Low Body Mass Index Not Associated with Alzheimer’s Disease

Low body mass index is not associated with an increased risk of Alzheimer’s disease after all, according to a recent study published in The Journal of Clinical Endocrinology & Metabolism.

Researchers led by Ruth Frikke-Schmidt, MD, DMSc, PhD, chief physician at Rigshospitalet in Copenhagen, Denmark, and associate research professor at the University of Copenhagen, point out that a recent study established that low BMI is associated with an increased risk of dementia, but Frikke-Schmidt’s team wanted to clarify whether this observational association reflects a causal effect.
“Although prior studies found an association between Alzheimer’s disease and low BMI, the new findings suggest this is not a causal relationship,” Frikke-Schmidt says. “The association can likely be explained by the fact that individuals with Alzheimer’s disease are more likely to have low BMIs due to loss of appetite and weight loss in the early stages of the disease.”

The researchers studied 95,578 individuals from the Copenhagen General Population Study (CGPS) with up to 36 years of follow-up. Of the participants, 645 individuals developed Alzheimer’s disease. The team also analyzed data from up to 249,796 individuals participating in the Genetic Investigation of ANthropometric Traits (GIANT) and the International Genomics of Alzheimer’s Project (IGAP) consortium for the genetic variants closely linked to low BMI, using a Mendelian randomization approach. They analyzed the study participants’ DNA for the presence of five genetic variants that have strong associations with BMI. Based on how many variants were found, participants were divided into four groups to reflect the likelihood of low BMI.

The analysis found the presence of the genetic variants tied to low BMI was not associated with increased risk of Alzheimer’s disease. For comparison, the researchers examined if individuals with genetic variants connected to high BMI were more likely to have type 2 diabetes and did find the expected causal relationship. The authors write: “The causal odds ratio for a 1 kg/m2
genetically determined lower BMI was 0.98 (95 % confidence interval: 0.77-1.23) for a weighted allele score in the CGPS. Using 32 BMI decreasing variants from GIANT and IGAP the causal odds ratio for Alzheimer disease for a one standard deviation lower genetically determined BMI was 1.02 (0.86-1.22).
Corresponding observational hazard ratios from the CGPS were 1.07 (1.05-1.09) and 1.32 (1.20-1.46) for a 1 kg/m2 and a 1 standard deviation lower BMI, respectively.”

Based on these results, the authors conclude 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.” “We found individuals with lifelong low BMI due to genetic variation were not at increased risk of Alzheimer’s disease,” Frikke-Schmidt says. “Since genetic variants are not affected by other risk factors or diseases, this is a clean measure that can help to determine causality. The findings highlight that testing causality of a risk factor is pivotal before considering changing public health recommendations based on observational data alone.”