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.