High BMI ups risk of vascular-related dementia

A Mendelian randomization (MR) study shows an association between a high BMI and a higher risk of vascular-related dementia, which is partly mediated through high blood pressure (BP).

“Observationally, we found the association between BMI and vascular-related dementia to be U-shaped; genetically, we found the association to be linear,” the investigators said. “We observed similar results using a set of well-established genetic variants and an extended number of genetic variants.”

According to the researchers, ‘well-established genetic variants’ were those originally genotyped due to their strong association with risk factors of interest, while ‘extended number of genetic variants’ were from more recent genome-wide association studies (GWAS), only available in the UK Biobank.

The analysis included prospective cohort studies of the general population from the Copenhagen (CGPS/CCHS*; n=126,655) area and the UK (UK Biobank; n=377,755), as well as consortia** data. [J Clin Endocrinol Metab 2026;doi:10.1210/clinem/dgaf662]

In the Danish population, 2,260 developed vascular-related dementia, 2,111 developed Alzheimer’s disease, and 14,188 developed ischaemic heart disease. In the UK cohort, the corresponding rates were 3,317, 2,215, and 45,539, respectively.

In the Danish cohorts, there was a U-shaped observational association between BMI and risk of vascular-related dementia, with the nadir at a BMI of 27 on a continuous scale using restricted cubic splines after adjusting for covariates. The UK Biobank showed largely similar findings.

“The weighted allele score for BMI generated from well-established genetic variants was confirmed to be positively associated with measured BMI. The well-established genetic variants, as well as an extended number of genetic variants for BMI, were all associated with BMI at p<5 × 10⁻⁸ in the original GWAS,” the researchers said.

One-sample MR

In a meta-analysis of the Danish and UK cohorts, the odds ratios (ORs) for the risk of vascular-related dementia were 1.63 per 1-SD higher BMI and 2.56 per 1-SD higher systolic BP (SBP) using well-established variants.

In the UK Biobank, the ORs for the risk of vascular-related dementia were 1.27 per 1-SD higher BMI and 1.52 per 1-SD higher SBP using an extended number of variants.

Two-sample MR

Using the inverse-variance-weighted, weighted median, and weighted mode methods, the ORs for the risk of vascular-related dementia per 1-SD higher BMI were 1.54, 1.87, and 1.98, respectively, using well-established genetic variants and summary-level data. In the analysis using an extended number of variants and summary-level data, the corresponding ORs were 1.07, 1.39, and 1.47, respectively.

Using the inverse-variance-weighted method, the ORs for the risk of vascular-related dementia per 1-SD higher SBP were 1.04 using well-established variants and 1.10 using an extended number of variants.

Mediation analysis

In the mediation analyses of well-established variants, SBP accounted for 18 percent of the association between BMI and vascular-related dementia, while diastolic BP accounted for 25 percent.

“The biological mechanisms underlying the present findings are most likely caused by the effect of high BP on the brain, where higher BMI is a direct cause of higher BP,” the researchers explained. [Diabetes Care 2011;34:1481-1486; Hypertension 2009;54:84-90; Eur Heart J 2024;45:4063-4098]

Important modifiable risk factors

The lack of treatment and prevention alternatives for dementia underlines the need to identify causal modifiable risk factors. [Lancet 2020;396:413-446]

“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 BP … [These] suggest that high BMI and BP are important modifiable risk factors for dementia prevention,” the investigators said.

“This is important, as the treatment and prevention of elevated BMI and high BP represent an unexploited opportunity for dementia prevention in the clinic,” they concluded.