Sex differences in the impact of genetic and clinical risk factors for Alzheimer's disease in midlife

Background Preclinical risk for Alzheimer's disease (AD), including amyloid-β (Aβ) deposition, begins 10–15 years prior to diagnosis. In addition to genetics, hypertension, type 2 diabetes, and depression in midlife are major risk factors for AD. Objective Here, we assessed sex differences in associations of AD risk status with memory circuitry function and AD pathology in midlife. Methods High- (HR) and low-risk (LR) participants (N = 99; ages 52–71 years) were recruited from the Mass General Brigham Biobank. HR participants have genetic risk ( APOE4 ) plus hypertension, type 2 diabetes, and/or depression; LR participants have no genetic or clinical risk. Participants underwent neuropsychological assessments of verbal, associative, and working memory, functional MRI (fMRI) scans while completing a working memory and verbal encoding task, and PET imaging scans. Aβ deposition was detected using PET C-11PiB and calculated as distribution volume ratio. Results HR status was significantly associated with lower scores in associative memory, altered fMRI BOLD activity in memory circuitry regions, and higher Aβ deposition, primarily in women. Further, altered task-based fMRI activity was related to worse memory performance and higher Aβ accumulation in women. While some effects were observed in men, effect sizes were smaller and did not survive correction for multiple comparisons. Conclusions Results demonstrated that genetic and clinical risk factors can help identify in a sex-dependent manner those in midlife who are at increased risk of developing AD to target for early intervention.