and localization, supporting approaches that clarify where pathogenic proteins and related processes are within cells, how they traffic, seed, spread, or disrupt organelles, and how those processes change as disease progresses.

Another explicit priority is investigating events both upstream and downstream of aggregated protein states. That means the program is interested in mechanisms that occur before visible aggregates form (such as early misfolding, impaired clearance, post-translational modifications, stress responses, or changes in RNA/protein homeostasis) as well as consequences after aggregation (such as synaptic dysfunction, inflammatory activation, vascular impairment, cell death pathways, and network-level dysfunction). The intent is to identify the sequence of events that explains why mixed proteinopathies or mixed etiologies lead to worse cognitive, behavioral, and neurologic outcomes, and to pinpoint the mechanistic links that could become targets for future interventions.

This is an R01 research project grant mechanism under the NIH and is designated Clinical Trial Not Allowed, so the funded work should be basic, translational, or preclinical in nature rather than testing interventions in humans as clinical trials. The opportunity sits within NIH’s health research portfolio (CFDA 93.853 and 93.866). The listing includes an award ceiling of $500,000, indicating the funding level referenced in the source summary, and an original closing date of 2024-10-04.

Eligibility is broad and includes many types of domestic U.S. organizations, such as public and private institutions of higher education, state and local governments, federally recognized tribal governments, certain tribal organizations, independent school districts, special district governments, public housing authorities/Indian housing authorities, nonprofits (with or without 501(c)(3) status), for-profit organizations (other than small businesses), and small businesses. The NOFO also explicitly calls out additional eligible applicant categories, including Alaska Native and Native Hawaiian Serving Institutions, Asian American Native American Pacific Islander Serving Institutions (AANAPISIs), Hispanic-serving Institutions, Historically Black Colleges and Universities (HBCUs), Tribally Controlled Colleges and Universities (TCCUs), faith-based or community-based organizations, eligible federal agencies, regional organizations, and U.S. territories or possessions.

Foreign eligibility is restricted in a specific way. Non-domestic (non-U.S.) entities are not eligible to apply as the applicant organization, and non-domestic components of U.S. organizations are also not eligible to apply. However, foreign components are allowed as defined in the NIH Grants Policy Statement, meaning a U.S.-based applicant may include well-justified collaborations or project elements conducted abroad if they meet NIH’s rules for foreign components and are scientifically necessary.

Overall, the opportunity is aimed at clarifying the mechanistic biology of mixed-etiology dementias by requiring at least two co-pathologies and encouraging detailed, time- and region-resolved studies of how interacting disease processes worsen neurodegeneration and alter clinical phenotypes. The program’s focus on cellular proximity, intracellular localization, and upstream/downstream events around aggregation signals a preference for projects that can map causal chains and interaction points, rather than purely descriptive co-occurrence studies.

• The National Institutes of Health in the health sector is offering a public funding opportunity titled "Mechanistic Investigations into ADRD Multiple Etiology Dementias (R01 - Clinical Trial Not Allowed)" and is now available to receive applicants.
• Interested and eligible applicants and submit their applications by referencing the CFDA number(s): 93.853, 93.866.
• This funding opportunity was created on 2024-02-06.
• Applicants must submit their applications by 2024-10-04. (Agency may still review applications by suitable applicants for the remaining/unused allocated funding in 2026.)
• Each selected applicant is eligible to receive up to $500,000.00 in funding.
• Eligible applicants include: State governments, County governments, City or township governments, Special district governments, Independent school districts, Public and State controlled institutions of higher education, Native American tribal governments (Federally recognized), Public housing authorities/Indian housing authorities, Native American tribal organizations (other than Federally recognized tribal governments), Nonprofits having a 501 (c) (3) status with the IRS, other than institutions of higher education, Nonprofits that do not have a 501 (c) (3) status with the IRS, other than institutions of higher education, Private institutions of higher education, For-profit organizations other than small businesses, Small businesses, Others.

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