Extension of Mendelian Randomization to Identify Earliest Manifestations of Alzheimer Disease: Association of Genetic Risk Score for Alzheimer Disease With Lower Body Mass Index by Age 50 Years

Weight loss or lower body mass index (BMI) could be an early symptom of Alzheimer disease (AD), but when this begins to emerge is difficult to estimate with traditional observational data. In an extension of Mendelian randomization, we leveraged variation in genetic risk for late-onset AD risk to estimate the causal effect of AD on BMI and the earliest ages at which AD-related weight loss (or lower BMI as a proxy) occurs. We studied UK Biobank participants enrolled in 2006-2010, who were without dementia, aged 39-73, with European genetic ancestry. BMI was calculated with measured height/weight (weight (kg)/height (m)(2)). An AD genetic risk score (AD-GRS) was calculated based on 23 genetic variants. Using linear regressions, we tested the association of AD-GRS with BMI, stratified by decade, and calculated the age of divergence in BMI trends between low and high AD-GRS. AD-GRS was not associated with BMI in 39- to 49-year-olds (beta = 0.00, 95% confidence interval (CI): -0.03, 0.03). AD-GRS was associated with lower BMI in 50- to 59-year-olds (beta = -0.03, 95% CI: -0.06, -0.01) and 60- to 73-year-olds (beta = -0.09, 95% CI:-0.12, -0.07). Model-based BMI age curves for high versus low AD-GRS began to diverge after age 47 years. Sensitivity analyses found no evidence for pleiotropy or survival bias. Longitudinal replication is needed; however, our findings suggest that AD genes might begin to reduce BMI decades prior to dementia diagnosis.