Sex modifies the APOE ‐related risk of developing Alzheimer disease
Open accessAbstract
Objective: The APOE4 allele is the strongest genetic risk factor for sporadic Alzheimer disease (AD). Case–control studies suggest the APOE4 link to AD is stronger in women. We examined the APOE4 ‐by‐sex interaction in conversion risk (from healthy aging to mild cognitive impairment (MCI)/AD or from MCI to AD) and cerebrospinal fluid (CSF) biomarker levels. Methods: Cox proportional hazards analysis was used to compute hazard ratios (HRs) for an APOE ‐by‐sex interaction on conversion in controls (n = 5,496) and MCI patients (n = 2,588). The interaction was also tested in CSF biomarker levels of 980 subjects from the Alzheimer's Disease Neuroimaging Initiative. Results: Among controls, male and female carriers were more likely to convert to MCI/AD, but the effect was stronger in women (HR = 1.81 for women; HR = 1.27 for men; interaction: p = 0.011). The interaction remained significant in a predefined subanalysis restricted to APOE3/3 and APOE3/4 genotypes. Among MCI patients, both male and female APOE4 carriers were more likely to convert to AD (HR = 2.16 for women; HR = 1.64 for men); the interaction was not significant ( p = 0.14). In the subanalysis restricted to APOE3/3 and APOE3/4 genotypes, the interaction was significant ( p = 0.02; HR = 2.17 for women; HR = 1.51 for men). The APOE4 ‐by‐sex interaction on biomarker levels was significant for MCI patients for total tau and the tau‐to‐Aβ ratio ( p = 0.009 and p = 0.02, respectively; more AD‐like in women). Interpretation: APOE4 confers greater AD risk in women. Biomarker results suggest that increased APOE ‐related risk in women may be associated with tau pathology. These findings have important clinical implications and suggest novel research approaches into AD pathogenesis. Ann Neurol 2014;75:563–573
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Sex differences in Aβ burden alone have not been reported in older adults.
“Sex differences in Aβ burden alone have not been reported in older adults,11–13”
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 [11]
The Discussion reports similar beta-amyloid levels in men and women with MCI and a pronounced APOE4 effect on beta-amyloid in healthy older adults of both sexes. However, the Results (CSF Biomarkers; page not provided) report a nominal sex-by-APOE4 interaction for CSF Aβ in healthy controls that did not survive correction for multiple tests. These findings support the absence of a robust difference in this study, but not the broader assertion that sex differences in Aβ burden have never been reported in older adults. (LLM, conf=0.82)
Experimental — accuracy not yet measuredEpidemiologic studies show sex differences in clinical risk are largely discernable within the context of APOE ε4, particularly between the ages of 65 to 75 years compared with APOE ε4 clinically normal male carriers.
“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 [11]
The Results (Clinical Conversion Risks; page unavailable) report a stronger APOE ε4–associated risk of conversion in clinically normal older women than in men, supporting the sex-difference point. They do not identify ages 65–75 as a particularly pronounced interval, and their reported risk estimates compare carriers with non-carriers within each sex rather than directly comparing female carriers with male carriers. (LLM, conf=0.84)
Experimental — accuracy not yet measuredMinimal, if any, sex differences have been found cross-sectionally in levels of global Aβ burden in clinically normal older adults.
“Minimal,6 if any,11,12,36 sex differences have been found cross sectionally in levels of global Aβ burden in clinically normal older adults”
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 [11]
The Results (CSF Biomarkers; page unavailable) found no statistically significant APOE4-by-sex interaction in CSF Aβ levels among healthy controls after correction for multiple testing, which supports the cited word “minimal.” The paper measured CSF Aβ and tested an APOE4-by-sex interaction; it did not establish minimal sex differences in global Aβ burden. (LLM, conf=0.82)
Experimental — accuracy not yet measuredThe increased risk of Alzheimer's disease associated with APOE E4 is associated with increased pTau.
“Indeed, the increased risk of Alzheimer’s disease associated with the E4 allele of the APOE gene is especially pronounced in women and is associated with increased pTau141.”
From Stress weakens prefrontal networks: molecular insults to higher cognition (2015) · cites this paper as [141]
The Discussion reports an APOE4 main effect on CSF p-tau in healthy older controls, supporting an association between APOE4 and p-tau. But the Results (CSF Biomarkers) report that the higher p-tau pattern in female APOE4 carriers with mild cognitive impairment was only nominally significant and did not survive correction for multiple comparisons. The paper therefore does not establish the claim’s unqualified link between increased AD risk and increased p-tau. (LLM, conf=0.84)
Experimental — accuracy not yet measuredFemale sex is a risk factor for Alzheimer's degeneration.
“Although the largest risk factor for Alzheimer’s disease is advanced age, TBI is also an established risk factor140, and new evidence suggests that psychological distress43 and female sex141 are also risk factors for Alzheimer’s degeneration.”
