INTRODUCTION:Leisure activities impact brain aging and may be prevention targets. We characterized how physical and cognitive activities relate to brain health for the first time in autosomal dominant frontotemporal lobar degeneration (FTLD).METHODS: 105 mutation carriers (C9orf72/MAPT/GRN) and 69 noncarriers reported current physical and cognitive activities at baseline, and completed longitudinal neurobehavioral assessments and brain MRIs. RESULTS:Greater physical and cognitive activities were each associated with an estimated >55% slower clinical decline per year among dominant gene carriers. There was also an interaction between leisure activities and frontotemporal atrophy on cognition in mutation carriers. High activity carriers with frontotemporal atrophy (−1SD/year) demonstrated >2-fold better cognitive performances per year compared to less their active peers with comparable atrophy rates. DISCUSSION: Active lifestyles were associated with less functional decline and moderated brain-to-behavior relationships longitudinally. More active carriers "outperformed" brain volume, commensurate with a cognitive reserve hypothesis. Lifestyle may confer clinical resilience, even in autosomal dominant FTLD.