Association of genetic predisposition to dyslipidemia and physical activity with incident dementia.

INTRODUCTION: The association between genetic predisposition to dyslipidemia and dementia risk is inconsistent. It remains unknown whether a physically active lifestyle is associated with a lower dementia risk across different levels of this genetic predisposition. METHODS: We analyzed 198,448 White participants (aged ≥ 60 years) with a median 14.8-year follow-up in UK Biobank. We used Cox proportional hazards models to assess associations between dyslipidemia polygenic risk scores (PRSs), physical activity, and incident dementia. RESULTS: Higher low-density lipoprotein cholesterol PRS and lower high-density lipoprotein cholesterol PRS were associated with increased risk of all-cause dementia, Alzheimer's disease, and vascular dementia (VaD). Being physically active was associated with lower risk of all-cause dementia and VaD. This beneficial association of a physically active lifestyle was observed across all genetic risk strata and was most pronounced for VaD. DISCUSSION: Regular physical activity may be a promising strategy for dementia prevention, even in individuals with high genetic risk of dyslipidemia. HIGHLIGHTS: Genetic predisposition to higher low-density lipoprotein cholesterol and lower high-density lipoprotein cholesterol is linked to increased dementia risk. Being physically active is associated with lower dementia risk across genetic risk profiles. Being physically active shows the strongest association with lower risk of vascular dementia.