Sex Differences in Mild Cognitive Impairment Risk by APOE Genotype

Abstract

AbstractBackgroundMale sex is suggested as a risk factor for mild cognitive impairment (MCI), but this association may be influenced by the female verbal memory advantage, and the use of verbal memory tests has been shown to delay MCI diagnosis in women. Moreover, this association may vary by apolipoprotein E (APOE) genotype. The National Alzheimer’s Coordinating Center (NACC) uniform data set (UDS) contains demographic data and annual standardized neuropsychological (with memory being assessed primarily with verbal tests) and clinical diagnostic data obtained by 41 NIA‐funded Alzheimer’s Disease Centers across the U.S. This large database is a rich resource for evaluating sex effects on MCI/Dementia diagnosis by APOE genotype.MethodWe restricted to NACC enrollees above 60 years old, with available APOE genotype, cognitively normal at their initial UDS visit, had at least one follow‐up visit, and without a documented dominantly inherited Alzheimer mutation, leaving 10,461 participants (35.3% men, 77.0% non‐Hispanic White). Cox proportional hazards models of time to incident MCI/dementia controlling for sex, baseline age, years of education, baseline Mini‐Mental Status Exam (MMSE), and interaction terms as indicated were fit separately to APOE E3/E3 homozygotes and E3/E4 heterozygotes. Small sample size precluded analyses of other APOE genotypes. Secondary analyses restricting to non‐Hispanic White participants were also examined.ResultAmong APOE E3/E3 homozygotes, male sex is a risk factor for clinically diagnosed MCI/dementia (Hazard ratio (HR) = 1.27, p < 0.001) independent of age at enrollment. Among APOE E3/E4 heterozygotes, male sex is a risk factor at the lower range of age (age 60–75), while female sex is a risk factor at the higher range (interaction p = 0.006). Similar findings were obtained when restricting to the non‐Hispanic White participants.ConclusionThe higher risk of MCI/dementia in men in the NACC cohort may reflect previously‐reported sex differences in verbal memory performance at early stage AD pathogenesis and the use of verbal memory diagnostic tests more sensitive in men early in the disease.