Alzheimer's & Dementia · Jun 27, 2026

Evidence of APOE4-related brain vulnerabilities in verbal memory systems in midlife women

By Wugalter KA, Thurston RC, Wu M et al.

INTRODUCTION: Women carrying the apolipoprotein E4 (APOE4) allele have a greater risk of Alzheimer's disease (AD) from ages 65-75 years compared to men, yet the effects of APOE4 on cognitive and neuroimaging outcomes among midlife women remain poorly understood. We investigated APOE4-related differences in memory-based functional neuroimaging outcomes in cognitively normal, midlife postmenopausal women. METHODS: We measured blood-oxygen-level-dependent activation and hippocampal functional connectivity during a functional magnetic resonance imaging verbal encoding task. Linear regression models tested APOE4 differences (carriers vs. non-carriers) and associations of neuroimaging indices with verbal memory measures and plasma AD biomarkers, adjusting for age, race, and education. RESULTS: Among 145 women from MsBrain, APOE4 carriers and non-carriers did not differ in verbal memory performance or AD biomarker levels. During verbal encoding, APOE4 carriers had significantly decreased activation and hippocampal functional connectivity in several regions compared to non-carriers. DISCUSSION: APOE4-related functional brain differences are present by midlife in postmenopausal women.

doi.org/10.1002/alz.71635 Open access PubMed 42363721 Mechanisms