From Stress weakens prefrontal networks: molecular insults to higher cognition (2015) · cites this paper as [141]
The Abstract Results and Interpretation report that APOE4-related risk of developing Alzheimer’s disease is greater in women, with more AD-like tau biomarkers among female APOE4 carriers with mild cognitive impairment. The paper studies a sex-by-APOE4 interaction; it does not establish female sex as a general risk factor independent of APOE4. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Female APOE4 carriers have a higher risk of developing AD and show accelerated pTau accumulation and memory decline than male carriers.
“The female-specific effect of APOE4 and pTau in seizure severity is intriguing because female APOE4 carriers have a higher risk of developing AD and show accelerated pTau accumulation and memory decline than male carriers (Altmann et al., 2014; Coughlan et al., 2025).”
From APOE4 reduces hippocampal expression of phosphoglycerate kinase 1 and sodium potassium pump to enhance seizure susceptibility in mice (2026) · cites this paper as Altmann et al., 2014
The Discussion and Results (pages unavailable in our copy) report a stronger APOE4-related risk of clinical conversion to AD in women than in men. They do not establish accelerated pTau accumulation: the pTau difference was measured at study entry and did not remain significant after correction for multiple comparisons. The paper reports clinical conversion, not a direct comparison of rates of memory decline. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe APOE-e4 genotype may have a stronger association with Alzheimer's dementia and neurodegeneration in women than in men.
“the APOE-e4 genotype, the best known common genetic risk factor for Alzheimer's dementia, may have a stronger association with Alzheimer's dementia 285,286 and neurodegeneration 287 in women than in men.”
From 2023 Alzheimer's disease facts and figures (2023) · cites this paper as [285]
Women are more vulnerable to effects of APOE4 on memory decline, risk for AD dementia, and neuropathology.
“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 [46]
Prior observations in AD mouse models and human epidemiology have implicated sex as a modifier of AD manifestation and progression.
“Prior observations in AD mouse models (Jiao et al., 2016) and human epidemiology (Altmann et al., 2014; Li and Singh, 2014; Mayeux and Stern, 2012) have implicated sex as a modifier of AD manifestation and progression.”
From Meta-Analysis of the Alzheimer’s Disease Human Brain Transcriptome and Functional Dissection in Mouse Models (2020) · cites this paper as Altmann et al., 2014
Our results are consistent with prior observations of sex effects in both mice and humans.
“Our results are consistent with prior observations in both mice (Jiao et al., 2016) and humans (Altmann et al., 2014; Li and Singh, 2014; Mayeux and Stern, 2012; Mathys et al., 2019; Sala Frigerio et al., 2019).”
From Meta-Analysis of the Alzheimer’s Disease Human Brain Transcriptome and Functional Dissection in Mouse Models (2020) · cites this paper as Altmann et al., 2014
In clinically normal older adults and individuals with mild cognitive impairment, higher cerebrospinal fluid tau levels have been observed in female APOE ε4 carriers compared with male carriers.
“In clinically normal older adults9,10 and individuals with mild cognitive impairment,11 higher cerebrospinal fluid (CSF) tau levels have been observed in female apolipoprotein E (APOE) ε4 carriers compared with male carriers.”
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 [11]
The increased risk of Alzheimer's disease associated with the E4 allele of the APOE gene is especially pronounced in women.
“Indeed, the increased risk of Alzheimer’s disease associated with the E4 allele of the APOE gene is especially pronounced in women and is associated with increased pTau141.”
From Stress weakens prefrontal networks: molecular insults to higher cognition (2015) · cites this paper as [141]
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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].”
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- Authors
- Altmann, A., Tian, L., Henderson, V. W., Greicius, M. D., & Alzheimer's Disease Neuroimaging Initiative Investigators
- Affiliations
- Stanford Center for Memory Disorders Department of Neurology and Neurological Sciences Stanford University Stanford CA
- Department of Health Research and Policy Stanford University Stanford CA
- Stanford Medicine (US)
- Corresponding author
- Greicius, Michael D.
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2014-04
- Volume
- 75
- Issue
- 4
- Pages
- 563-573
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- PMC
- PMC4117990
- OpenAlex
- W2159285109
- Cited by
- 891
- References
- 32
- Citations by year
- 2026: 97 · 2025: 109 · 2024: 98 · 2023: 69 · 2022: 77 · 2021: 100 · 2020: 73 · 2019: 76 · 2018: 65 · 2017: 37 · 2016: 44 · 2015: 32 · 2014: 12 · 2013: 1
- FWCI
- 31.79
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- National Institutes of Health (5u01ag024904-10)
- National Institute on Aging (U01-AG-024904, U01AG016976, P50AG005142, U19AG024904)
- National Institute of Neurological Disorders and Stroke (R01NS073498, NS073498)
- 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 › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Keywords
- Alzheimer's disease, APOE ε4, sex differences, genetic risk, mild cognitive impairment, cerebrospinal fluid biomarkers, tau protein, amyloid-beta
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Apolipoproteins E, Female, Follow-Up Studies, Genetic Testing, Humans, Male, Risk Factors, Sex Factors, Proportional Hazards Models, Case-Control Studies, Databases, Factual, Amyloid beta-Peptides, tau Proteins, Genetic Predisposition to Disease, Cognitive Dysfunction
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