Observational studies have suggested for some time that obesity might raise the risk of dementia for a person with obesity. But observational studies have limitations. They can suggest a hypothesis. Not prove causality. So the news of evidence from a Mendelian randomization study that obesity can cause vascular dementia is important.

Methods and Findings

This study used Mendelian randomization (MR). The aim was to test whether high BMI is a causal risk factor for vascular-related dementia. Further, the investigator aimed to explore potential mediators such as blood pressure and other metabolic traits. MR takes advantage of genetic variants that influence BMI to approximate the effect of long-term higher BMI on dementia risk. Doing so introduces less potential for confounding than traditional observational studies. The investigators combined data from large cohorts in Denmark (Copenhagen City Heart Study and Copenhagen General Population Study) and the UK Biobank and incorporated both one-sample and two-sample MR approaches using genetic association summary statistics.

Across methods, genetically predicted higher BMI was consistently associated with an increased odds of vascular-related dementia: approximately 1.5–1.9 times higher risk per 1 standard deviation increase in BMI depending on the MR estimator used. Mediation analyses indicated that elevated systolic and diastolic blood pressure explained a meaningful portion (roughly 18–25%) of the BMI effect on dementia risk, suggesting that high blood pressure is a key pathway linking adiposity to vascular cognitive decline.

An Opportunity for Preventing Dementia

Liv Tybjærg Nordestgaard and her study co-authors were quite clear about the importance of their findings:

“In conclusion, we find that high BMI is likely to be on the causal pathway to vascular-related dementia, and that a substantial fraction of this risk is mediated through high blood pressure. This is important, as the treatment and prevention of elevated BMI and high blood pressure represent an unexploited opportunity for dementia prevention in the clinic.”

The recent failure of semaglutide for delaying the progression of Alzheimer’s disease was a disappointment. But it was not the end of the quest for understanding the implications of the link between dementia and obesity.

This new study fills a gap in our understanding. Certainly, Mendelian randomization has its limitations. But it does point the way for further research on ways to prevent dementia, possibly by treating and preventing obesity.

Click here for the study, here, here, and here for further perspective.

Maria, painting by Helene Schjerfbeck / Wikimedia Commons