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Effects of Age, Sex, and Ethnicity on the Association Between Apolipoprotein E Genotype and Alzheimer Disease: A Meta-analysis
Abstract
Objective. —To examine more closely the association between apolipoprotein E (APOE) genotype and Alzheimer disease (AD) by age and sex in populations of various ethnic and racial denominations. Data Sources. —Forty research teams contributed data onAPOEgenotype, sex, age at disease onset, and ethnic background for 5930 patients who met criteria for probable or definite AD and 8607 controls without dementia who were recruited from clinical, community, and brain bank sources. Main Outcome Measures. —Odds ratios (ORs) and 95% confidence intervals (Cls) for AD, adjusted for age and study and stratified by major ethnic group (Caucasian, African American, Hispanic, and Japanese) and source, were computed forAPOEgenotypes ∈2/∈2,∈2/∈3,∈2/∈4,∈3/∈4 and ∈4/∈4 relative to the ∈3/∈3 group. The influence of age and sex on the OR for each genotype was assessed using logistic regression procedures. Results. —Among Caucasian subjects from clinic- or autopsy-based studies, the risk of AD was significantly increased for people with genotypes ∈2/∈4 (OR=2.6, 95% Cl=1.6-4.0), ∈3/∈4 (OR=3.2, 95% Cl=2.8-3.8), and ∈4/∈4 (OR=14.9, 95% CI=10.8-20.6); whereas, the ORs were decreased for people with genotypes ∈2/∈2 (OR=0.6, 95% Cl=0.2-2.0) and ∈2/∈3 (OR=0.6, 95% Cl=0.5-0.8). TheAPOE∈4-AD association was weaker among African Americans and Hispanics, but there was significant heterogeneity in ORs among studies of African Americans (P<.03). TheAPOE∈4—AD association in Japanese subjects was stronger than in Caucasian subjects (∈3/∈4: OR=5.6, 95% Cl=3.9-8.0; ∈4/∈4: OR=33.1, 95% Cl=13.6-80.5). The ∈2/∈3 genotype appears equally protective across ethnic groups. We also found that among Caucasians,APOEgenotype distributions are similar in groups of patients with AD whose diagnoses were determined clinically or by autopsy. In addition, we found that theAPOE∈4 effect is evident at all ages between 40 and 90 years but diminishes after age 70 years and that the risk of AD associated with a given genotype varies with sex. Conclusions. —TheAPOE∈4 allele represents a major risk factor for AD in all ethnic groups studied, across all ages between 40 and 90 years, and in both men and women. The association betweenAPOE∈4 and AD in African Americans requires clarification, and the attenuated effect ofAPOE∈4 in Hispanics should be investigated further.
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In the citing paper
“The greatest risk factors for late-onset Alzheimer's are older age, 62,63 genetics 64,65 -especially the e4 form of the apolipoprotein E (APOE) gene -and having a family history of Alzheimer's.[66][67][68][69]”
From 2023 Alzheimer's disease facts and figures (2023) · cites this paper as [65]
In the citing paper
“such that APOE4 homozygotes are at the highest risk”
From Exceptionally low likelihood of Alzheimer’s dementia in APOE2 homozygotes from a 5,000-person neuropathological study (2020) · cites this paper as [4]
In the citing paper
“Also, previous studies of clinically and neuropathologically characterized cases and controls may have been too small to demonstrate that APOE2 homozygotes have an even lower OR than the relatively low-risk APOE2/3 group due to the paucity of APOE2 homozygotes, who comprise <1% of the general population1,4.”
From Exceptionally low likelihood of Alzheimer’s dementia in APOE2 homozygotes from a 5,000-person neuropathological study (2020) · cites this paper as [4]
In the citing paper
“Compared to the most common APOE3/3 genotype, each additional copy of the APOE4 allele is associated with a higher risk of Alzheimer’s dementia and a younger mean age at dementia onset, such that APOE4 homozygotes are at the highest risk”
From Exceptionally low likelihood of Alzheimer’s dementia in APOE2 homozygotes from a 5,000-person neuropathological study (2020) · cites this paper as [4]
In the citing paper
“Apolipoprotein E (APOE), the major susceptibility gene for late-onset Alzheimer’s disease (AD), has three common alleles (APOE2, 3, and 4), giving rise to six genotypes (APOE2/2, 2/3, 3/3, 2/4, 3/4, and 4/4).”
