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AD-Related Dementias Focus
Elucidate the mechanisms of cell type vulnerability and cell-intrinsic and –extrinsic effects on FTD pathogenesis, with the goal of accelerating development of therapeutic targets.
2032 PAR-22-029: Longitudinal Single Cell Characterization of ADRD Postmortem Tissue (R01 Clinical Trial Not Allowed) PAR-24-234: Mechanistic Investigations into ADRD Associated Protein Structures in Biological Settings (R01 - Clinical Trial Not Allowed) RFA-NS-25-011: Functional Target Validation for Alzheimer's Disease-Related Dementias (R61/R33 Clinical Trial Not Allowed) 2.AA In Progress DN 2022 ADRD Summit: Frontotemporal Dementia, Milestone 7, Priority 3 Scientists discover a new molecular pathway shared by two neurodegenerative disorders Press Release: Abnormal proteins found in the spinal fluid of people with ALS and frontotemporal dementia Highlight: Abnormal proteins found in the spinal fluid of people with ALS and frontotemporal dementia Research on Disease Mechanisms Projects funded under PAR-22-029
- At least three new studies focused on cell-intrinsic and cell-environment mechanisms that result in susceptibly to or resilience against clinically relevant FTD disease mechanisms, and that are potential targets for intervention.
- Develop at least 2 human or humanized cell-based models that recapitulate cell-specific vulnerability or resilience to FTD disease mechanisms.
Summary of Key Accomplishments:
FTD involves progressive atrophy involving the frontal and/or temporal lobes of the brain. No treatments currently exist that can stop or prevent neurodegeneration in FTD. NIH funds efforts to identify disease-modifying treatments for FTD, in part through research aimed at better understanding the underlying cellular mechanisms driving FTD pathogenesis and clinical syndromes. These mechanisms may be leveraged as therapeutic targets and/or biomarkers.
As one example, NIH-funded scientists discovered that the protein TAF15 forms pathological fibers in the brain tissue of a subset of FTD patients who do not have the typical pathology associated with tau or TDP-43 proteins. These discoveries hint at potential new disease mechanisms and possible new therapeutic targets. To further support therapy development and a better understanding of what underlies FTD at a cellular level, NIH has issued a funding opportunity to develop novel and complex models of FTD, as well as other dementias, that reflect multiple aspects of how the disease manifests in humans.
In addition, NIH-funded scientists have discovered that mislocalization of a protein, known as TDP-43, alters the genetic instructions for a set of genes, including UNC13A and stathmin 2, both of which are known to be linked to neurodegeneration in FTD and are possible therapeutic targets. Research here may have broader impacts given that TDP-43 mislocalization is seen in other degenerative diseases, including Alzheimer’s, chronic traumatic encephalopathy (CTE), limbic predominant age-related TDP-43 encephalopathy (LATE), and neuromuscular disorders.
The key accomplishments summary is current as of June 2024.