Skip to main content
U.S. flag

An official website of the United States government

Milestone 2.N

AD Related Dementias – Specific

Clarify unique and converging cellular mechanisms related to tau pathogenesis, C9orf72 hexanucleotide repeat expansions, GRN mutations, and other targets and pathways contributing to FTD neurodegeneration.

Success Criteria

  • Support research that investigates mechanism of tau-driven neurotoxicity and its relationship to the formation and spreading of tau pathological inclusions in a prion-like manner.

  • Support research to identify the predominant mechanism(s) of C9orf72 hexanucleotide repeat expansion pathogenesis in FTD.

  • Support research examining the role of GRN mutations in FTD pathogenesis.

Summary of Key Accomplishments

To advance knowledge about the diverse mechanisms underlying neurodegeneration in FTD, NINDS and NIA recently awarded three new grants of the “Center without Walls for Mechanisms of Neurodegeneration in Frontotemporal Dementia (FTD)” program. These team-based science projects are developing new approaches to better understand several different cellular defects have been associated with FTD.

Another NIH-funded project has led to the development of an exciting new non-animal model, called an organoid, which is a 3D multicellular reconstruction of the mouse brain that can better mimic the complex function of a brain than can traditional cellular models. Using these organoids, researchers identified cellular events that precede neurodegeneration in FTD and could potentially be targeted for therapeutic intervention.

NIH-funded researchers have also discovered a mechanistic link between FTD/ALS-linked mutations and abnormal TDP-43 protein aggregation and identified drug candidates that might be able to block this interaction. These mechanistic clues are critically important to develop new therapeutic strategies for FTD.

Further, mutations in the progranulin (PGRN) and C9ORF72 genes are well-established genetic causes of FTD and FTD-ALS, but they seem to trigger different disease pathways that ultimately lead to FTD vs. FTD-ALS. Recently, NIH-funded studies provided new insights into the different ways that PGRN and C9ORF72 mutations cause neurons to die. These discoveries are a critical step toward devising new therapeutic strategies for FTD and FTD-ALS.

This information is current as of July 2022.

Research Implementation Area
AD Related Dementias - Specific
In Progress

Accomplishments/Implementation Activities

Funding Initiatives

Research Programs and Resources

Research Highlights

Relevant Recommendations

An official website of the National Institutes of Health