Connecting Vascular Dementia to Obesity and High Blood Pressure, With Ruth Frikke-Schmidt, MD, PhD

Patients with a higher body mass index (BMI) may have a higher risk of vascular-related dementia later in life; this association is mediated in part through genetic predisposition to high blood pressure.1

A recent Mendelian randomization study has revealed the correlation between vascular dementia and obesity, a connection difficult to investigate directly due to the advanced age of most patients with dementia. The Mendelian format instead mimics a randomized controlled trial by using common genetic variants causing high BMI as proxies for BMI-altering medications.2

“What we were interested in was to create causal evidence for modifiable risk factors for dementia, because then they are actionable,” Ruth Frikke-Schmidt, MD, PhD, professor and chief physician at Copenhagen University Hospital, told HCPLive in an exclusive interview. “The association has been out there in literature as observational, but if it’s causal, that’s something we should deal with and prevent.”

Frikke-Schmidt and colleagues collected data from the UK Biobank and the Copenhagen General Population Study, among other databases. The study’s primary endpoint was the diagnosis of Alzheimer’s or dementia, the latter of which included vascular dementia and unspecified dementia due to sharing similar cardiovascular risk factors. Additionally, due to associations between BMI and ischemic heart disease (IHD), investigators included IHD as a positive control.2

The team performed Cox regression restricted cubic splines with 3 knots placed to give the best model fit in both the Copenhagen and UK Biobank groups. A multivariable model was fitted, adjusted for sex, age, smoking status, physical activity, alcohol consumption, and level of education. Observational associations between mediators and vascular-related dementia were also analyzed with the same methods.2

A total of 504,410 patients were included in the study, with 126,655 coming from the Copenhagen studies and 377,755 from the UK Biobank. Among the Copenhagen arm, 2260 participants developed vascular-related dementia, including 413 with vascular dementia and 1847 with unspecified dementia. 2111 developed Alzheimer’s disease, and 14,188 developed IHD. Of the 377,755 participants sourced from the UK Biobank, 3317 developed vascular-related dementia, including 1145 with vascular dementia and 2172 with unspecified dementia. Additionally, 2215 UK Biobank patients developed Alzheimer’s disease, and 45,539 developed IHD.2

Among the Copenhagen group, the observational association between BMI and vascular-related dementia risk was U-shaped after adjusting for age, sex, cohort, et cetera. Higher BMI was associated with a higher risk of IHD, while lower BMI was associated with a higher risk of Alzheimer’s disease. These results were similar in the UK Biobank cohort. However, following 1-sample Mendelian randomization, the odds ratio (OR) of risk of vascular-related dementia per 1-SD higher BMI in analyses using well-established genetic variants was 1.63 (95% CI, 1.13-2.35) in a meta-analysis of all involved studies. Corresponding estimates were 1.04 (0.92-1.16) for Alzheimer’s disease and 1.24 (1.1-1.39) for IHD.2

2-sample mendelian randomization analysis found an OR per 1-SD higher BMI for vascular-related dementia were 1.54 (95% CI, 1.1-2.16) using the inverse-variance weighted, 1.87 (1.22-2.85) using weighted median, and 1.98 (1.21-3.22) using weighted mode methods. Corresponding estimates were 1.08 (0.72-1.64) for Alzheimer’s disease and 1.23 (1.08-1.4) for IHD. Additionally, systolic blood pressure mediated 18% (95% CI, 10%-61%) and diastolic blood pressure mediated 25% (13%-75%) of the genetic effect of BMI on vascular-related dementia.2

Ultimately, investigators concluded that, observationally (U-shaped) and genetically (linear), high BMI is associated with an increased risk of vascular-related dementia, which is partly mediated through high blood pressure.2

“We should, of course, advocate as professionals for a heart-healthy diet in the general population,” Frikke-Schmidt said. “What is good for the heart is good for the brain – and we can start with the guidelines for heart-healthy diets and the guidelines for treating and preventing high blood pressure.”

Editor’s Note: Frikke-Schmidt reports a disclosure with Novo Nordisk.

References

1. The Endocrine Society. People with obesity may have a higher risk of dementia. Eurekalert. January 22, 2026. Accessed January 28, 2026. https://www.eurekalert.org/news-releases/1112842

2. Nordestgaard LT, Luo J, Emanuelsson F, et al. High body mass index as a causal risk factor for vascular-related dementia: A Mendelian randomization study. The Journal of Clinical Endocrinology & Metabolism. Published online January 22, 2026. doi:10.1210/clinem/dgaf662