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APOE ε2 is associated with milder clinical and pathological Alzheimer disease
Open accessAbstract
Objective: The Alzheimer disease (AD) APOE ε4 risk allele associates with an earlier age at onset and increased amyloid‐β deposition, whereas the protective APOE ε2 allele delays the onset and appears to prevent amyloid‐β deposition. Yet the clinical and pathological effects of APOE ε2 remain uncertain because of its relative rarity. We investigated the effects of APOE ε2 and ε4 alleles on AD pathology and cognition in a large US data set of well‐characterized AD patients. Methods: We studied individuals from the National Alzheimer's Coordinating Center autopsy cohort across the entire clinicopathological continuum of AD. Multivariate models were built to examine the associations between APOE alleles and AD neuropathological changes, using the APOE ε3/ε3 group as comparator. Mediation analysis was used to estimate the direct and indirect effects of APOE alleles on AD pathology and cognition (Clinical Dementia Rating Sum of Boxes and Mini‐Mental State Examination). Results: Compared to APOE ε3/ε3, APOE ε2 is independently associated with lower Braak neurofibrillary tangle (NFT) stages and possibly fewer neuritic plaques, but has no direct effect on cerebral amyloid angiopathy (CAA) severity, whereas APOE ε4 is associated with more neuritic plaques and CAA, but has no independent effect on Braak NFT stage. Unadjusted analyses showed marked differences among APOE genotypes with respect to cognitive performance (ε2 > ε3 > ε4). Mediation analysis suggests that this is largely explained through effects on pathology. Interpretation: Even when adjusted for age at onset, symptom duration, and other demographic variables, APOE ε2 is associated with milder AD pathology and less severe antemortem cognitive impairment compared to APOE ε3 and ε4 alleles, suggesting a relative neuroprotective effect of APOE ε2 in AD. Ann Neurol 2015;77:917–929
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“Relative to the APOEε3 homozygote reference group, carrying one or two APOEε4 alleles is independently associated with a higher Aβ plaque burden and more severe cerebral amyloid angiopathy (CAA), whereas APOEε2/ε2 and ε2/ε3 individuals have fewer Aβ plaques46–50 but are more likely to have CAA51.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [48]
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“Homozygous APOE4 individuals have a 6 to 18-fold increase in AD risk compared to APOE2/3 individuals [9, 10].”
From APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology (2025) · cites this paper as [9]
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“The study supports known effects of APOE genotypes on standard measures of neuritic Aβ plaque and tau tangle severity13”
From Exceptionally low likelihood of Alzheimer’s dementia in APOE2 homozygotes from a 5,000-person neuropathological study (2020) · cites this paper as [13]
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“Apolipoprotein E ε4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimer’s disease (LOAD).”
From APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology (2025) · cites this paper as [9]
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“In contrast to Aβ pathology, the existence of a direct effect of APOE genotype on the severity of tau neurofibrillary tangle pathology remains controversial, with most studies agreeing that APOEε4-linked effect on tangles is primarily indirect, mediated through its increase of Aβ plaque burden46–48,53.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [48]
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“By contrast, APOEε2 has been found to have both direct and indirect (through Aβ) protective effects against tangle pathology48,49.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [48]
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Frequency of the apolipoprotein E ε2 allele is diminished in sporadic Alzheimer disease
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Self-citationMild to moderate Alzheimer dementia with insufficient neuropathological changes
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Apolipoprotein E Genotype and Rate of Decline in Probable Alzheimer's Disease
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Most rapid cognitive decline in APOE ε4 negative Alzheimer's disease with early onset
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“the presence of hippocampal sclerosis all independently predict a higher degree of antemortem cognitive impairment as measured by CDR-SOB, whereas education level is an independent protective factor against cognitive impairment.(52) Herein, we examined whether the APOE genotype impacts cognition independently of both…”
BackgroundMethodResultInfluentialSelf-citationAmyloid mediates the association of apolipoprotein E e4 allele to cognitive function in older people
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“found such an association,(11,20) including those controlling for plaque burden in multivariate models.(35,36) In contrast to APOEe4 carriers, APOEe2 carriers are thought to bear fewer amyloid plaques(14,17,19,34,37,38) and possibly also fewer NFTs.”