From Exceptionally low likelihood of Alzheimer’s dementia in APOE2 homozygotes from a 5,000-person neuropathological study (2020) · cites this paper as [4]
In the citing paper
“while the presence of one or two copies of the APOE2 allele is associated with a lower risk of Alzheimer’s dementia and an older mean age at dementia onset1–4.”
From Exceptionally low likelihood of Alzheimer’s dementia in APOE2 homozygotes from a 5,000-person neuropathological study (2020) · cites this paper as [4]
In the citing paper
“Fourth, findings from our non-Hispanic White groups cannot yet be extended to other ethnic and racial groups4.”
From Exceptionally low likelihood of Alzheimer’s dementia in APOE2 homozygotes from a 5,000-person neuropathological study (2020) · cites this paper as [4]
In the citing paper
“APOE is genetically linked to late-onset sporadic Alzheimer’s disease (LOAD), with APOE4 being a significant risk factor, APOE3 considered the “neutral” allele, and APOE2 exerting a protective role against LOAD [6, 7].”
In the citing paper
“In addition, APOE4 is linked to hypercholesterolemia and increased risk of cardiovascular disorders (CVD) [7, 41]”
In the citing paper
“Compared to ε3 homozygotes, individuals with one or two ε4 alleles harbor approximately 3 and 15 times increased risk, respectively”
From Effects of APOE2 and APOE4 on brain microstructure in older adults: modification by age, sex, and cognitive status (2024) · cites this paper as [1]
In the citing paper
“whereas carriers of the protective ε2 allele have an estimated 1.7 times decreased risk [1]”
From Effects of APOE2 and APOE4 on brain microstructure in older adults: modification by age, sex, and cognitive status (2024) · cites this paper as [1]
In the citing paper
“Between 45% and 50% of AD patients carry at least one APOE4 allele compared to only 15% of age-matched healthy controls.5,11”
From AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease (2018) · cites this paper as [11]
In the citing paper
“APOE4 is the strongest genetic determinant of late-onset AD, increasing risk in a gene dose-dependent manner, whereas APOE2 confers substantial protection 1 -5 .”
From APOE2 attenuates APOE4-associated amyloid pathology and related toxicity in a mouse model of Alzheimer’s disease (2026) · cites this paper as [5]
In the citing paper
“In humans, the APOE2/4 genotype confers an intermediate risk, higher than that of APOE3/3 but lower than APOE3/4 and APOE4/4 5,6 .”
From APOE2 attenuates APOE4-associated amyloid pathology and related toxicity in a mouse model of Alzheimer’s disease (2026) · cites this paper as [5]
In the citing paper
“Population studies have demonstrated that the ε4 allele increases the risk of developing AD by either 3-fold (1 allele) or 12-fold (2 alleles) [6]”
From In Vivo Human Apolipoprotein E Isoform Fractional Turnover Rates in the CNS (2012) · cites this paper as [6]
In the citing paper
“ApoE4, found in 65–80% of cases of sporadic and familial Alzheimer's disease, increases the occurrence of AD by ∼12 fold in two ɛ4 allele carriers, compared with those with no ɛ4 allele (Farrer et al., 1997).”
From Apolipoprotein E in Synaptic Plasticity and Alzheimer’s Disease: Potential Cellular and Molecular Mechanisms (2014) · cites this paper as Farrer et al., 1997
In the citing paper
“The APOE4 allele is a major genetic risk factor for late-onset AD and was previously shown to accelerate AD progression in humans and in mouse models 6-11 .”
From APOE4 impairs the microglial response in Alzheimer’s disease by inducing TGFβ-mediated checkpoints (2023) · cites this paper as [6]
In the citing paper
“The APOE4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD).”
