ObjectiveEvidence from observational studies for the effect of physical activity on the risk of Alzheimer disease (AD) is inconclusive. We performed a 2-sample mendelian randomization analysis to examine whether physical activity is protective for AD.MethodsSummary data of genome-wide association studies on physical activity and AD were used. The primary study population included 21,982 patients with AD and 41,944 cognitively normal controls. Eight single nucleotide polymorphisms (SNPs) known at p < 5 × 10⁻⁸ to be associated with average accelerations and 8 SNPs associated at p < 5 × 10⁻⁷ with vigorous physical activity (fraction of accelerations >425 milligravities) served as instrumental variables.ResultsThere was no association between genetically predicted average accelerations with the risk of AD (inverse variance weighted odds ratio [OR] per SD increment: 1.03, 95% confidence interval 0.97–1.10, p = 0.332). Genetic liability for fraction of accelerations >425 milligravities was unrelated to AD risk.ConclusionThe present study does not support a causal association between physical activity and risk of AD.