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No association between apolipoprotein E epsilon 4 allele and rate of decline in Alzheimer's disease
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Differential Binding of Apolipoprotein E Isoforms to Tau and Other Cytoskeletal Proteins
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Apolipoprotein E-epsilon 2 and Alzheimer's disease
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Protective effect of apoE ∈2 in Alzheimer's disease
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“found such an association,(11,20) including those controlling for plaque burden in multivariate models.(35,36) In contrast to APOEe4 carriers, APOEe2 carriers are thought to bear fewer amyloid plaques(14,17,19,34,37,38) and possibly also fewer NFTs.”
BackgroundApoE3 binding to tau tandem repeat I is abolished by tau serine262 phosphorylation
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Apolipoprotein E Genotype and Deposits of Aβ40 and Aβ42 in Alzheimer Disease
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“Of note, these analyses also suggested a protective effect of the APOEe2 allele against neuritic plaques resulting from 2 effects of similar size: a direct effect against neuritic plaques and an indirect consequence of its protective effect on NFTs. Mediation analyses also revealed that the APOEe2 allele has no signif…”
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“Second, APOEe2 may indirectly contribute to restrict NFT spreading to cortical areas and determine a lower Braak stage by protecting against the accumulation of soluble amyloid-b (Ab) oligomeric species—probably not well captured by the CERAD neuritic plaque score— and plaques(61) and by protecting against the synapto…”
BackgroundSelf-citationNeocortical β‐amyloid area is associated with dementia and APOE in the oldest‐old
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Knopman, D. S., Amieva, H., Petersen, R. C., Chételat, G., Holtzman, D. M., Hyman, B. T., Nixon, R. A., & Jones, D. T. (2021) · Nature Reviews Disease Primers · doi:10.1038/s41572-021-00269-y · Cited by 2,606
Self-citationMasters, C. L., Bateman, R., Blennow, K., Rowe, C. C., Sperling, R. A., & Cummings, J. L. (2015) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2015.56 · Cited by 1,853
Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies
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APOE and Alzheimer’s disease: Advances in genetics, pathophysiology, and therapeutic approaches
Serrano-Pozo, A., Das, S., & Hyman, B. T. (2021) · The Lancet Neurology · doi:10.1016/s1474-4422(20)30412-9 · Cited by 1,037
Self-citationApoE in Alzheimer’s disease: pathophysiology and therapeutic strategies
Raulin, A.-C., Doss, S. V., Trottier, Z. A., Ikezu, T. C., Bu, G., & Liu, C.-C. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00574-4 · Cited by 756
Metadata
- Authors
- Serrano‐Pozo, A., Qian, J., Monsell, S. E., Betensky, R. A., & Hyman, B. T.
- Affiliations
- University of Iowa Hospitals and Clinics (US)
- University of Massachusetts Amherst (US)
- University of Washington (US)
- Harvard University (US)
- Massachusetts General Hospital (US)
- Corresponding author
- Hyman, Bradley T.
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2015-05-27
- Volume
- 77
- Issue
- 6
- Pages
- 917-929
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- PMC
- PMC4447539
- OpenAlex
- W1958554455
- Cited by
- 176
- References
- 96
- Citations by year
- 2026: 13 · 2025: 24 · 2024: 17 · 2023: 20 · 2022: 20 · 2021: 22 · 2020: 11 · 2019: 7 · 2018: 8 · 2017: 9 · 2016: 16 · 2015: 9
- FWCI
- 10.32
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (P50 AG005134)
- 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 › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, APOE ε2, APOE ε4, APOE ε3, risk alleles, neurofibrillary tangles, neuritic plaques, cerebral amyloid angiopathy, amyloid-beta deposition, cognitive impairment, neuropathology, neuroprotection, age of onset
- MeSH terms
- Aged, Aged, 80 and over, Alleles, Alzheimer Disease, Female, Humans, Male, Severity of Illness Index, Cohort Studies, Apolipoprotein E3, Apolipoprotein E4, Apolipoprotein E2
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