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The Apolipoprotein E ε2 Allele and the Pathological Features in Cerebral Amyloid Angiopathy-related Hemorrhage
Abstract
Cerebral amyloid angiopathy (CAA) is associated with apolipoprotein E (APOE gene, apoE protein) polymorphism: current evidence suggests that the epsilon4 allele is a risk factor for the development of CAA and the epsilon2 allele predisposes to hemorrhage. We sought to determine the relationship between the APOE epsilon2 allele and both the immunoreactivity profiles and vascular complications of CAA. We performed immunohistochemistry for amyloid beta-protein (A beta), apoE, cystatin C, and activated microglia, and examined the morphology of cortical and leptomeningeal vessels in 37 CAA-related hemorrhage (CAAH), 26 Alzheimer disease (AD) patients, and 20 controls. The extent of immunostaining of vessels for A beta, apoE, cystatin C, and perivascular activated microglia increased from controls through AD to a maximum in CAAH patients. Among cases with CAA (37 CAAH, 19 AD, and 6 controls, n = 62) vascular apoE (p < 5 x 10(-4)), cystatin C (p < 10(-4)), activated microglia (p < 10(-4)), vessels with a high ratio of wall thickness to lumen diameter (p < 0.003) as well as dilated/microaneurysmal vessels (p < 0.01) were present more frequently in patients with hemorrhage than without; however, these features were not associated with the APOE epsilon2 allele. Fibrinoid necrosis alone was associated with the APOE epsilon2 allele (p < 0.04) and we suggest that over-representation of APOE epsilon2 in CAAH may result from its association with fibrinoid necrosis.
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In the citing paper
“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 [54]
In the citing paper
“Evidence independently supports link of both the APOE ε4 and ε2 allele with increased risk for microhemorrhages in humans [51, 52, 54–57].”
From APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice (2017) · cites this paper as [56]
In the citing paper
“Several human autopsy studies have shown that the ε2 allele is an exacerbating factor of microhemorrhages among subjects with VAβ pathology and that this effect is linked to fibrinoid necrosis of vascular wall specifically associated with the ε2 allele [55–57].”
From APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice (2017) · cites this paper as [56]
In the citing paper
“Of note, APOEε2/ε4 individuals have a particularly high risk of intracerebral lobar haemorrhage in the presence of CAA50, possibly because the APOEε2 allele has been associated with fibrinoid necrosis of the vessel wall56,57.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [57]
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Neuropathology of human Alzheimer disease after immunization with amyloid-β peptide: a case report
Nicoll, J. A. R., Wilkinson, D., Holmes, C., Steart, P., Markham, H., & Weller, R. O. (2003) · Nature Medicine · doi:10.1038/nm840 · Cited by 1,397
Self-citationMechanisms of brain injury after intracerebral haemorrhage
Xi, G., Keep, R. F., & Hoff, J. T. (2005) · The Lancet Neurology · doi:10.1016/s1474-4422(05)70283-0 · Cited by 1,366
Clinical diagnosis of cerebral amyloid angiopathy: validation of the Boston criteria
Knudsen, K. A., Rosand, J., Karluk, D., & Greenberg, S. M. (2001) · Neurology · doi:10.1212/wnl.56.4.537 · Cited by 1,015
Weller, R. O., Subash, M., Preston, S., Mazanti, I., & Carare, R. O. (2008) · Brain Pathology · doi:10.1111/j.1750-3639.2008.00133.x · Cited by 697
Cerebral amyloid angiopathy in the elderly
Viswanathan, A., & Greenberg, S. M. (2011) · Annals of Neurology · doi:10.1002/ana.22516 · Cited by 643
Metadata
- Authors
- McCarron, M. O., Nicoll, J. A. R., Stewart, J., Ironside, J. W., Mann, D. M. A., Love, S., Graham, D. I., & Dewar, D.
- Affiliations
- Southern General Hospital (GB)
- Western General Hospital (GB)
- University of Manchester (GB)
- Frenchay Hospital (GB)
- University of Glasgow (GB)
- ORCID
- Venue
- Journal of Neuropathology and Experimental Neurology
- Publisher
- Oxford University Press (OUP)
- Published
- 1999-07
- Volume
- 58
- Issue
- 7
- Pages
- 711-718
- ISSN
- 0022-3069 (ISSN-L)
- OpenAlex
- W1985093052
- Cited by
- 160
- References
- 0
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 5 · 2023: 5 · 2022: 2 · 2021: 3 · 2020: 4 · 2019: 2 · 2018: 5 · 2017: 4 · 2016: 3 · 2015: 10 · 2014: 13 · 2013: 11 · 2012: 7
- FWCI
- 5.28
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neuropathology & Experimental Neurology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust
- 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
- cerebral amyloid angiopathy, APOE ε2 allele, intracerebral hemorrhage, amyloid-beta, cystatin C, activated microglia, fibrinoid necrosis, leptomeningeal vessels, cortical vessels, Alzheimer's disease, APOE polymorphism, microaneurysms
- MeSH terms
- Aged, Alleles, Alzheimer Disease, Apolipoproteins E, Intracranial Aneurysm, Cerebral Hemorrhage, Female, Humans, Immunohistochemistry, Male, Necrosis, Reference Values, Amyloid beta-Peptides, Cerebral Amyloid Angiopathy, Apolipoprotein E2
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