The NIH's Novel Mechanism Research on Neuropsychiatric Symptoms (NPS) in Alzheimer's Dementia (R01 Clinical Trial Optional) funding opportunity supports research into the biological, behavioral, and social mechanisms underlying NPS in Alzheimer’s Disease (AD) and Alzheimer’s Disease-Related Dementias (ADRD). NPS, also referred to as Behavioral and Psychological Symptoms of Dementia (BPSD), include symptoms such as aggression, psychosis, anxiety, apathy, agitation, and sleep disturbances. These symptoms significantly affect patients' quality of life and caregiver burden and often accelerate functional decline and institutionalization. The initiative aims to enhance mechanistic understanding to identify novel therapeutic targets for intervention.

Key objectives include exploring neural, behavioral, and environmental pathways contributing to NPS. Applications may integrate advanced methodologies such as neuroimaging, epigenetics, cognitive neuroscience, and behavioral intervention research. Studies may focus on mechanisms driving NPS, identifying biomarkers for treatment response, or clarifying how unmet needs (e.g., medical comorbidities, social isolation) exacerbate symptoms. This funding also seeks innovative approaches like leveraging the NIMH's Research Domain Criteria (RDoC) framework to explore dimensional constructs across behavioral and neurobiological domains.

This R01 mechanism allows for comprehensive studies with preliminary data and a project duration of up to five years. The companion R21 mechanism (PAR-25-064) is available for exploratory research without preliminary data. Topics of interest include assessing circadian disruptions, examining the gut-brain axis, analyzing neural circuitry differences, and using digital technologies or computational modeling to study NPS. NIA-specific interests include multi-omics approaches, sex and racial disparities in NPS mechanisms, and systems biology studies.

Eligible applicants include higher education institutions, nonprofits, for-profit organizations, and foreign entities. Collaborative, interdisciplinary applications are highly encouraged. Award budgets are not capped but must align with project needs. NIH-defined mechanistic clinical trials are permitted under this funding opportunity, focusing on understanding processes or pathways rather than testing clinical efficacy or safety.

Applications will be reviewed for scientific merit, significance, innovation, rigor, feasibility, and alignment with program priorities. Specific criteria include the integration of multiple analytic levels, the quality of mechanistic hypotheses, and plans for addressing diversity and inclusion in study populations. The deadline for initial applications is February 5, 2025, with subsequent cycles in June and October. Data management and sharing plans are mandatory, with an emphasis on transparency and reproducibility.

Researchers must ensure compliance with NIH policies, including human subjects protections, data safety monitoring, and use of Common Data Elements (CDEs). The NIH strongly encourages data sharing through repositories like the NIMH Data Archive and the NIA's AD Knowledge Portal. For additional guidance, potential applicants are advised to consult with program contacts listed in the funding announcement.