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Apolipoprotein E Genotype and Sex Risk Factors for Alzheimer Disease: A Meta-analysis
Open accessAbstract
Importance: It is unclear whether female carriers of the apolipoprotein E (APOE) ε4 allele are at greater risk of developing Alzheimer disease (AD) than men, and the sex-dependent association of mild cognitive impairment (MCI) and APOE has not been established. Objective: To determine how sex and APOE genotype affect the risks for developing MCI and AD. Data Sources: Twenty-seven independent research studies in the Global Alzheimer's Association Interactive Network with data on nearly 58 000 participants. Study Selection: Non-Hispanic white individuals with clinical diagnostic and APOE genotype data. Data Extraction and Synthesis: Homogeneous data sets were pooled in case-control analyses, and logistic regression models were used to compute risks. Main Outcomes and Measures: Age-adjusted odds ratios (ORs) and 95% confidence intervals for developing MCI and AD were calculated for men and women across APOE genotypes. Results: Participants were men and women between ages 55 and 85 years. Across data sets most participants were white, and for many participants, racial/ethnic information was either not collected or not known. Men (OR, 3.09; 95% CI, 2.79-3.42) and women (OR, 3.31; CI, 3.03-3.61) with the APOE ε3/ε4 genotype from ages 55 to 85 years did not show a difference in AD risk; however, women had an increased risk compared with men between the ages of 65 and 75 years (women, OR, 4.37; 95% CI, 3.82-5.00; men, OR, 3.14; 95% CI, 2.68-3.67; P = .002). Men with APOE ε3/ε4 had an increased risk of AD compared with men with APOE ε3/ε3. The APOE ε2/ε3 genotype conferred a protective effect on women (OR, 0.51; 95% CI, 0.43-0.61) decreasing their risk of AD more (P value = .01) than men (OR, 0.71; 95% CI, 0.60-0.85). There was no difference between men with APOE ε3/ε4 (OR, 1.55; 95% CI, 1.36-1.76) and women (OR, 1.60; 95% CI, 1.43-1.81) in their risk of developing MCI between the ages of 55 and 85 years, but women had an increased risk between 55 and 70 years (women, OR, 1.43; 95% CI, 1.19-1.73; men, OR, 1.07; 95% CI, 0.87-1.30; P = .05). There were no significant differences between men and women in their risks for converting from MCI to AD between the ages of 55 and 85 years. Individuals with APOE ε4/ε4 showed increased risks vs individuals with ε3/ε4, but no significant differences between men and women with ε4/ε4 were seen. Conclusions and Relevance: Contrary to long-standing views, men and women with the APOE ε3/ε4 genotype have nearly the same odds of developing AD from age 55 to 85 years, but women have an increased risk at younger ages.
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“APOE-e4 was related to higher Alzheimer's risk in women than men between ages 55 to 70”
From 2023 Alzheimer's disease facts and figures (2023) · cites this paper as [288]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Carrying one APOE4 allele increases the risk of AD by 3–4 times, and carrying two alleles increases the risk by 9–15 times.168”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [168]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“Women are more vulnerable to effects of APOE4 on memory decline [45] as well as risk for AD dementia [16] and neuropathology [46], and more limited data suggest that APOE2 also confers greater protection against AD risk for women than men [16].”
From Effects of APOE2 and APOE4 on brain microstructure in older adults: modification by age, sex, and cognitive status (2024) · cites this paper as [16]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“That is, APOE‐e4 was related to higher Alzheimer's risk in women than men between ages 55 and 70, when APOE is thought to exert its largest effects.”
From 2024 Alzheimer's disease facts and figures (2024) · cites this paper as [314]
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In the citing paper
“A recent meta-analysis found no difference between men and women in the association between APOE-e4 and Alzheimer's dementia overall, although age played an interesting interactive role.”
From 2023 Alzheimer's disease facts and figures (2023) · cites this paper as [288]
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“APOE is differentially associated with AD risk across populations [16]”
From Effects of APOE2 and APOE4 on brain microstructure in older adults: modification by age, sex, and cognitive status (2024) · cites this paper as [16]
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In the citing paper
“Women are more vulnerable to effects of APOE4 on memory decline [45] as well as risk for AD dementia [16] and neuropathology [46], and more limited data suggest that APOE2 also confers greater protection against AD risk for women than men [16].”
From Effects of APOE2 and APOE4 on brain microstructure in older adults: modification by age, sex, and cognitive status (2024) · cites this paper as [16]
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“However, a meta‐analysis found no difference between men and women in the association between APOE‐e4 and Alzheimer's dementia overall, although age played an interesting interactive role.”
From 2024 Alzheimer's disease facts and figures (2024) · cites this paper as [314]
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“Epidemiologic studies show sex differences in clinical risk are largely discernable within the context of APOE ε4,11,42,43 particularly between the ages of 65 to 75 years compared with APOE ε4 clinically normal male carriers.44”
From Sex Differences in the Association of Global Amyloid and Regional Tau Deposition Measured by Positron Emission Tomography in Clinically Normal Older Adults (2019) · cites this paper as [44]
In the citing paper
“Attempts to quantify the duration of AD should be age-specific, because age imposes the greatest risk for both dementia and mortality, and take into account APOE genotype, sex, and cerebrospinal fluid (CSF) tau levels [4, 6, 10-12].”
From Duration of preclinical, prodromal, and dementia stages of Alzheimer's disease in relation to age, sex, and APOE genotype (2019) · cites this paper as [10]
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Metadata
- Authors
- Neu, S. C., Pa, J., Kukull, W., Beekly, D., Kuzma, A., Gangadharan, P., Wang, L.-S., Romero, K., Arneric, S. P., Redolfi, A., Orlandi, D., Frisoni, G. B., Au, R., Devine, S., Auerbach, S., Espinosa, A., Boada, M., Ruiz, A., Johnson, S. C., Koscik, R., Wang, J.-J., Hsu, W.-C., Chen, Y.-L., & Toga, A. W.
- Affiliations
- University of Southern California (US)
- University of Washington (US)
- University of Pennsylvania (US)
- Critical Path Institute (US)
- Coalition Against Major Disease, Critical Path Institute, Tucson, Arizona
- Centro San Giovanni di Dio Fatebenefratelli (IT)
- University of Geneva (CH)
- Boston University (US)
- Fundació ACE (ES)
- Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain
- University of Wisconsin–Madison (US)
- Chang Gung University (TW)
- Chang Gung Memorial Hospital (TW)
- Corresponding author
- Toga, Arthur W.
- ORCID
- Venue
- JAMA Neurology
- Publisher
- American Medical Association (AMA)
- Published
- 2017-10-01
- Volume
- 74
- Issue
- 10
- Pages
- 1178
- ISSN
- 2168-6149 (ISSN-L)
- PMC
- PMC5759346
- OpenAlex
- W2745657465
- Cited by
- 674
- References
- 74
- Citations by year
- 2026: 74 · 2025: 81 · 2024: 74 · 2023: 93 · 2022: 78 · 2021: 96 · 2020: 69 · 2019: 67 · 2018: 37 · 2017: 3
- FWCI
- 39.51
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- JAMA Neurology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (UL1TR000130, 5u01ag024904-10, n01hc25195-41-0-1, UL1TR001855)
- U.S. Food and Drug Administration (U18FD005320)
- National Institute on Aging (U01-AG-024904, P30AG010129, P30AG010133, P30AG028383, P30AG012300, P50AG005133, U01AG016976, P50AG005131, P50AG005138, P50AG016570, P30AG010124, P50AG016573, RF1AG027161, P50AG047366, P30AG008017, P30AG010161, R01AG033040, P30AG008051, P50AG008702, R01AG016495, P50AG033514, P30AG035982, P50AG005681, P50AG005142, P50AG047270, P30AG019610, P50AG005146, P01AG003991, RF1AG054617, P30AG013846, P50AG005136, P50AG005134, P30AG013854, P50AG025688, P50AG047266, R01AG008122, R01AG027161, U24AG041689, U19AG024904, P01AG026276, P50AG023501, P50AG016574)
- National Heart, Lung, and Blood Institute (N01-HC-025195)
- National Institute of Neurological Disorders and Stroke (R01NS017950)
- National Institute of Biomedical Imaging and Bioengineering (U54EB020406, P41EB015922)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Keywords
- Alzheimer's disease, apolipoprotein E, APOE ε4, APOE ε2, sex differences, mild cognitive impairment, genetic risk factors
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Apolipoproteins E, Female, Humans, Male, Middle Aged, Risk Factors, Sex Characteristics, Logistic Models, Case-Control Studies, Databases, Factual
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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