The National Institutes of Health (NIH), through the National Institute of Mental Health (NIMH) and the National Institute on Aging (NIA), seeks applications for the R21 program "Novel Mechanism Research on Neuropsychiatric Symptoms (NPS) in Alzheimer's Dementia." This program aims to advance understanding of the mechanisms underlying neuropsychiatric symptoms (NPS) in individuals with Alzheimer’s disease (AD) or Alzheimer’s disease-related dementias (ADRD). Findings are expected to inform therapeutic target discovery and interventions to mitigate NPS, which includes symptoms like aggression, anxiety, depression, agitation, sleep disturbances, and wandering.

This funding opportunity is specifically suited for exploratory projects with high risk/high reward potential that may lack preliminary data but offer strong theoretical foundations. The maximum budget is $275,000 in direct costs over two years, with no more than $200,000 requested in any single year. The award project period is capped at two years, and the mechanism allows applications that may or may not propose clinical trials.

Key research areas include understanding the neurobiological, behavioral, and environmental mechanisms underlying NPS in AD/ADRD. Encouraged studies include those employing advanced methods such as neuroimaging, neurophysiology, gene expression analysis, and behavioral interventions. Topics of interest encompass neural circuit dysfunction, circadian rhythm disruptions, and the role of historical psychiatric conditions. Projects may also explore novel technologies like passive sensing and computational modeling to identify factors influencing NPS. Studies that utilize multidimensional frameworks, such as those informed by the Research Domain Criteria (RDoC), are particularly encouraged.

Applications must emphasize multidimensional approaches, integrating genetic, cellular, physiological, and behavioral analyses. Nonresponsive applications include those examining mechanisms at a single level of analysis, such as isolated genetic or behavioral studies without integration across domains. NIA has additional priorities, such as the role of the gut-brain axis, multi-omics approaches, and addressing sex and racial disparities in NPS mechanisms.

Eligible applicants include higher education institutions, nonprofits, for-profit organizations, and foreign institutions. Required registrations include SAM.gov, eRA Commons, and Grants.gov, and all proposals must conform to NIH guidelines for data management and transparency. Submissions are due on NIH standard deadlines: February 16, June 16, and October 16.

Applications will be evaluated based on their significance, innovation, rigor, and feasibility. The R21 mechanism supports conceptual advances and innovative approaches, and reviewers will focus on the project’s potential to advance scientific understanding of NPS mechanisms. NIH policies on data sharing, rigor, and reproducibility must be addressed in all applications. The program expects investigators to share data through platforms such as the NIMH Data Archive or other NIH-designated repositories to maximize research impact.

Investigators are encouraged to engage with NIMH and NIA contacts early in the application process to ensure alignment with program goals. This funding opportunity supports innovative projects poised to transform understanding and treatment of NPS in AD/ADRD.