NIH R01 Mechanistic Investigations into ADRD Multiple Etiology Dementias

Funding Opportunity Number: PAR-24-147

Deadlines: June 4, 2024 and October 4, 2024

Purpose/Research Objectives

Goal 1 of the National Plan to Address Alzheimer’s Disease is to prevent and effectively treat Alzheimer’s disease (AD) and Alzheimer’s Disease Related Dementias (ADRD). ADRD are defined as Frontotemporal dementia (FTD), Vascular Contributions to Cognitive Impairment and Dementia (VCID), Lewy Body Dementias (LBD) and Multiple Etiology Dementias (MED). Starting in 2012, the National Institute on Aging (NIA) and the National Institute of Neurological Disorders and Stroke (NINDS) have held research summits to assess the needs and set AD/ADRD research implementation milestones. The NINDS ADRD Summit in 2022 resulted in ADRD research priorities for advancing the state-of-the-science toward meeting Goal 1 of the National Plan. This NOFO is responsive to several high priority milestones established at the 2022 ADRD Summit (, including advancing basic research on the common and interacting mechanisms and risk factors of multiple etiology cognitive impairment and dementia in diverse populations, and identifying life course and multi-level mechanisms of and pathways to AD/ADRD.

Co-pathologies (e.g., tau, alpha-synuclein, TDP-43, TMEM106B, vascular) commonly occur in ADRD and having multiple pathologies results in worse cognitive impairment and dementia outcomes; however, the mechanisms behind this are unclear. More knowledge is needed around what are triggering events and what are distinct and shared mechanistic pathways, disrupted circuits, and interactions that result in cognitive deficits. This NOFO is to support research into these cellular and molecular mechanisms and spatiotemporal sequence of events of ADRD co-pathologies that drive worsening ADRD pathophysiology and how and when these lead to enhanced cognitive, behavioral, and/or functional deficits and dementia. Co-pathologies may be in the same cells or in proximate cell populations within the same model system as appropriate. Co-pathologies may interact and impact various processes, including, but not limited to, cell type selectivity and vulnerability, cellular compartmentalization/subcellular localization, brain region vulnerability and spatiotemporal evolution, neuroinflammation, apoptosis/autophagy/lysosomal pathways, metabolism and bioenergetics, circuits and synapses, microbiome dysfunction, neurovascular compromise, senescence, transcriptome and epigenome regulation, interacting protein networks, conformational changes, etc. The goal is to determine at a molecular level how ADRD-relevant co-pathologies causally accelerate disease progression and exacerbate phenotypic outcomes and how or whether such mechanisms differ among diverse human populations.

This NOFO accepts studies using various model systems, including animal models, animal/human cellular systems, organoids, postmortem tissue and other biospecimens, etc. to support investigations with a minimum of two ADRD co-pathologies (e.g., tau, alpha-synuclein, TDP-43, TMEM106B, vascular), with or without risk factors and co-morbidities, in the same model system to identify cellular and molecular mechanisms of how and when these multi-pathology interactions drive worsening ADRD pathophysiology and phenotypic outcomes, such as cognitive, behavioral, or functional impairment.

Mechanisms and risk factors may vary across diverse human populations; thus, investigators are strongly encouraged to consider this in their samples or model systems. NINDS encourages activities focused on understanding and improving health equity in neurologic outcomes in disparate populations.

For more information, please see the opportunity website.