Obesity, White Matter Hyperintensities, and Cognitive Decline: Sex-Specific DTI-ALPS Index Mediation

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. 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. RESULTS: In 37 684 middle-aged and aging participants (mean age 63.9±7.6 years), significant sex-by-obesity interactions were observed ( P inter <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. 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.