Objectives – To examine whether genetically proxied lean mass is associated with risk of Alzheimer’s disease. Design – Two-sample Mendelian randomization (MR) study. Setting – The UK Biobank study and genome-wide association study meta-analyses of Alzheimer’s disease (AD) and intelligence. Participants – Summary-level genetic data from 1) 450,243 UK Biobank participants with impedance measures of lean mass and fat mass, 2) an independent sample of 21,982 cases of AD and 41,944 controls without Alzheimer’s disease, 3) a replication sample of 7,329 cases of AD and 252,879 controls, and 4) 269,867 individuals partaking in a genome-wide association study of intelligence. Exposure – Genetic variants proxying variation in lean mass. Main outcome measures – Clinically diagnosed Alzheimer’s disease. Results - A one-standard deviation increase in genetically proxied appendicular lean mass (ALM) was associated with a 12% reduced risk of Alzheimer’s disease (odds ratio 0.88, 95% confidence interval 0.82-0.95, P=5x10-4). This finding was replicated in an independent AD cohort (0.89, 0.81-0.99, P=0.03) and was consistent in sensitivity analyses more robust to the inclusion of pleiotropic variants. Adjusting for potential mediation through genetically proxied intelligence did not attenuate the effect of ALM on AD. Higher genetically proxied ALM was also associated with increased intelligence (standard deviation increase in intelligence per standard deviation increase in ALM 0.09, 95% confidence interval 0.06-0.11, P=2.09x10-4), and adjusting for potential mediation through genetically liability to AD did not attenuate this association. We found similar results for the outcomes of AD and intelligence when using the exposures of genetically proxied trunk lean mass and whole-body lean mass respectively, adjusted for genetically proxied fat mass. Conclusions – These findings support that lean mass as a possible modifiable causal protective factor for AD. The mechanisms underlying this finding, as well as its clinical and public health implications warrant further investigation
