Cited by 269Intracerebral and Subarachnoid Hemorrhage ResearchAlzheimer's disease research and treatmentsCerebrovascular and genetic disorders

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Association of apolipoprotein E ϵ2 and vasculopathy in cerebral amyloid angiopathy

Greenberg, S. M., Vonsattel, J.-P. G., Segal, A. Z., Chiu, R. I., Clatworthy, A. E., Liao, A., Hyman, B. T., Rebeck, G. W.·1998·Neurology

DOI 10.1212/wnl.50.4.961

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Abstract

Objective Hemorrhage related to cerebral amyloid angiopathy (CAA) appears to occur through a multistep pathway that includes deposition of beta-amyloid in cerebral vessels and specific vasculopathic changes in the amyloid-laden vessels, such as cracking of the vessel wall. Recent reports suggest a positive association between CAA-related hemorrhage and both the apolipoprotein E (APOE) epsilon4 allele and, unexpectedly, the APOE epsilon2 allele. Unlike APOE epsilon4, APOE epsilon2 does not appear to act through increased beta-amyloid deposition. We therefore sought to determine whether it might specifically accelerate the second step in this pathway, that is, development of the vasculopathic changes that lead to hemorrhage. Methods To determine the role of APOE in development of vasculopathic changes, we compared APOE genotypes in two groups of postmortem brains: 52 brains with complete amyloid replacement of vessel walls but without vasculopathic changes, and 23 brains with complete amyloid replacement of vessels with the accompanying changes of cracking of the vessel wall and paravascular leaking of blood. Results Frequency of APOE epsilon2 was significantly greater in the group with vasculopathy (0.09) than the group without (0.01, p = 0.03). The groups did not differ in mean age or extent of neuritic plaques. Analysis of a clinical series of patients with CAA-related hemorrhage confirmed an overrepresentation of APOE epsilon2 as well as an association between this allele a…

