Investigating sex differences in the effects of APOEε2 genotype, vascular risk, and hormonal factors on longitudinal cognitive decline

Over two-thirds of Canadians suffering from Alzheimer’s disease are female. APOEε2 is a gene that protects against cognitive decline and Alzheimer’s disease. There is some evidence that the effects of APOEε2 on cognition may differ between sexes. If APOEε2 is more protective against cognitive decline in males than females, this could be a reason why females have greater risk for Alzheimer’s disease. This study will investigate sex differences in associations between the APOEε2 gene and change in cognition over time, in a large sample of healthy middle-aged/older Canadians. We will also explore biological mechanisms that may contribute to these sex differences, such as vascular disease pathology. Our findings will help us learn more about why females are more likely to develop Alzheimer’s disease than males. This is important because understanding sex differences in dementia risk is crucial to develop sex-specific strategies to prevent this devastating condition with no cure. In addition to APOE ε2, vascular risk factors and the menopause transition may contribute to female vulnerability to Alzheimer’s disease. We will investigate whether sex differences in vascular risk factors and female hormonal processes (such as menopause) drive greater cognitive decline in females, either in combination with or separately from APOE genotype.