INTRODUCTION: Little is known about effects of physical activity (PA) in genetically driven early-onset autosomal dominant Alzheimer’s disease (AD). METHODS: A total of 372 individuals participating at the Dominantly Inherited Alzheimer Network study were examined to evaluate the cross-sectional relationship of PA with cognitive performance, functional status, cognitive decline, and AD biomarkers in cerebrospinal fluid. Mutation carriers were categorized as high or low exercisers according to WHO recommendations. RESULTS: Mutation carriers with high PA showed significantly better cognitive and functional performance and significantly less AD-like pathology in cerebrospinal fluid than individuals with low PA. Mutation carriers with high PA scored 3.4 points better on Mini Mental State Examination at expected symptom onset and fulfilled the diagnosis of very mild dementia 15.1 years later compared with low exercisers. DISCUSSION: These results support a beneficial effect of PA on cognition and AD pathology even in individuals with genetically driven autosomal dominant AD. Copyright © 2018 the Alzheimer’s Association. All rights reserved.