Integrative Research to Understand the Impact of Sex Differences on the Molecular Determinants of AD Risk and Responsiveness to Treatment (U01 Clinical Trial Optional) | PAR 25 224

Opportunity Information: Apply for PAR 25 224

This funding opportunity, titled "Integrative Research to Understand the Impact of Sex Differences on the Molecular Determinants of AD Risk and Responsiveness to Treatment (U01 Clinical Trial Optional)," is a National Institutes of Health (NIH) cooperative agreement solicitation (Funding Opportunity Number PAR 25 224) focused on Alzheimer s disease (AD) and AD-related dementias (ADRD). The program is designed to support research that explains, in a mechanistic and clinically meaningful way, how sex differences shape brain aging trajectories, influence AD/ADRD risk and clinical presentation, and affect how individuals respond to both pharmacologic and non-pharmacologic prevention or treatment approaches. The emphasis is on integrative work that connects basic biology to translational and clinical insights, with the flexibility to include clinical trials but not requiring them.

At its core, the NOFO is asking applicants to move beyond single-factor explanations and build comprehensive research programs that can account for the heterogeneity seen in AD/ADRD. The central scientific goal is to understand how multiple drivers interact across different levels of biology to produce different risk profiles and treatment responses in females and males. This includes the interaction of genes and genetic architecture, environmental exposures and social or behavioral factors, and host factors such as hormonal status. Importantly, the NOFO explicitly calls out both gonadal hormones and brain-derived hormonal influences, signaling an interest in endocrine biology, neurosteroid pathways, life stage transitions, and other hormone-linked processes that may alter vulnerability or resilience over time. The initiative is also framed around trajectories, meaning it is not only concerned with end-stage disease outcomes but also with how risk and biology evolve across aging and disease progression.

A notable feature of this opportunity is its insistence on studying these questions across multiple tiers of biological complexity. Applicants are encouraged to consider designs that connect evidence from cells to tissues, organs and organ systems, and up to populations. In practice, that points to research strategies that might combine molecular and cellular experiments with animal or human model systems, and then integrate those findings with observational cohorts, clinical phenotyping, biomarkers, or computational modeling. The term "integrative experimental and analytical approaches" suggests the NIH is looking for projects that can synthesize diverse data types or methodological perspectives, such as multi-omics, imaging, neuropathology, physiology, immunology, and rigorous analytic frameworks that make sex-informed inference more precise rather than treating sex as a simple covariate.

The program also explicitly ties sex differences to individualized prevention and responsiveness to interventions. That means the science is expected to have a line of sight to practical implications, such as identifying sex-linked molecular determinants that predict who is more likely to benefit from a therapy, who might need a different prevention strategy, or why a given intervention works better in one sex or in specific hormonal contexts. Because the mechanism is a U01 cooperative agreement, awardees should generally expect a more collaborative relationship with NIH program staff than under a typical investigator-initiated research grant, with shared responsibilities and potential coordination across projects to advance the broader goals of the initiative.

From an administrative standpoint, the opportunity is categorized as discretionary funding and uses the cooperative agreement funding instrument type. The activity category is health, and the CFDA number listed is 93.866. The application closing date is 2025-02-21, and the opportunity record indicates a creation date of 2024-12-10. The award ceiling and expected number of awards are not specified in the provided source information, which often means applicants should rely on the full announcement or NIH communications for budget expectations, typical project period guidance, and any institute-specific funding ranges.

Eligibility is broad and includes many types of domestic organizations, such as state, county, and local governments; special district governments; independent school districts; public and state-controlled institutions of higher education; private institutions of higher education; federally recognized Native American tribal governments; public housing authorities and Indian housing authorities; and a wide range of nonprofit organizations both with and without 501(c)(3) status. For-profit organizations (other than small businesses) and small businesses are also eligible, as are other types of organizations as allowed by NIH policy. In addition to these standard categories, the NOFO highlights additional eligible applicants, including Alaska Native and Native Hawaiian Serving Institutions; Asian American, Native American, and Pacific Islander Serving Institutions (AANAPISISs); Hispanic-serving Institutions; Historically Black Colleges and Universities (HBCUs); Tribally Controlled Colleges and Universities (TCCUs); Indian or Native American Tribal Governments other than federally recognized; faith-based or community-based organizations; eligible federal agencies; regional organizations; non-domestic (non-U.S.) entities (foreign organizations); and U.S. territories or possessions. This emphasis signals a clear interest in broad participation and, potentially, in research that can represent diverse populations and settings.

Overall, this NOFO is aimed at strengthening the evidence base for sex-informed, mechanism-driven understanding of AD/ADRD, with the expectation that successful projects will connect molecular determinants to real-world differences in risk, presentation, and treatment response. The most competitive applications are likely to be those that treat sex differences as a central biological and translational question, build a coherent cross-level research plan from mechanism to phenotype, and generate insights that can inform more personalized and effective prevention and therapeutic strategies for AD/ADRD.

• The National Institutes of Health in the health sector is offering a public funding opportunity titled "Integrative Research to Understand the Impact of Sex Differences on the Molecular Determinants of AD Risk and Responsiveness to Treatment (U01 Clinical Trial Optional)" and is now available to receive applicants.
• Interested and eligible applicants and submit their applications by referencing the CFDA number(s): 93.866.
• This funding opportunity was created on 2024-12-10.
• Applicants must submit their applications by 2025-02-21. (Agency may still review applications by suitable applicants for the remaining/unused allocated funding in 2026.)
• 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 25 224

[Watch] Creating a grant proposal using the step-by-step wizard inside the applicant portal: