APOE ɛ4 Gene Dose and Sex Effects on Alzheimer’s Disease MRI Biomarkers in Older Adults with Mild Cognitive Impairment
Open accessAbstract
BACKGROUND: APOEɛ4 and sex have been linked to increased risk for conversion to Alzheimer's disease (AD). However, the relationship between APOEɛ4 gene dose, sex, and AD biomarkers remains understudied. OBJECTIVE: To investigate the effect of APOEɛ4 dose on AD biomarkers in a sample of older adults with mild cognitive impairment (MCI), and to examine whether APOEɛ4 dose modifies AD risk differently in MCI women and men. METHODS: We examined cross-sectional AD biomarkers for participants with MCI (n = 930, 55-96 years old) from three large aging cohorts. Region of interest MRI volumes, global cognition, and episodic memory were analyzed by number of APOEɛ4 alleles and stratified by sex. RESULTS: Across all participants, number of APOEɛ4 alleles was associated with smaller hippocampal and amygdala volumes and poorer cognition. When stratified by sex, women showed an APOEɛ4 dose effect for bilateral hippocampal and left amygdala volumes and cognition. In contrast, men showed an APOEɛ4 dose effect for hippocampal volumes with a trend in amygdala, but cognition did not differ between men with 1 and 2 APOEɛ4 alleles. Women with 2 APOEɛ4 alleles had poorer memory between 65-69 and poorer global cognition between 70-74 compared to men with 2 APOEɛ4 alleles. CONCLUSION: APOEɛ4 confers a dose effect on AD biomarkers in patients with MCI, and the number of APOEɛ4 alleles has a greater detrimental impact in women than men, which may be specific to a critical time window.
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Studies reporting sex-specific associations of APOE4 with WM integrity and stronger APOE-related differences in brain metabolism and cortical atrophy for women than men provide grounds for deeper exploration of sex differences.
“studies reporting sex-specific associations of APOE4 with WM integrity [19] and stronger APOE-related differences in brain metabolism and cortical atrophy for women than men [20, 21] provide grounds for deeper exploration of sex differences in underlying cytoarchitecture.”
From Effects of APOE2 and APOE4 on brain microstructure in older adults: modification by age, sex, and cognitive status (2024) · cites this paper as [21]
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References 51 · Cited by 40
- Authors
- Hobel, Z., ageing, F. T. A. D. N. I. A. T. A. I. B. A. L. F. S. O., Isenberg, A. L., Raghupathy, D., Mack, W., & Pa, J.
- Affiliations
- University of Southern California (US)
- Corresponding author
- Pa, Judy
- Venue
- Journal of Alzheimer's Disease
- Publisher
- SAGE Publications
- Published
- 2019-09-17
- Volume
- 71
- Issue
- 2
- Pages
- 647-658
- ISSN
- 1387-2877 (ISSN-L)
- 1875-8908
- PMC
- PMC6839478
- OpenAlex
- W2968503742
- Cited by
- 40
- References
- 51
- Citations by year
- 2026: 1 · 2025: 9 · 2024: 6 · 2023: 9 · 2022: 4 · 2021: 7 · 2020: 4
- FWCI
- 2.99
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Alzheimer s Disease (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- Foundation for the National Institutes of Health (P50 AG016574, AG016574, P30 AG010133, P50 AG005138, U01 AG016976)
- Alzheimer's Association (P30 AG013854, U01 AG016976, P50 AG025688, P50 AG008702, P30 AG010133, P50 AG005146)
- Pfizer
- University of Southern California
- Meso Scale Diagnostics
- Novartis Pharmaceuticals Corporation
- Northern California Institute for Research and Education
- Commonwealth Scientific and Industrial Research Organisation
- Servier
- H. Lundbeck A/S
- National Institutes of Health (5u01ag024904-10, AG016574, AG016976, AG005138, AG008051, AG019610, AG005134, AG013854, AG025688, AG013846, AG047266, AG008702)
- Canadian Institutes of Health Research (P50 AG016574)
- National Institute on Aging (U01-AG-024904, AG 005138, AG010133, AG 016976, P30AG010129, P30AG010133, AG008051, AG005134, P30AG028383, P30AG012300, AG 025688, AG016574, P50AG005133, U01AG016976, P50AG005131, AG-013854, P50AG005138, P50AG016570, AG019610, P30AG010124, AG047266, P50AG016573, P50AG047366, P30AG008017, P30AG010161, P30AG008051, P50AG008702, P50AG033514, P30AG035982, AG013846, P50AG005681, P50AG005142, P50AG047270, P30AG019610, P50AG005146, RF1AG054617, P30AG013846, P50AG005136, P50AG005134, P30AG013854, P50AG025688, P50AG047266, R01AG046928, P50AG023501, P50AG016574)
- National Institute of Biomedical Imaging and Bioengineering (U54EB020406, P41EB015922)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cancer-related cognitive impairment studies
- Keywords
- APOE ε4, gene dosage
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Brain, Cross-Sectional Studies, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Sex Characteristics, Cohort Studies, Gene Dosage, Apolipoprotein E4, Cognitive Dysfunction
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