Sex differences in the associations between the risk for late‐life Alzheimer's disease, protective lifestyle factors and cognition in mid‐life: The PREVENT Dementia study.

Background: It is now acknowledged that Alzheimer's Disease (AD) processes are present decades before the symptoms manifest, but whether lifestyle activities can protect against these early AD processes in mid‐life remains poorly understood. Furthermore, the impact of sex as a biological variable on associations between dementia risk, protective lifestyle activities and cognition is unknown. In this study, we aimed to replicate findings from our two recent studies (Deng et al., 2022; Heneghan et al., 2022) on the contribution of mid‐life modifiable activities to cognition in individuals with dementia risk, in a larger independent cohort (N = 461 vs N = 208 used previously). Second, we investigated associations between biological sex, dementia risk, protective lifestyle activities and cognitive performance. Method: Cognitively unimpaired middle‐aged participants (40‐59 years; N = 461) completed cognitive and clinical assessments cross‐sectionally. Risk factors (Apolipoprotein E [APOE] ε4 allele status, family history of dementia, and the Cardiovascular Risk Factors Aging and Dementia score [CAIDE]) were assessed and mid‐life activities were measured with the Lifetime of Experiences Questionnaire. Result: Replicating our key previous findings, we found that episodic and relational memory was (a) significantly negatively associated with the CAIDE risk score (Figure 1a), (b) positively associated with stimulating lifestyle activities (Figure 1b), and (c) that females performed significantly better than males in episodic and relational memory (Figure 2a). The key novel finding of this study was that APOE ε4 genotype modulated the association between sex, lifestyle and cognition. Only for APOE ε4+ females, not APOE ε4‐, higher occupational attainment was associated with better episodic and relational memory (Figure 2c, 2d). Conversely, only for APOE ε4+ males, not APOE ε4‐, higher occupational attainment was associated with worse episodic and relational memory (Figure 2c, 2d). Conclusion: These findings suggest that modifiable lifestyle activities offset cognitive decrements due to inherited AD risk in mid‐life and support the targeting of modifiable lifestyle activities for the prevention of AD. Furthermore, these findings suggest an urgent need for targeted research on female‐specific risk factors, to inform personalised strategies for AD prevention and the promotion of female brain health. [ABSTRACT FROM AUTHOR]