ArticleAlzheimer's research & therapy2024
Effects of APOE2 and APOE4 on brain microstructure in older adults: modification by age, sex, and cognitive status.
Article in Alzheimer's research & therapy, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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11 citing papers in PubMed, 14 citations in OpenAlex.
- Sex and APOE genotype specific brain regional vulnerability to Alzheimer's Disease.GeroScience · 2026Article
- Sex-Specific Structural Vulnerability in Alzheimer's Disease: Insights from APOE ε 4-Negative Patients.Life (Basel, Switzerland) · 2026Article
- Correlations between white matter hyperintensities, magnetic resonance imaging findings, and cognition in the oldest old: a multimodal cross-sectional study.GeroScience · 2026Article
- The apolipoprotein gene: a modulating role on brain volume and cognitive function in carriers of the fragile X premutation.Neurobiology of disease · 2026Article
- Ventral hippocampal-postcentral gyrus functional connectivity mediates the association of APOE ε4 gene dose, depressive symptoms, and cognitive function in mild cognitive impairment with subsyndromal depression.Frontiers in aging neuroscience · 2026Article
- Cortical mean diffusivity detects early age-related changes and associates with cognition and plasma biomarkers.Brain communications · 2026Article
- Proteome profiling of cerebrospinal fluid using machine learning shows a unique protein signature associated with APOE4 genotype.Aging cell · 2025Article
- Longitudinal effects of sex differences and apolipoprotein E genotype on white matter engagement among elderly.Brain communications · 2025Article
- APOE 𝜀4-related blood-brain barrier breakdown is associated with microstructural abnormalities.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2024Article
- APOE4 and age affect the brain entorhinal cortex structure and blood arachidonic acid and docosahexaenoic acid levels after mild TBI.Scientific reports · 2024Article
- Proteome profiling of cerebrospinal fluid using machine learning shows a unique protein signature associated with APOE4 genotype.bioRxiv : the preprint server for biology · 2024Article
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Authors and funding
4 authors at 3 institutions in 1 country.
Funding
Abstract
backgroundAPOE4 is the strongest genetic risk factor for sporadic Alzheimer's disease (AD), whereas APOE2 confers protection. However, effects of APOE on neurodegeneration in cognitively intact individuals, and how these associations evolve with cognitive decline, are unclear. Furthermore, few studies have evaluated whether effects of APOE on neurodegenerative changes are modified by other AD key risk factors including age and sex.
methodsParticipants included older adults (57% women; 77 ± 7 years) from 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. Participants underwent diffusion MRI, and multicompartment restriction spectrum imaging (RSI) metrics were computed in white matter, gray matter, and subcortical regions of interest. Participants were classified as APOE4 carriers, APOE2 carriers, and APOE3 homozygotes. Analysis of covariance among CN (adjusting for age, sex, and scanner) assessed differences in brain microstructure by APOE, as well as interactions between APOE and sex. Analyses across all participants examined interactions between APOE4 and cognitive status. Linear regressions assessed APOE by age interactions.
resultsAmong CN, APOE4 carriers showed lower entorhinal cortex neurite density than non-carriers, whereas APOE2 carriers showed lower cingulum neurite density than non-carriers. Differences in entorhinal microstructure by APOE4 and in entorhinal and cingulum microstructure by APOE2 were present for women only. Age correlated with lower entorhinal restricted isotropic diffusion among APOE4 non-carriers, whereas age correlated with lower putamen restricted isotropic diffusion among APOE4 carriers. Differences in microstructure between cognitively normal and impaired participants were stronger for APOE4-carriers in medial temporal regions, thalamus, and global gray matter, but stronger for non-carriers in caudate.
conclusionsThe entorhinal cortex may be an early target of neurodegenerative changes associated with APOE4 in presymptomatic individuals, whereas APOE2 may support beneficial white matter and entorhinal microstructure, with potential sex differences that warrant further investigation. APOE modifies microstructural patterns associated with aging and cognitive impairment, which may advance the development of biomarkers to distinguish microstructural changes characteristic of normal brain aging, APOE-dependent pathways, and non-AD etiologies.
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