| Title: | Obesity, White Matter Hyperintensities, and Cognitive Decline: Sex-Specific DTI-ALPS Index Mediation. |
| Journal: | Stroke |
| Published: | 18 Jun 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/42312370/ |
| DOI: | https://doi.org/10.1161/strokeaha.125.053462 |
Publication 20825
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
BACKGROUND: Obesity is a risk factor for white matter hyperintensities (WMH) and cognitive decline, but underlying mechanisms regarding sex differences, obesity metrics, and the glymphatic system remain unclear.</p>
METHODS: Using data from the UK Biobank, we performed sex-stratified analyses. Our approach integrated obesity trajectory modeling (over a mean 9-year period), genome-wide association studies, and 2-sample Mendelian randomization. We examined associations of body mass index, waist-hip ratio, and body fat percentage with glymphatic system function assessed via the diffusion tensor image analysis along the perivascular space (DTI-ALPS) index, WMH volume, and cognitive performance. Models were adjusted for age, education, socioeconomic status, vascular risk factors, and intracranial volume, and a sensitivity check was conducted.</p>
RESULTS: In 37 684 middle-aged and aging participants (mean age 63.9±7.6 years), significant sex-by-obesity interactions were observed (Pinter<0.05). Males showed consistently greater effects for obesity-related declines in total DTI-ALPS index, total WMH burden, and symbol digit substitution test compared with females (all P<0.001). Trajectory analysis identified waist-hip ratio as the primary driver for males, specifically for deep WMH, middle DTI-ALPS index (all P<0.001), whereas body mass index/body fat percentage predominated in females. Sex-stratified genome-wide association studies confirmed divergent genetic architectures supporting these phenotypes. MR validated stronger causal effects of waist-hip ratio on deep WMH in males than in females (P<0.001). Crucially, mediation analyses demonstrated a significant role of the DTI-ALPS index in females. The effect of body fat percentage on periventricular WMH was primarily explained by an indirect pathway via total DTI-ALPS index (indirect effect, β=0.037 [95% CI, 0.032-0.042]; P<0.001), with a nonsignificant direct effect (β=-0.002 [95% CI, -0.016 to 0.011]; P=0.806), indicating full mediation.</p>
CONCLUSIONS: Obesity impacts WMH burden or cognition via sex-divergent pathways, with central adiposity (waist-hip ratio) more detrimental in males and general adiposity (body mass index/body fat percentage) acting through DTI-ALPS index in females. These findings advocate for sex-tailored interventions to control weight, thereby protecting the glymphatic system and reducing the risk of brain injury.</p>
15 Authors
- Lusen Ran
- Hao Huang
- Yuqin He
- Qilong Xing
- Yuanyuan Fang
- Chang Cheng
- Man Cheng
- Wei Yang
- Shabei Xu
- Xiang Luo
- Zhi Lu
- Tingting Qin
- Wei Wang
- Zhouping Tang
- Minghuan Wang
1 Application
| Application ID | Title |
|---|---|
| 90311 | Association of Lifestyle Behaviors and Genetic Risk With cardio-cerebrovascular diseases. |
Enabling scientific discoveries that improve human health