Unravelling the Relationship Between Height, Lean Mass, Alzheimer’s Disease and Cognition Through Mendelian Randomization

Background: Genetic evidence from Mendelian randomization (MR) analyses suggests that higher lean mass causally protects against Alzheimer’s disease (AD) and enhances cognitive function. However, the potential confounding role of height, which shares genetic etiology with lean mass, has not been fully examined. Methods: Genetic predictors of whole-body lean mass were obtained from a genome-wide association study (GWAS) performed in the UK Biobank cohort (UKB; n = 448,322). Genetic predictors of height were also obtained from UKB (height_0.5M = 455,332) and from a GWAS meta-analysis (height_1.5M n = 1,578,425). The study outcomes included clinically diagnosed AD (21,982 cases and 41,944 controls) and cognitive performance (n = 269,867). All study participants were of European ancestry. We conducted univariable and multivariable MR analyses to examine the total and independent effects of lean mass and height on the specified outcomes under different statistical adjustment strategies. Results: In univariable MR analyses, genetically proxied lean mass (odds ratio [OR] per 1-standard deviation [SD] increase 0.81, 95% confidence interval [CI] 0.72–0.91, p = 3.8 × 10⁻⁴) and height (OR 0.90, 95% CI 0.84–0.96, p = 0.001) were associated with reduced risk of AD. Genetically proxied lean mass (β 0.10, 95% CI 0.08–0.12, p = 6.24 × 10⁻⁶) and height (β 0.07, 95% CI 0.05–0.08, p = 1.16 × 10⁻¹⁵) were further associated with improved cognitive performance. In multivariable MR analyses, adjustment for height_1.5M partially attenuated the lean mass association with AD (OR 0.91, 95% CI 0.74–1.12, p = 0.40), whereas the height_1.5M-AD association remained similar after adjusting for lean mass (OR 0.89, 95% CI 0.79–1.00, p = 0.04). Adjustment for height also attenuated the association of lean mass with cognitive performance (β 0.00, 95% CI −0.07–0.06, p = 0.94), whereas height maintained a similar association with improved cognitive performance after adjustment for lean mass (β 0.07, 95% CI 0.03–0.10, p = 0.001). Conclusions: Height may confound the genetic associations between lean mass and both cognitive performance and AD risk. Residual direct effects of lean mass on AD risk cannot be excluded due to limitations in statistical power and genetic instrument strength in MVMR. These findings emphasize the necessity of adjusting for height when using MR to investigate the clinical effects of lean mass.