From APOE4 impairs the microglial response in Alzheimer’s disease by inducing TGFβ-mediated checkpoints (2023) · cites this paper as [6]
In the citing paper
“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 [43]
In the citing paper
“Separately, clinical studies have reported that women APOE ε4 carriers had a higher risk of Alzheimer’s dementia than men carriers [21].”
From Sex differences in Alzheimer’s disease and common neuropathologies of aging (2018) · cites this paper as [21]
In the citing paper
“Furthermore, a recent meta-analysis of 58000 participants showed that APOE ε3/ε4 women have the same increased odds of AD dementia as APOE ε3ε4 men have, in contrast to a previous meta-analysis which reported APOE ε4 women to carry a higher risk of Alzheimer’s dementia compared to APOE ε4 men [21].”
From Sex differences in Alzheimer’s disease and common neuropathologies of aging (2018) · cites this paper as [21]
In the citing paper
“As APOE4 carriers make up 55–75% of AD cases17–20”
From The APOE-R136S mutation protects against APOE4-driven tau pathology, neurodegeneration, and neuroinflammation (2023) · cites this paper as [18]
In the citing paper
“The initial intriguing observation that the APOEε4 allele increases AD risk differentially across races and ethnicities, with the greatest increase in risk seen in East Asian people, followed by white, then Black, then Hispanic people6, has now been confirmed by a larger meta-analysis using not only self-reported race and ethnicity but also global genetic ancestry to ascertain the biological basis”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [6]
In the citing paper
“Rather, age and sex moderate the effects of the APOE genotype on AD risk so that the risk associated with the APOEε3/ε4 genotype is highest in women of ages 60–70 years (or 70–80 years according to ref. 6) but decreases in older women and equalizes to that of non-Hispanic White, Black and Hispanic men of the same age10.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [6]
In the citing paper
“The APOE polymorphism is the most studied, successfully replicated, and well-established risk factor for AD where APOE*2 is the protective allele and APOE*4 is the risk allele as compared to APOE*3 [7–10].”
From Genome-wide analysis identifies novel loci influencing plasma apolipoprotein E concentration and Alzheimer’s disease risk (2023) · cites this paper as [8]
In the citing paper
“The original association study implicating L28P with LOAD risk was carried out in a relatively small sample size.”
From Investigation of the independent role of a rare APOE variant (L28P; APOE*4Pittsburgh) in late-onset Alzheimer disease (2023) · cites this paper as [9]
In the citing paper
“due to the complete linkage disequilibrium of L28P with APOE*4 (C112R)”
From Investigation of the independent role of a rare APOE variant (L28P; APOE*4Pittsburgh) in late-onset Alzheimer disease (2023) · cites this paper as [9]
In the citing paper
“it was associated with an elevated risk for AD [9]”
From Investigation of the independent role of a rare APOE variant (L28P; APOE*4Pittsburgh) in late-onset Alzheimer disease (2023) · cites this paper as [9]
In the citing paper
“In 1999, two groups independently identified a novel and rare missense mutation in the APOE gene [9, 10] in which the leucine residue is replaced by proline at codon 28 (L28P; rs769452).”
From Investigation of the independent role of a rare APOE variant (L28P; APOE*4Pittsburgh) in late-onset Alzheimer disease (2023) · cites this paper as [9]
In the citing paper
“with the East Asian population having a higher risk of AD associated with the APOE ε4 allele”
From Genetics of Alzheimer’s disease: An East Asian perspective (2023) · cites this paper as [11]
In the citing paper
“while the effect of APOE ε4 is weaker in African American and Hispanic populations”
From Genetics of Alzheimer’s disease: An East Asian perspective (2023) · cites this paper as [11]
In the citing paper
“The AD risk associated with common APOE alleles ε4 1 and ε2 2 is well established in European-ancestry individuals but varies considerably across other ancestries (Table 1). 3”
From Association of African Ancestry–Specific APOE Missense Variant R145C With Risk of Alzheimer Disease (2023) · cites this paper as [3]
In the citing paper
“Among the AD susceptibility genes/loci identified to date, APOE remains the most significant genetic risk factor across populations.”
