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

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.

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.

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). Men showed consistently greater effects for obesity-related declines in total DTI-ALPS index, total WMH burden, and symbol digit substitution test compared with women (all P<0.001). Trajectory analysis identified waist-hip ratio as the primary driver for men, specifically for deep WMH, middle DTI-ALPS index (all P<0.001), whereas body mass index/body fat percentage predominated in women. 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 men than in women (P<0.001). Crucially, mediation analyses demonstrated a significant role of the DTI-ALPS index in women. 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.

Obesity impacts WMH burden or cognition via sex-divergent pathways, with central adiposity (waist-hip ratio) more detrimental in men and general adiposity (body mass index/body fat percentage) acting through DTI-ALPS index in women. These findings advocate for sex-tailored interventions to control weight, thereby protecting the glymphatic system and reducing the risk of brain injury.