Using a genetic risk score to estimate the earliest age of Alzheimer's disease-related physiologic change in Body Mass Index

Abstract Objectives: Weight loss is common in the years before an Alzheimer9s disease (AD) diagnosis, likely due to changes in appetite and diet. The age at which this change in body mass index (BMI) emerges is unclear but may point to the earliest manifestations of AD, timing that may be important for identifying windows of intervention or risk reduction. We examined the association between AD genetic risk and cross-sectional BMI across adults in mid- to late-life as an innovative approach to determine the age at which BMI changes and may indicate preclinical AD. Design: Observational study Setting: UK Biobank Participants: 407,386 UK Biobank non-demented participants aged 39-70 with Caucasian genetic ancestry enrolled 2007-2010. Main Outcome Measures: BMI (kg/m2) was constructed from height and weight measured during the initial visit. A genetic risk score for AD (AD-GRS) was calculated as a weighted sum of 23 genetic variants previously confirmed to be genome-wide significant predictors of AD (Z-scored). We evaluated whether the association of AD-GRS with BMI differed by age using linear regression with adjustment for sex and genetic ancestry, stratified by age grouping (40-60, 61+). We calculated the earliest age at which high AD-GRS predicted divergence in BMI compared to normal age-related BMI trends with linear and quadratic terms for age and interactions with AD-GRS. Results: In 39-49 year olds, AD-GRS was not significantly associated with lower BMI (0.00 kg/m2 per SD in AD-GRS; 95%CI: -0.03,0.03). In 50-59 year olds AD-GRS was associated with lower BMI (-0.03 kg/m2 per 1 SD in AD-GRS; 95%CI:-0.06,-0.01) and this association was stronger in 60-70 year olds (-0.09 kg/m2 per 1 SD in AD-GRS; 95%CI:-0.12,-0.07). Model-based BMI age-curves for people with high versus low AD-GRS scores began to diverge after age 47. Interpretation: Genetic factors that increase AD risk begin to predict lower BMI in adults by age 50, with greater effect later in older ages. Weight loss may manifest as an early pathophysiologic change associated with AD.