From Association of rare APOE missense variants with Alzheimer's disease in the Japanese population (2025) · cites this paper as [8]
In the citing paper
“Although there is only about 20% of the population carrying the APOE ε4, this isoform is vastly enriched in AD patients with over 60% of symptomatic AD patients carrying at least one APOE ε4 allele”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Farrer et al 1997
In the citing paper
“The ε4 allele of apolipoprotein E (APOE) is the dominant genetic risk factor for late-onset Alzheimer’s disease (AD).”
From APOE4 is Associated with Differential Regional Vulnerability to Bioenergetic Deficits in Aged APOE Mice (2020) · cites this paper as [5]
In the citing paper
“The genetic polymorphism of human apolipoprotein E (ApoE) has been shown to confer differential susceptibility to late-onset AD, which accounts for the majority of the AD cases (Farrer et al., 1997).”
From Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention (2018) · cites this paper as Farrer et al., 1997
In the citing paper
“occurs in approximately two-thirds of all cases [1–3]”
From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [2]
In the citing paper
“Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer’s disease (AD)”
From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [2]
In the citing paper
“In contrast, APOE3 is defined as risk-neutral while APOE2 represents the strongest genetic protective factor (Corder et al., 1994; Farrer et al., 1997; Reiman et al., 2020).”
From APOE genotype-dependent differences in human astrocytic energy metabolism (2025) · cites this paper as Farrer et al., 1997
In the citing paper
“Since then, numerous studies have confirmed that possession of the ε4 allele is the strongest genetic risk factor for both AD and CAA, or a combination of both disorders (Bertram et al., 2007; Farrer et al., 1997).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Farrer et al., 1997
In the citing paper
“However, in certain ethnic groups, the apoE ε4 allele seems to have either a weaker effect or no clear effect on AD (Farrer et al., 1997; Kalaria et al., 2008; Mayeux, 2003; Tang et al., 1998).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Farrer et al., 1997
In the citing paper
“Finally, it is important to note that the ε2 allele of apoE is associated with a lower risk for AD (Corder et al., 1994; Farrer et al., 1997).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Farrer et al., 1997
In the citing paper
“APOE genotypes were in Hardy-Weinberg equilibrium in both cases and controls; their frequencies (Table 4) were similar to previous reports for the relevant age groups (44;47;48).”
From Association of ALS with head injury, cigarette smoking and APOE genotypes (2010) · cites this paper as [47]
In the citing paper
“The ε4 allele of apolipoprotein E (APOE) is the strongest genetic risk factor for sporadic Alzheimer's Disease (AD).”
From APOE loss-of-function variants: Compatible with longevity and associated with resistance to Alzheimer’s disease pathology (2024) · cites this paper as [4]
In the citing paper
“An APOE ε4/ε4 individual of European ancestry has a sixteen-fold increase in AD risk and eighteen year earlier age at AD onset compared to a European ancestry individual carrying two copies of the more prevalent APOE ε3 allele 4 .”
From APOE loss-of-function variants: Compatible with longevity and associated with resistance to Alzheimer’s disease pathology (2024) · cites this paper as [4]
In the citing paper
“The global frequency of the human ε4 allele is 13.7%, and the frequency of ε4 carriers is increased to 40% in AD patients [452, 453].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [453]
In the citing paper
“Clinical incidence and average age of AD onset was found to be 91% at 68 years of age in ε4 homozygous carriers, 47% at 76 years of age in ε4 heterozygous carriers, and 20% at 84 years of age in non-ε4 individuals [453].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [453]
In the citing paper
“ApoE4 is present in roughly 20–25% of the human population, and apoE4 carriers account for 60–75% of AD cases in most clinical studies [11], highlighting the importance of apoE4 in AD pathogenesis.”
From Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease (2019) · cites this paper as [11]
In the citing paper
“ApoE4 increases the risk and decreases the age of onset of AD in a gene dose dependent manner [4–11].”
From Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease (2019) · cites this paper as [11]
In the citing paper
“the effect of APOEε4 has been reported to differ across ethnicities [58–61]”
From Genetic architecture of Alzheimer's disease (2020) · cites this paper as [58]
In the citing paper
“the association between ε4 and disease is reported to be weaker among African-American and Hispanic individuals [58, 61, 62] and nonexistent among Nigerian individuals [63].”
