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APOE-ε2 and APOE-ε4 Correlate With Increased Amyloid Accumulation in Cerebral Vasculature
Open accessAbstract
The APOE-ε4 allele correlates with increased risk of Alzheimer disease (AD) and increased parenchymal amyloid plaques. We tested how the APOE genotype correlated with cerebral amyloid angiopathy (CAA) by analyzing 371 brains for parenchymal and meningeal CAA in 4 brain regions (frontal, parietal, temporal, and occipital neocortex). The overall severity of CAA was highest in the occipital lobe. APOE-ε4/4 brains (n = 22) had the highest levels of CAA across regions. In the occipital lobe, nearly all APOE-ε4/4 cases were scored with the highest level of CAA (meninges, 95% of cases; parenchyma, 81%). In this brain region as in others, APOE-ε3/4 brains (n = 115) showed consistently less CAA than APOE-ε4/4 brains (meninges, 43%; parenchyma, 43%). APOE-ε3/3 brains (n = 182) showed even less CAA (meninges, 19%; parenchyma, 19%). Interestingly, APOE-ε2/3 cases (n = 42) had more CAA than APOE-ε3/3 (meninges, 44%; parenchyma, 32%), despite a reduced risk for AD in the APOE-ε2/3 individuals. APOE-ε4/4 brains also had the fewest regions without CAA, whereas APOE-ε3/3 brains had the most. Ordinal regression analyses demonstrated significant impacts of APOE-ε2 and APOE-ε4 on CAA at least in some brain regions. These data demonstrate that APOE genotype correlations with Aβ deposition in CAA only incompletely correspond to other AD-linked brain pathologies.
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“However, human studies have linked APOE2 to greater CAA severity in some cohorts 52 , and to CAA-related vasculopathic changes and hemorrhagic complications 53,54 .”
From APOE2 attenuates APOE4-associated amyloid pathology and related toxicity in a mouse model of Alzheimer’s disease (2026) · cites this paper as [52]
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“These findings may reflect human AD studies in which both E4 and E2 carriage were associated with higher CAA compared to E3/E3 individuals47,48”
From APOE4 to APOE2 allelic switching in mice improves Alzheimer’s disease-related metabolic signatures, neuropathology and cognition (2025) · cites this paper as [48]
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“These data add further evidence for AD pathology (mainly neurofibrillary tangles and neuritic plaques) being the main morphological substrate of clinical dementia [51],[79],[80].”
From The overlap between vascular disease and Alzheimer’s disease - lessons from pathology (2014) · cites this paper as [80]
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Metadata
- Authors
- Nelson, P. T., Pious, N. M., Jicha, G. A., Wilcock, D. M., Fardo, D. W., Estus, S., & Rebeck, G. W.
- Affiliations
- University of Kentucky (US)
- Georgetown University (US)
- Corresponding author
- Rebeck, G. William
- ORCID
- Venue
- Journal of Neuropathology & Experimental Neurology
- Publisher
- Oxford University Press (OUP)
- Published
- 2013-07
- Volume
- 72
- Issue
- 7
- Pages
- 708-715
- ISSN
- 0022-3069 (ISSN-L)
- 1554-6578
- PMC
- PMC3715146
- OpenAlex
- W2046985190
- Cited by
- 150
- References
- 43
- Citations by year
- 2026: 13 · 2025: 20 · 2024: 20 · 2023: 20 · 2022: 14 · 2021: 12 · 2020: 12 · 2019: 6 · 2018: 6 · 2017: 2 · 2016: 8 · 2015: 10 · 2014: 7
- FWCI
- 5.29
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Neuropathology & Experimental Neurology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (P01AG030128, P30AG028383, R01AG035379)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Intracerebral and Subarachnoid Hemorrhage Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Clinical Neurology › Cerebrovascular and genetic disorders
- Keywords
- APOE ε2, APOE ε4, APOE genotype, cerebral amyloid angiopathy, amyloid-beta deposition, Alzheimer's disease, occipital lobe, APOE ε3
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Blood Vessels, Cerebral Cortex, Female, Humans, Male, Logistic Models, Amyloid beta-Peptides, Cerebral Amyloid Angiopathy, Apolipoprotein E4, Apolipoprotein E2
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