Functional Target Validation for Alzheimer's Disease-Related Dementias (ADRDs) (R61/R33 Clinical Trial Not Allowed) | RFA NS 22 055

Opportunity Information: Apply for RFA NS 22 055

This NIH funding opportunity (RFA-NS-22-055) supports projects that take promising, newly identified therapeutic targets for Alzheimer’s disease-related dementias (ADRDs) and put them through rigorous, practical functional validation before anyone invests heavily in drug development. The central goal is to reduce risk in the therapy pipeline by showing, with strong experimental evidence, that changing a target’s activity or expression produces meaningful and reproducible biological effects in relevant disease models. A key requirement is that the target or pathway must already be implicated by human evidence, specifically through tissue expression findings or genetic data generated from human samples. In other words, the program is designed for targets that have already emerged from human-driven discovery, and now need careful validation to confirm they are truly actionable and therapeutically relevant.

The award uses a two-stage phased structure under the R61/R33 mechanism and explicitly does not allow clinical trials. The first phase (R61, up to two years) is focused on building and proving the tools needed to test the target properly. That can include developing or tailoring model systems, assays, protocols, and technologies that can modulate the target in cells or tissues, then measuring the downstream functional consequences. Modulation could involve increasing or decreasing expression, inhibiting or activating the target, or otherwise altering pathway function, as long as the approach is fit for purpose and can generate interpretable functional readouts in vitro or in vivo. The main point of this initial stage is feasibility: demonstrating that the team can reliably manipulate the target and measure biologically meaningful outcomes in disease-relevant settings.

If the R61 phase meets its milestones and establishes technical feasibility, the project can transition into the second phase (R33). The R33 phase emphasizes careful measurement, replication, and cross-validation of results, including testing the impact of target modulation using different modalities and confirming findings across collaborating laboratories. This phase is explicitly tied to NIH rigor and reproducibility expectations, meaning applicants should plan for strong experimental design, appropriate controls, blinding or randomization when applicable, pre-specified analysis approaches, transparent reporting, and strategies to ensure results are not lab-specific artifacts. The program is structured to reward targets that hold up under independent or multi-site scrutiny, helping the field avoid false leads and focus on targets that are more likely to translate.

Collaboration is not optional in spirit: the FOA expects a substantial team effort that involves independent laboratories working together, which aligns with the emphasis on reproducibility and cross-site validation. Applications are expected to address objectives for both phases at submission, laying out a coherent plan that begins with tool and model development and then progresses into robust, reproducible functional testing. While the text includes a reference to UG3/UH3, the listed mechanism is R61/R33; practically, the expectation is the same: propose a milestone-driven, two-part project where the first stage enables the second, and where the second stage focuses on confirmation and robustness.

The scientific scope is intentionally broad across the ADRD spectrum rather than being limited to a single diagnosis. Projects may target mechanisms relevant to frontotemporal degeneration (FTD), Lewy body dementias (including dementia with Lewy bodies), Parkinson disease dementia (PDD), vascular contributions to cognitive impairment and dementia (VCID), and mixed dementias, including the diagnostic and biological complexity associated with multiple-etiology dementias. This breadth signals that NIH is looking for well-supported targets wherever they arise across dementia-related disorders, as long as they are grounded in human data and can be validated with strong functional evidence.

Eligibility is broad across U.S.-based organizations and includes many common applicant types: state, county, and local governments; special district governments; independent school districts; public and private institutions of higher education; federally recognized Native American tribal governments; tribal organizations; 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 FOA also highlights eligibility for a range of mission-driven or capacity-building institution types, including HBCUs, Hispanic-serving institutions, Tribally Controlled Colleges and Universities, Alaska Native and Native Hawaiian Serving Institutions, and Asian American Native American Pacific Islander Serving Institutions, as well as faith-based or community-based organizations and eligible federal agencies. At the same time, it places firm limits on foreign involvement: non-U.S. entities and foreign institutions are not eligible to apply, non-U.S. components of U.S. organizations are not eligible, and foreign components (as defined by NIH policy) are not allowed.

Administratively, the opportunity is offered by the National Institutes of Health under a grant funding instrument in the health category, associated with CFDA numbers 93.853 and 93.866. The original posting date is July 21, 2022, and the original closing date listed is November 8, 2022. Overall, the program is best understood as a targeted push to move from human-implicated targets to experimentally validated targets that can justify the next steps in translational development, with an unusually strong emphasis on multi-lab confirmation and rigor before the field commits major resources.

• The National Institutes of Health in the health sector is offering a public funding opportunity titled "Functional Target Validation for Alzheimer's Disease-Related Dementias (ADRDs) (R61/R33 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 2022-07-21.
• Applicants must submit their applications by 2022-11-08. (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 RFA NS 22 055

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