From Genetic architecture of Alzheimer's disease (2020) · cites this paper as [58]
In the citing paper
“APOEε2/APOEε4 individuals are still at increased risk for AD, suggesting the APOEε4 isoform exhibits some dominant effect over the APOEε2 isoform [58].”
From Genetic architecture of Alzheimer's disease (2020) · cites this paper as [58]
In the citing paper
“Several studies have demonstrated APOE genotype has an exacerbated effect on disease risk in females [58]”
From Genetic architecture of Alzheimer's disease (2020) · cites this paper as [58]
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Autophagy and Proteostasis: A Unifying Theory of Neurodegenerative Disease
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Cardiovascular factors in dementia
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“Przykładem godnym uwagi jest to, że wspomniany już poprzednio allel ε4 apolipoproteiny E wiąże się zarówno z większym ryzykiem chorób sercowo-naczyniowych [57], jak i jest uznanym czynnikiem ryzyka choroby Alzheimera [6].”
BackgroundYadav, J., Verma, A., Singla, A., & Garg, R. K. (2023) · Indian Journal of Behavioural Sciences · doi:10.55229/ijbs.v26i2.10 · Cited by 1
“57 Although the association between ApoE4 genotype and severity of NFT pathology have not been found from human data.”
BackgroundThe Alzheimer disease continuum : findings from monogenic Alzheimer disease
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The Path of Alzheimer’s disease
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“Consistent with this notion, the odd risk of AD among APOE-e4 allele carriers appears to have a curvilinear relationship with age (Farrer et al., 1997).”
BackgroundResultInfluentialDietary patterns for healthier cognitive ageing
Berendsen, A. A. M. (2017) · doi:10.18174/417204
Ensemble Statistical Modelling of Risk Factors in Health
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A is for Autophagy and Alzheimer's
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“Interestingly, the APOE«2 allele appears to be protective against AD (Farrer et al., 1997).”
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“Genetic studies that define the clinical diagnosis as an outcome variable found that risk of AD increases and the age at onset decreases with the number of ApoE ε4 alleles (Corder et al., 1993; Farrer et al., 1997), thus suggesting a G × E.”
BackgroundThe Different Strategies used for the Early Diagnosis of Alzheimer’s Disease
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Characterization of Hepatitis C Virus interaction with heparan sulfate proteoglycans
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Benzodiazepines and risk of dementia in the elderly
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Characterization of novel mitochondrial modulators for the development of neuroprotective strategies
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Stratégies de ré-analyse d'un essai de prévention du déclin des fonctions cognitives non concluant
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Association between balance ability and memory function in community-dwelling older adults
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“[29] The e2/e3 genotype has been associated with a lower risk of Alzheimer disease than the e3/e3 genotype, [30] so the participants in the present study may have had a relatively low genetic risk for dementia.”
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Novel genetic profile linked to cognitive decline in Hispanics/Latinos
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Emerging therapeutic strategies to target APOE4 in Alzheimer's disease
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Association of TOMM40 polymorphisms with Alzheimer's disease risk in an Iranian population
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Metadata
- Authors
- Farrer, L. A.
- Corresponding author
- Farrer, Lindsay A.
- ORCID
- Farrer, Lindsay A.
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 1997-10-22
- Volume
- 278
- Issue
- 16
- Pages
- 1349
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- OpenAlex
- W7028228764
- Cited by
- 124
- References
- 0
- Citations by year
- 2026: 16 · 2025: 8 · 2024: 6 · 2023: 12 · 2022: 12 · 2021: 11 · 2020: 12 · 2019: 7 · 2018: 5 · 2017: 7 · 2016: 3 · 2015: 5 · 2014: 4 · 2013: 1 · 2012: 4
- FWCI
- 0.82
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- JAMA (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Florence Research (University of Florence) (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- apolipoprotein E, APOE ε4, Alzheimer's disease, genetic risk, age of onset, sex differences, ethnic differences, African Americans, Hispanic population, Japanese population, genetic heterogeneity, dementia risk
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