Effects of apolipoprotein E2 and E4 on brain microstructure in cognitively intact and mildly impaired older adults: Modification by sex and age

Abstract

AbstractBackgroundAPOE4 is the strongest single genetic risk factor for sporadic Alzheimer’s disease (AD), whereas APOE2 confers protection against AD. However, effects of APOE on neurodegeneration in cognitively intact individuals, and how these associations differ from those presenting with mild cognitive impairments, are unclear. Furthermore, few studies have evaluated whether effects of APOE on early neurodegenerative changes are modified by other AD risk factors including age and sex.MethodSubjects included older adult participants (77±7 years; 57% women) of the Rancho Bernardo Study of Health Aging and the University of California San Diego Alzheimer’s Disease Research Center, including 192 cognitively normal (CN) individuals and 33 with mild cognitive impairment (CI). Participants completed a multi‐shell diffusion MRI scan and restriction spectrum imaging (RSI) metrics were computed in white matter, gray matter, and subcortical regions of interest. Participants were classified as APOE4‐carriers (33%), APOE2‐carriers (10%), and APOE3 homozygotes (57%). Linear regressions, adjusting for age, sex, and scanner, were conducted among CN to assess associations between APOE and RSI measures, as well as interactions of APOE with sex, and with linear or squared age. Regressions across all subjects examined interactions between APOE4 and cognitive status.ResultAmong CN participants, entorhinal cortex neurite density was lower for APOE4‐carriers than non‐carriers, whereas entorhinal restricted isotropic diffusion decreased with age among APOE4 non‐carriers but not among carriers. Entorhinal cortex hindered diffusion was lower for APOE2‐carriers than non‐carriers among women only. Age more strongly correlated with white matter and subcortical microstructure among APOE2 non‐carriers than among APOE2 carriers. Across the full sample, associations between cognitive status and microstructure were modified by APOE4, with greater differences between CN and CI for APOE4‐carriers in medial temporal regions, but stronger differences for APOE4 non‐carriers in the striatum.ConclusionThe entorhinal cortex may be an early target of neurodegenerative changes associated with APOE4 preceding cognitive decline, whereas APOE2 may protect against entorhinal microstructural injury, particularly among women. APOE modifies patterns of microstructural abnormalities associated with aging and cognitive impairment, which may support the development of biomarkers differentially indicative of cytoarchitectural changes occurring with normal brain aging, APOE‐dependent pathways, and non‐AD etiologies.