Mechanistic Investigations into ADRD Multiple Etiology Dementias (R01 - Clinical Trial Not Allowed) | PAR 23 211

Opportunity Information: Apply for PAR 23 211

The NIH funding opportunity PAR 23-211, titled "Mechanistic Investigations into ADRD Multiple Etiology Dementias (R01 - Clinical Trial Not Allowed)," supports research projects that dig into why and how Alzheimer’s disease and related dementias (ADRD) become more severe when more than one disease process is present at the same time. The central focus is on multiple-etiology dementias, meaning proposals should not treat dementia as driven by a single hallmark pathology. Instead, applicants are expected to study at least two relevant co-pathologies together and explain how their interactions accelerate neurodegeneration and worsen clinical or behavioral outcomes. Examples of co-pathologies highlighted in the announcement include tau, alpha-synuclein, TDP-43, TMEM106B-related biology, and vascular contributions. Risk factors and co-morbidities can be included as optional layers, but the core requirement is a mechanistic emphasis on co-pathology interactions.

A key theme of the FOA is mechanistic depth. Projects should aim to identify cellular and molecular mechanisms that explain multi-proteinopathy (or mixed pathology) interactions, not just describe correlations or co-occurrence. The announcement emphasizes studying how these pathologies interact in close-by (proximate) cell populations, how their relationships vary across different brain regions, and how those interactions evolve over time. It also encourages work that examines intracellular dynamics and localization, meaning applicants should consider where within cells these pathologic processes occur (and potentially move), how cellular compartments are involved, and how those details relate to neuronal and glial dysfunction. Another important expectation is that studies look both upstream and downstream of aggregated protein states. In practice, that means not limiting the work to end-stage protein aggregates, but also investigating earlier triggering events and later consequences that connect mixed pathology to worse phenotypic outcomes, such as faster decline, broader symptom profiles, or more treatment-resistant disease trajectories.

The mechanism is an NIH R01 research project grant, and the FOA explicitly states "Clinical Trial Not Allowed," so applications must be designed as non-clinical-trial research. While human data, biospecimens, or observational analyses may be possible depending on NIH definitions and study design, the work cannot be proposed as an NIH-defined clinical trial that prospectively assigns human participants to interventions. The listing indicates an award ceiling of $500,000, and the funding instrument is a grant under the health-related activity category. The associated CFDA numbers are 93.853 and 93.866, reflecting NIH program areas relevant to neuroscience and aging/dementia research. The opportunity was created on 2023-05-23, with an original closing date listed as 2023-10-04.

Eligibility is broad and includes many U.S.-based organizational types commonly eligible for NIH grants: public and state-controlled institutions of higher education, private institutions of higher education, nonprofit organizations (with or without 501(c)(3) status), for-profit organizations (other than small businesses), small businesses, and multiple levels of government entities (state, county, city/township, special district), along with independent school districts and public housing/Indian housing authorities. Tribal eligibility is also included, spanning federally recognized Native American tribal governments and other Native American tribal organizations. The FOA additionally calls out categories often emphasized for outreach and inclusion, such as Historically Black Colleges and Universities (HBCUs), Hispanic-serving Institutions, Tribally Controlled Colleges and Universities (TCCUs), Alaska Native and Native Hawaiian Serving Institutions, and Asian American Native American Pacific Islander Serving Institutions (AANAPISIs), as well as faith-based or community-based organizations and regional organizations.

At the same time, the FOA draws clear lines around foreign participation. Non-domestic (non-U.S.) entities and non-domestic components of U.S. organizations are not eligible to apply. However, "foreign components" as defined by the NIH Grants Policy Statement are allowed, meaning a U.S. applicant organization can include certain discrete project elements performed outside the U.S. when properly justified and compliant with NIH policy. This structure is meant to keep the applicant organization domestic while still permitting specific international collaborations or resources when they are essential to the science.

Overall, this opportunity is aimed at pushing the field beyond single-pathology explanations of dementia and toward integrated, mechanism-driven models that can explain why mixed pathology cases tend to show worse neurodegeneration and more severe or complex clinical outcomes. Competitive applications under this FOA would typically be expected to articulate a clear mechanistic hypothesis about co-pathology interaction, specify how the team will track these interactions across regions and time, and connect molecular/cellular events to meaningful phenotypic consequences without proposing an NIH-defined clinical trial.

• 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 2023-05-23.
• Applicants must submit their applications by 2023-10-04. (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.

Apply for PAR 23 211

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