PROJECT SUMMARY Frontotemporal dementia (FTD) is a severe neurodegenerative disorder with marked heterogeneity in underlying pathology, genetics, clinical presentation and disease course. No treatment options are available to cure FTD or to slow its disease progression, and FTD is eventually fatal with a disease duration ranging between 2 and >20 years. Currently, reliable predictors of prognosis are limited, which is crucial in terms of patient management but also hampers the evaluation of potential disease modifying treatments. Genetic and epigenetic markers seem to be promising prognostic markers, but their utility have not been examined in FTD. The overall aim of the proposed study is to improve prediction of prognosis in FTD. To this end, we will (i) examine epigenetic profiles of FTD disease status, (ii) assess the contribution of epigenetic age predictors and genetic risk profiles to FTD disease status, and (iii) perform an integrated analysis of available genetic, molecular, and clinical data to establish its predictive value of FTD disease progression and outcome. We will make use of a unique cohort of deeply phenotyped FTD patients and controls, including extensive neuropsychological information, genetic data (i.e., mutation carrier-status, sequencing data), biofluid (e.g., cerebrospinal fluid (CSF)) and, for some patients, post-mortem tissue and data. We will select the most relevant clinical features of disease progression, including conventional outcomes (i.e., age of onset, disease duration) and FTD-specific measures, such as longitudinal neuroimaging measures, (social) cognition, behavior and personality. It is now firmly established that epigenetic markers are associated with aging and mortality. We will therefore measure genome-wide DNA methylation levels from genomic DNA extracted from whole blood, to examine aging and disease progression in FTD. Moreover, we will establish whether genetic risk profiles are also predictive of FTD progression and outcome. In short, our project will increase the ability to predict the rate of progression in FTD patients, which is imperative for patients and their caregivers, as well as for patient stratification in future clinical trials in FTD. This is a high-risk, high-reward project using an extremely well-characterized cohort of patients and controls from a biobank in Amsterdam, The Netherlands. If biological markers for FTD disease and disease progression can be identified in this relatively homogenous sample, large-scale studies will ensue to validate the findings in clinical samples of diverse genetic backgrounds across the United States and the globe.