PROJECT SUMMARY/ABSTRACT Frontotemporal Dementia (FTD) is a fatal neurodegenerative disease that presents with behavioral, cognitive, or motor dysfunction and has no effective treatments. About 20-30% of cases are familial (fFTD), caused by autosomal dominant mutations. Increasing numbers of novel therapeutics targeting these genetic abnormalities are entering clinical trials. A major barrier to fFTD therapeutic development is the lack of clinically meaningful outcome measures that can be easily collected and are sensitive to treatment effects at early stages of disease. Because fFTD is rare, participants are geographically dispersed and travel is another recruitment barrier for in-person clinical trials. To facilitate more inclusive clinical trials, investigators from the ARTFL/ LEFFTDS Longitudinal FTD (ALLFTD) consortium partnered with Datacubed Health to develop a novel smartphone application that enables remote testing of executive and motor functioning, domains affected early in fFTD. The goal of this proposal is to validate these innovative remote smartphone assessments for early detection, longitudinal monitoring, and prognostication of fFTD symptoms. To achieve this goal, the project will recruit two separate but related cohorts. The first is a cross-sectional cohort of 1,000 cognitively and functionally intact adults from across the lifespan enrolled through a collaboration with the NIH-funded Brain Health Registry (BHR). BHR participants will take the smartphone tests and online BHR clinical measures. The BHR cohort will be used to develop psychometrically robust composite scores and will be used to validate the scores in a healthy aging cohort. The second arm is a longitudinal clinical validation cohort of 400 participants from kindreds with known pathogenic fFTD mutations who will be recruited through the ALLFTD consortium, including 100 symptomatic and 150 presymptomatic fFTD mutation carriers and 150 noncarrier family controls. Participants in this cohort will complete the digital app assessments every six months for three years, along with comprehensive, annual in-person visits conducted through the parent ALLFTD study. Aim 1 will investigate the cross-sectional construct validity of the app composite scores by testing for associations with gold-standard measures of neuropsychological functioning, disease severity, and biomarkers of neurodegeneration. Aim 1 will also test whether the composites can detect early cross-sectional deficits in presymptomatic fFTD. Aim 2 will study the utility of these smartphone measures for longitudinal tracking of fFTD disease progression, and Aim 3 investigates whether these measures predict future clinical progression. If successful, this project will yield a scalable digital assessment tool for early detection, prognosis, and disease monitoring that could lead to more inclusive and powerful fFTD trials. Furthermore, as changes in executive and motor function are ubiquitous in neurological and agin...