Sex differences in modifiable risk profiles for cognitive decline: findings from DeCo Chair Project

Dementia prevention strategies increasingly focus on modifiable risk factors, yet sex-specific risk profiles remain insufficiently characterized. In addition to biological mechanisms, social, behavioural, and environmental determinants may shape sex-specific trajectories of cognitive aging. Using the framework of the Lancet Commission on dementia prevention, intervention, and care modifiable risk factors, we investigated sex differences in cumulative risk burden and their association with cognitive decline in a community-based population. We conducted a cross-sectional study including 1162 adults recruited in community pharmacies in Valencia (Spain) between 2018 and 2024 as part of the DeCo Chair project. A cumulative risk score based on Lancet Commission modifiable risk factors was calculated using population-attributable fraction weighting. Logistic regression analyses evaluated associations between individual risk factors and cognitive decline. Men accumulated a higher burden of modifiable risk factors, including smoking, higher body mass index, alcohol consumption, diabetes, and hearing loss. Higher BMI and traumatic brain injury history were associated with increased odds of cognitive decline in men. In contrast, women showed higher prevalence of low cognitive reserve, physical inactivity, depression, and social isolation, which were all associated with increased likelihood of cognitive decline. Higher cognitive reserve was protective in both sexes. These findings reveal distinct sex-specific risk profiles, with cardiometabolic and lifestyle risk factors predominating in men and psychosocial and cognitive reserve–related vulnerabilities in women. Our results highlight the importance of sex-tailored prevention strategies to optimize dementia risk reduction.