| Title: | High Body Mass Index as a Causal Risk Factor for Vascular-Related Dementia: A Mendelian Randomization Study |
| Journal: | The Journal of Clinical Endocrinology & Metabolism |
| Published: | 22 Jan 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41568975/ |
| DOI: | https://doi.org/10.1210/clinem/dgaf662 |
| URL: | https://research-information.bris.ac.uk/en/publications/9fee1327-ca28-434d-a0e8-2eb298f23b36 |
Publication 18500
WARNING: the interactive features of this website use CSS3, which your browser does not support. To use the full features of this website, please update your browser.
Abstract
CONTEXT: Obesity is associated with a high risk of vascular-related dementia with metabolic risk factors as potential mediators, but questions of causality remain unanswered.</p>
OBJECTIVE: We aimed to determine whether high body mass index (BMI) is a causal risk factor for vascular-related dementia, and whether any effect is mediated by hypertension, hyperlipidemia, hyperglycemia, and low-grade inflammation.</p>
METHODS: Prospective cohort studies of the general populations from the Copenhagen area and from across the United Kingdom and consortia data were included in the study. Interventions included one-sample mendelian randomization (MR), two-sample MR, and MR in mediation analyses. Both individual-level and summary-level data was used. Main outcome measures included risk of vascular-related dementia, Alzheimer's disease, and ischemic heart disease.</p>
RESULTS: In a meta-analysis of 2 one-sample MR studies, the odds ratio (OR) for 1-SD higher BMI in predicting vascular-related dementia was 1.63 (95% CI, 1.13-2.35). In a two-sample MR study, the OR for vascular-related dementia per 1-SD higher BMI was 1.54 (1.10-2.16) using the inverse-variance weighted, 1.87 (1.22-2.85) using the weighted median, and 1.98 (1.21-3.22) using the weighted mode methods. Results from MR analyses including extended numbers of genetic variants were directionally consistent. Finally, 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.</p>
CONCLUSION: Observationally (U-shaped) and genetically (linearly), high BMI is associated with a higher risk of vascular-related dementia, an association partly mediated through high blood pressure. This suggests that high BMI and high blood pressure are important modifiable risk factors for dementia prevention.</p>
12 Authors
- Liv Tybjærg Nordestgaard
- Jiao Luo
- Frida Emanuelsson
- Genevieve Leyden
- Eleanor Sanderson
- George Davey Smith
- Mette Christoffersen
- Shoaib Afzal
- Marianne Benn
- Børge G Nordestgaard
- Anne Tybjærg-Hansen
- Ruth Frikke-Schmidt
Enabling scientific discoveries that improve human health