Body Mass Index and Risk of Alzheimer's Disease: A Mendelian Randomization Study of 399,536 Individuals

Context: Recently, data on 2,000,000 people established that low body mass index (BMI) is associated with increased risk of dementia. Whether this observational association reflects a causal effect remains to be clarified.

Objective: We tested the hypothesis that there is a causal association between low BMI and high risk of Alzheimer's disease.

Design, Setting, and Participants: Using a Mendelian randomization approach, we studied 95,578 individuals from the Copenhagen General Population Study (CGPS) with up to 36 years of follow-up and consortia data on 303,958 individuals from the Genetic Investigation of Anthropometric Traits (GIANT) and the International Genomics of Alzheimer's Project (IGAP).

Main Outcome Measure: Risk of Alzheimer's disease.

Results: The causal odds ratio for a 1-kg/m2 genetically determined lower BMI was 0.98 [95% confidence interval (CI), 0.77 to 1.23] for a weighted allele score in the CGPS. Using 32 BMI-decreasing variants from GIANT and IGAP the causal odds ratio for Alzheimer's disease for a 1-standard deviation (SD) lower genetically determined BMI was 1.02 (95% CI, 0.86 to 1.22). Corresponding observational hazard ratios from the CGPS were 1.07 (95% CI, 1.05 to 1.09) and 1.32 (95% CI, 1.20 to 1.46) for a 1-kg/m2 and a 1-SD lower BMI, respectively.

Conclusions: Genetic and hence lifelong low BMI is not associated with increased risk of Alzheimer's disease in the general population. These data suggest that low BMI is not a causal risk factor for Alzheimer's disease and that the corresponding observational association likely is explained by reverse causation or confounding.