Association of genetic risk score for Alzheimer's disease with late-life body mass index in all of us: Evaluating reverse causation

INTRODUCTION Decreases in body mass index (BMI) may be early consequences of Alzheimer's disease (AD) pathophysiological changes. Previous research in the UK Biobank estimated that AD-related genes began affecting BMI around age 47. We assessed whether this result could be replicated using longitudinal data in an independent cohort. METHODS Using All of Us (AOU) (N = 197,619, aged 30+) data, we estimated linear mixed models for associations of Z-scored AD-Genetic Risk Score (AD-GRS) with BMI, stratified by decade of age. We calculated the earliest age at which AD-GRS was associated with differences in BMI using cross-validated models adjusted for demographics. RESULTS Higher AD-GRS was statistically associated with lower BMI in participants aged 60-70 (b = -0.060 [-0.113, -0.007]). Best fitting models suggested the inverse association of AD-GRS and BMI emerged beginning at ages 47-54. DISCUSSION AD genes accelerate age-related weight loss starting in middle age. Highlights Understanding when physiological changes from amyloid pathology begin is key for AD prevention. Our findings indicate that AD-associated genes accelerate midlife weight loss, starting between 47 and 54 years. AD prevention research should consider that disease pathology likely begins by middle age.