Investigating Distinct and Overlapping Mechanisms in TDP-43 Proteinopathies, including in LATE, FTD and other ADRDs (R01 - Clinical Trial Not Allowed)

Notice of Funding Opportunity Description 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 (https://www.ninds.nih.gov/news-events/events/adrd-summit-2022), including identifying overlapping pathologic mechanisms between FTD and other neurodegenerative disorders and syndromes, and defining LATE classification and diagnostic boundaries across FTLD-TDP, AD and other dementia related pathologies and their syndromes to enhance diagnosis, research, and awareness assuring diversity, inclusion, equity and accessibility. Many studies report the presence of pathologic TDP-43 (TAR DNA-binding protein 43, encoded by the TARDBP gene) in the brains of FTD, ALS, LATE, AD, LBD, TBI, Hippocampal Sclerosis, and MED cases and correlations with cognitive decline and dementia. Every TDP-43 proteinopathy manifests differently clinically; therefore, more basic research is needed to increase understanding of underlying mechanisms, to determine how this TDP-43 pathology may be causally involved in neurodegeneration and cognitive deficits, and how it may contribute to clinical heterogeneity. Mechanistic studies under this NOFO should focus on TDP-43, either alone or with other ADRD-relevant pathologies (e.g., TMEM106B, tau, alpha-synuclein, vascular) that may impact its regulation or function. Comparisons between TDP-43 proteinopathies are needed to determine commonalities and differences in cellular and molecular mechanisms and pathways, including, but not limited to, those impacted by ultrastructural aspects, spatiotemporal regulation and evolution in disease progression, regulatory elements and modulation, changes in the transcriptome/epigenome/proteome/metabolome/lipidome, risk versus resilience factors, vulnerable cell types, cellular/subcellular localization, and vascular pathology. The ultimate goal is to determine the role of these cellular and molecular mechanisms in ADRD pathogenesis, disease progression, neurodegeneration, and cognitive decline and dementia and to distinguish causal from non-causal effects. This NOFO supports studies using various model systems, including animal models, animal/human cellular systems, organoids, postmortem tissue and other biospecimens, etc. to establish deeper mechanistic insights and causal cellular and molecular relationships between TDP-43 pathology and clinical phenotypic outcomes. Additionally, it requires comparisons between at least two TDP-43 proteinopathies, one of which must be an ADRD, to further understand distinct and overlapping mechanisms in these syndromes and what is causally involved in cognitive decline and dementia. 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. Applications Not Responsive to this NOFO: Projects where the majority of the proposed research is not within NINDS's mission Projects without an ADRD cognitive decline and dementia relevance Projects that do not compare at least two TDP-43 proteinopathies, one of which must be an ADRD Projects that only focus on comparing FTD and ALS Projects that do not include any mechanistic investigations and are solely descriptive and correlative Projects that focus solely on epidemiology studies, pathology correlations, -omics analysis, or other descriptive, correlative studies Projects that are focused on biomarker discovery and/or development Non-responsive applications will be administratively withdrawn without review. Additional Considerations Applicants are strongly encouraged to consult with NINDS Scientific/Research Staff early on during the planning stage of their application (see Agency contacts, Section VII). This early contact will provide an opportunity to clarify the applicant's understanding of NINDS’s goals, policies and guidelines. See Section VIII. Other Information for award authorities and regulations.