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

Abstract

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 (β = 0.00, 95% confidence interval (CI): -0.03, 0.03). AD-GRS was associated with lower BMI in 50- to 59-year-olds (β = -0.03, 95% CI: -0.06, -0.01) and 60- to 73-year-olds (β = -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.

Keywords: Alzheimer disease; Mendelian randomization; body mass index; disease natural history.

Figure 1

Hypothesized relationships between genetic risk for Alzheimer disease (AD) and body mass index (BMI). Based on our conceptual model (A), we hypothesized that there would be an association between AD genetic risk score (AD-GRS) and lower late-life BMI but no association between the AD-GRS and midlife BMI. Individuals with higher genetic risk for AD are at higher likelihood of developing AD, which we conceptualize as beginning with neurodegeneration and early cognitive decline and subsequently leading to dementia. High midlife BMI might also promote AD/cognitive decline through alternative pathways. However, AD-related changes might also lead to lower late-life BMI or weight loss. The age at which an association between AD-GRS and lower BMI emerges could also point to an early manifestation of AD-related BMI change. This interpretation requires several assumptions, violations of which are represented by dashed lines (B): that there are no pleiotropic or independent effects of the AD-GRS on BMI via mechanisms unrelated to AD and that survival factors do not strongly affect the composition of the analytical sample.

Figure 2

Age-related curves for body mass index (BMI) (A) and smoking (negative control) (B) for high and low Alzheimer disease genetic risk score (AD-GRS), UK Biobank, United Kingdom, 2006–2010. Predicted curves for 10th (low) versus 90th (high) percentile of genetic risk for AD began to diverge at age 47 years and were significantly different by age 56 years.