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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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“An individual who is homozygous for the ε4 allele has an 8-12 times greater chance of developing AD (Genin et al., 2011; Serrano-Pozo et al., 2015).”
BackgroundIs Alzheimer’s Disease Risk Modifiable?
Serrano‐Pozo, A., & Growdon, J. H. (2019) · Journal of Alzheimer s Disease · doi:10.3233/jad181028 · Cited by 168
Self-citationAPOE and cerebral amyloid angiopathy in community-dwelling older persons
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“However, the relationship of ε2 with CAA is not clear as the association was not replicated in a more recent study using data from the National Alzheimer’s Coordinating Center autopsied subjects (Serrano-Pozo et al., 2015).”
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ResultPlaque-associated local toxicity increases over the clinical course of Alzheimer disease
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“The pathophysiology of NFTs in AD patients with the ε4 allele in the cortex is worsened compared to those who do not have the ε4 allele.”
BackgroundInfluentialAβ propagation and strains: Implications for the phenotypic diversity in Alzheimer's disease
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“Conversely, AC CE PT ED M AN US CR IP T carriers of the APOE2 allele have milder AD symptoms despite relatively abundant pathology (Conejero-Goldberg et al. 2014, Serrano-Pozo et al. 2015, Shinohara et al. 2016), but much less is known about the mechanisms underlying this apparent protection.”
Jackson, R. J., Keiser, M. S., Meltzer, J. C., Fykstra, D. P., Dierksmeier, S. E., Hajizadeh, S., Kreuzer, J., Morris, R., Melloni, A., Nakajima, T., et al. (2024) · Molecular Therapy · doi:10.1016/j.ymthe.2024.03.024 · Cited by 86
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“APOE2 in particular may be protective against AD partially through lipid and metabolic mechanisms that lead to fewer tau tangles [44].”
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“These results largely agree with those from a NACC sample of cognitively impaired (CDR-SOB score >0) selected to represent the AD clinicopathologic continuum.(5)”
ResultInfluentialSelf-citationAPOE2 orchestrated differences in transcriptomic and lipidomic profiles of postmortem AD brain
Lefterov, I., Wolfe, C. M., Fitz, N. F., Nam, K. N., Letronne, F., Biedrzycki, R. J., Kofler, J., Han, X., Wang, J., Schug, J., et al. (2019) · Alzheimer's Research & Therapy · doi:10.1186/s13195-019-0558-0 · Cited by 74
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“APOE ε2 remains protective against longitudinal Aβ accumulation, particularly in those without the APOE ε4 allele 52,53 , con firmed by neuropathological studies 33,54 .”
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“In older adults, the ε2 allele is associated with decreased cognitive decline in both healthy individuals (Helkala et al., 1995, 1996; Wilson et al., 2002; Blair et al., 2005) and patients with AD (Serrano-Pozo et al., 2015).”
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“…in Aβ burden among ApoE variants in our cohort, which may be due to analysis of brain at an end-stage of disease where Aβ neuritic plaque levels may have already plateaued, as suggested from post-mortem neuropathological analysis of Aβ plaque burden in E2 carriers (Serrano-Pozo et al., 2015).”
BackgroundResultLarge multi-ethnic genetic analyses of amyloid imaging identify new genes for Alzheimer disease
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“Contrarily, APOE ε2 carriers, showing reduced Aβ deposition [53], have been associated with milder clinical and pathological AD when compared to ε4 carriers [54].”
BackgroundBrain Lipids and Lipid Droplet Dysregulation in Alzheimer’s Disease and Neuropsychiatric Disorders
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“As the strongest AD risk variant, ApoE4 is associated with higher A β plaque burden and more severe tau pathology in the postmortem brain, whereas the opposite effect was observed for ApoE2, a protective isoform [109 – 111].”
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“ThioS-/NEUN+ neuronal cell bodies from human AD donors38; (7) a pan-neurodegenerative (PAN) signature obtained from a meta-analysis of 60 bulk microarray studies encompassing more than 2,600 samples from AD, Lewy body diseases (LBD), and ALS-frontotemporal dementia (FTD) spectrum and CTRL individuals39,40; (8) an AD r…”
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“APOE*ε2 on the other hand is associated with reduced numbers of neuritic plaques (Serrano-Pozo et al., 2015).”
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Multi-functional role of apolipoprotein E in neurodegenerative diseases
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Apolipoprotein E isoform-dependent effects on the processing of Alzheimer's amyloid-β
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“Among the ApoE family, ApoE2 is considered as a neuroprotector against AD pathology, while ApoE4 promotes the Aβ accumulation and AD symptoms (Fleisher et al., 2013; Serrano-Pozo et al., 2015).”
BackgroundSchreiber, S., Schreiber, F., Lockhart, S. N., Horng, A., Bejanin, A., Landau, S. M., Jagust, W. J., & Initiative, A. D. N. (2017) · JAMA Neurology · doi:10.1001/jamaneurol.2016.5349 · Cited by 33
APOE2 mitigates disease-related phenotypes in an isogenic hiPSC-based model of Alzheimer’s disease
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“These data are consistent with evidence seen clinically where APOE2 is associated with milder AD pathology including significantly reduced amyloid deposited in the neocortex, as well as animal studies that suggest the APOE2 allele markedly reduces brain amyloid pathology in Alzheimer’s disease mouse models [11, 74, 75…”
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The Relationship of APOE ε4, Race, and Sex on the Age of Onset and Risk of Dementia
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Apolipoprotein E and Sex Bias in Cerebrovascular Aging of Men and Mice
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“…successfully against the (cid:2) 3 allele is not surprising given that its benefit on longevity and cognition [5], and protection from AD pathology [6, 7] does not contribute to survivability until an advanced age well after the average life expectancy, particularly of hunter gatherer populations.”
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“Conversely, the presence of the ε2 allele seems to correlate with a protective phenotype in neurodegenerative disorders (Serrano-Pozo et al., 2015).”
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“phenotype in these neurodegenerative disorders (Talbot et al., 1994; Berge et al., 2014; Serrano-Pozo et al., 2015).”
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Alzheimer's disease phenotype based upon the carrier status of the apolipoprotein E ɛ4 allele
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“An autopsy cohort study reported that relative to APOE3 homozygotes, APOE4 is associated with more A β plaques and cerebral amyloid angiopathy (CAA), while APOE2 displayed lower A β plaques burden and CAA [32].”
Background
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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