Aging
Association of Genetic Risk Score for Alzheimer’s Disease With Late-Life Body Mass Index and Alcohol Use in All of Us Participants: Evaluating Reverse Causation Minhyuk Choi* Minhyuk Choi Maria Glymour Scott Zimmerman
Background
Identifying the earliest age of physiologic or behavioral changes associated with Alzheimer’s Disease (AD) is essential to guide prevention efforts and understand confounding in observational research. Changes in body mass index (BMI) or alcohol use may be early symptoms of AD but BMI and alcohol use may also influence AD risk. Using genetic risk of AD in a reverse Mendelian Randomization design establishes temporal order. We estimated the age at which differences in BMI and drinking behavior could first be detected comparing individuals with higher compared with lower genetic risk of AD.
Methods
For All of Us cohort participants (N=160,740) who were dementia-free and aged 40+ at baseline, we calculated BMI with measured height and weight. Weekly drink count was self-reported at enrollment. An AD genetic risk score (AD-GRS) was calculated based on 23 single-nucleotide polymorphisms. We regressed weekly drinks on AD-GRS in linear models. We used linear mixed models to assess the age-specific association of AD-GRS with BMI, stratified by decade of age. We calculated the age at which AD-GRS began to be associated with differences in each outcome by comparing people with low to high AD-GRS using cross-validated sex- and ancestry-adjusted models.
Results
Average baseline age was 60.58 (SD=11.21). Alcohol use declined slightly with age (-0.018/year [95% CI -0.020, -0.155]), and this decline was roughly 17% faster for people with a 1 SD higher AD-GRS, but there was no clear age at which this association emerged. BMI declined slightly with age (-0.019 units/year [95% CI: -0.020, -0.018]) and this decline was roughly 35% faster for people with a 1-SD higher AD-GRS. This association was first detectable in people ages 50-60.
Conclusion
Our findings suggest that AD genes accelerate age-related weight loss starting in middle age and may also be associated with alcohol use reductions.
