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 22 228

Frequently Asked Questions (FAQs) - NIH PAR-22-228 (U01) Sex Differences in AD/ADRD

1) What is PAR-22-228?

PAR-22-228 is a National Institutes of Health (NIH) Funding Opportunity Announcement (FOA) that supports cooperative agreement research projects using the U01 mechanism. The scientific focus is Alzheimer disease (AD) and Alzheimer disease-related dementias (ADRD), with a specific emphasis on understanding how sex differences shape brain aging, AD/ADRD risk, disease trajectories, and responses to prevention or treatment.

2) What is the main goal of this funding opportunity?

The program aims to move beyond broad, averaged findings by developing a more biologically grounded understanding of how sex-related biology influences heterogeneity in AD/ADRD. NIH is seeking research that can help explain why different individuals develop different AD/ADRD phenotypes, progress at different rates, or respond differently to interventions, and to support a precision-medicine approach that treats sex differences as a central biological driver rather than a secondary demographic variable.

3) What does "Clinical Trial Optional" mean for this FOA?

"Clinical Trial Optional" means applicants may propose studies that include clinical trials, but a clinical trial is not required. Projects may be basic, translational, clinical, or integrative across these areas as long as they align with the core goals described in the opportunity.

4) What types of research approaches does NIH want to see?

NIH emphasizes integrative experimental and analytical approaches that connect multiple layers of biology and evidence. The program is interested in studies that link sex-related biology with genetics, environment, and other host factors to explain differences in risk, progression, phenotype, and treatment response in AD/ADRD.

5) How is "sex" treated in this program's scientific framing?

This FOA explicitly pushes applicants to treat sex-related biology as a central driver to be studied directly, rather than using sex only as a demographic covariate or a secondary subgroup analysis. The goal is to better understand biological mechanisms behind sex differences and how those mechanisms interact with other factors relevant to AD/ADRD.

6) What "host factors" are specifically highlighted in the opportunity?

The announcement specifically calls out hormonal status as a host factor of interest, including both gonadal hormones and hormones produced within the brain. This reflects interest in endocrine and neuroendocrine influences and how they may alter molecular pathways relevant to neurodegeneration, resilience, and treatment response.

7) At what biological levels are applicants expected to study these questions?

A key expectation is that funded projects will examine interactions at multiple levels of biological complexity. The FOA explicitly mentions work spanning cells, tissues, organs or organ systems, and populations.

8) Are basic science projects allowed?

Yes. The opportunity describes potential inclusion of mechanistic laboratory studies, such as cell-based experiments or animal model work examining sex-linked molecular pathways relevant to AD/ADRD.

9) Are translational projects allowed?

Yes. The FOA describes translational efforts that bridge model systems to human biology, such as biomarker development or validation, as examples of approaches that can fit the program goals.

10) Are clinical or population-based studies allowed?

Yes. The opportunity notes clinical or population-based analyses, including cohort studies and carefully designed intervention studies, as potential approaches to evaluate sex-specific risk profiles or treatment effects in AD/ADRD.

11) What kinds of outcomes or impacts is NIH aiming for?

The end goal is a more comprehensive framework for individualized prevention and therapy in AD/ADRD that incorporates sex differences as a meaningful part of precision medicine. NIH is seeking research that can clarify mechanisms and trajectories in ways that ultimately support more tailored prevention and treatment strategies.

12) What funding mechanism is used, and what does it imply?

The FOA uses the U01 cooperative agreement mechanism. In general, a cooperative agreement implies that NIH program staff typically have a more active role than they would under a standard research project grant, often to support coordination, shared expectations, or stewardship so that the work stays aligned with program goals and produces broadly useful outputs.

13) What is the CFDA number associated with this opportunity?

The opportunity is identified as a discretionary health research program under CFDA 93.866.

14) Is there an award ceiling or a stated expected number of awards?

The source information provided does not list an award ceiling or an expected number of awards. Those details may vary or may be defined in the full FOA and related NIH budget guidance.

15) Who is eligible to apply?

Eligibility is broad and includes a wide range of organizations capable of biomedical research. Eligible applicants include state, county, city, and special district governments; public and state-controlled institutions of higher education; private institutions of higher education; independent school districts; federally recognized Native American tribal governments and other tribal organizations; public housing authorities/Indian housing authorities; nonprofits with and without 501(c)(3) status; for-profit organizations (other than small businesses) as well as small businesses; and other entities.

16) Are minority-serving institutions and community-based organizations eligible?

Yes. The FOA explicitly highlights additional eligible applicants, including Historically Black Colleges and Universities (HBCUs), Hispanic-serving Institutions, Tribally Controlled Colleges and Universities (TCCUs), Alaska Native and Native Hawaiian Serving Institutions, Asian American Native American Pacific Islander Serving Institutions (AANAPISIs), and faith-based or community-based organizations.

17) Are federal agencies, U.S. territories, or non-U.S. organizations eligible?

Yes. The FOA notes eligibility can include eligible federal agencies, U.S. territories or possessions, and non-U.S. entities (foreign organizations).

18) When was this opportunity created and what closing date is listed?

The opportunity was created on 2022-08-16 and the provided data lists an original closing date of 2023-01-10.

19) What does NIH mean by addressing "heterogeneity" in AD/ADRD?

In the context provided, heterogeneity refers to meaningful differences across individuals in AD/ADRD presentation and course, such as differences in phenotypes, disease trajectories, rates of progression, and responses to prevention strategies and treatments. The FOA prioritizes research that can explain how sex differences contribute to these variations.

20) Does the FOA encourage combining multiple disciplines or evidence types?

Yes. The opportunity emphasizes integrative experimental and analytical approaches and describes work that spans multiple biological levels (from cells to populations). The broad eligibility and focus on connecting biology, genetics, environment, and host factors also signal interest in multidisciplinary teams and cross-cutting programs of research.