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Age-Dependent Association of Apolipoprotein E Genotypes With Stroke Subtypes in a Japanese Rural Population
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The Role of Cystatin C in Cerebral Amyloid Angiopathy and Stroke: Cell Biology and Animal Models
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“Whereas the ApoE ε4 allele promotes deposition of Aβ in the cerebral vasculature (59, 108, 109, 117, 146, 177, 179), possession of ApoE ε2 promotes the development of hemorrhage in vessels already laden with amyloid (57, 59, 109, 117, 118, 177).”
Background
Genetic risk factors for spontaneous intracerebral haemorrhage
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Quantitation of apoE Domains in Alzheimer Disease Brain Suggests a Role for apoE in Aß Aggregation
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Self-citation
Cortical superficial siderosis and bleeding risk in cerebral amyloid angiopathy
Charidimou, A., Boulouis, G., Greenberg, S. M., & Viswanathan, A. (2019) · Neurology · doi:10.1212/wnl.0000000000008590 · Cited by 99
Self-citation
Apolipoprotein E Genotype and Cerebral Amyloid Angiopathy‐related Hemorrhage
McCarron, M. O., & Nicoll, J. A. R. (2000) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2000.tb06366.x · Cited by 99
A novel AβPP mutation exclusively associated with cerebral amyloid angiopathy
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Cerebral Amyloid Angiopathy–Related Hemorrhage: Interaction of APOE ε2 With Putative Clinical Risk Factors
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Understanding the Pathophysiology of Cerebral Amyloid Angiopathy
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“[59] and later supported by the finding that ε2 is associated with larger ICH-related haematoma volume and poorer functional outcome [60].”
Result
Clinical diagnosis of cerebral amyloid angiopathy: Validation of the Boston Criteria
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Self-citation
Cortical superficial siderosis and first-ever cerebral hemorrhage in cerebral amyloid angiopathy
Charidimou, A., Boulouis, G., Xiong, L., Jessel, M. J., Roongpiboonsopit, D., Ayres, A. M., Schwab, K. M., Rosand, J. M., Gurol, M. E., Greenberg, S. M., et al. (2017) · Neurology · doi:10.1212/wnl.0000000000003866 · Cited by 87
Self-citation
Apolipoprotein E Genotype Predicts Hematoma Expansion in Lobar Intracerebral Hemorrhage
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Self-citation
Apolipoprotein E levels in cerebrospinal fluid and the effects of ABCA1polymorphisms
Wahrle, S. E., Shah, A. R., Fagan, A. M., Smemo, S., Kauwe, J. S., Grupe, A., Hinrichs, A., Mayo, K., Jiang, H., Thal, L. J., et al. (2007) · Molecular Neurodegeneration · doi:10.1186/1750-1326-2-7 · Cited by 84
“This research would not only be relevant to AD, but also to a number of other neurological diseases that may be modulated by apoE such as stroke [50,51], multiple sclerosis [52] and traumatic brain injury [53].”
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“…that APOE ε 2 promotes vasculopathic changes (vessel cracking, vessel-within-vessel appearance and ﬁ brinoid necrosis-the most severe stage of CAA) which can in turn result to vessel rupture (Greenberg et al., 1998) including lobar ICH (Charidimou et al., 2015c; Martinez-Ramirez et al., 2014).”
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“…well as other clinical disorders that involve amyloid (e.g., cerebral amyloid angiopathy), apoE4 is associated with increased amyloid deposi- tion compared with apoE3 (Deb et al., 2000; Greenberg et al., 1998; Jordan et al., 1997; Nicoll et al., 1995; Polvikoski et al., 1995; Rebeck et al., 1993).”
William M. Feinberg Lecture: Stroke Therapy in the Year 2025
Broderick, J. P. (2003) · Stroke · doi:10.1161/01.str.0000106160.34316.19 · Cited by 77
Prevalence of cortical superficial siderosis in a memory clinic population
Zonneveld, H. I., Goos, J. D. C., Wattjes, M. P., Prins, N. D., Scheltens, P., van der Flier, W. M., Kuijer, J. P. A., Muller, M., & Barkhof, F. (2014) · Neurology · doi:10.1212/wnl.0000000000000150 · Cited by 78
Interrelationship of superficial siderosis and microbleeds in cerebral amyloid angiopathy
Shoamanesh, A., Martínez‐Ramírez, S., Filho, J. O., Reijmer, Y. D., Falcone, G. J., Ayres, A. M., Schwab, K. M., Goldstein, J. N., Rosand, J. M., Gurol, M. E., et al. (2014) · Neurology · doi:10.1212/wnl.0000000000000984 · Cited by 75
Self-citation
Advances in the genetics of cerebrovascular disease and stroke
Hádemenos, G. J., Alberts, M. J., Awad, I. A., Mayberg, M. R., Shephard, T. J., Jagoda, A. S., Latchaw, R. E., Todd, H. W., Viste, K. M., Starke, R. M., et al. (2001) · Neurology · doi:10.1212/wnl.56.8.997 · Cited by 73
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Self-citation
Hemorrhagic stroke associated with the Iowa amyloid precursor protein mutation
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Self-citation
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Influential
Apolipoprotein E Genotype Regulates Amyloid-β Cytotoxicity
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Background
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Interaction between Alzheimer’s Disease and Cerebral Small Vessel Disease: A Review Focused on Neuroimaging Markers
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Authors: Greenberg, S. M., Vonsattel, J.-P. G., Segal, A. Z., Chiu, R. I., Clatworthy, A. E., Liao, A., Hyman, B. T., & Rebeck, G. W.
Affiliations: Harvard University (US)
ORCID: Greenberg, S. M.
Segal, A. Z.
Clatworthy, A. E.
Hyman, B. T.
Rebeck, G. W.
Venue: Neurology
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 1998-04
Volume: 50
Issue: 4
Pages: 961-965
ISSN: 0028-3878 (ISSN-L)
1526-632X
DOI: 10.1212/wnl.50.4.961
OpenAlex: W2041396523
Cited by: 267
References: 23
Citations by year: 2026: 7 · 2025: 10 · 2024: 11 · 2023: 6 · 2022: 6 · 2021: 10 · 2020: 8 · 2019: 11 · 2018: 12 · 2017: 9 · 2016: 4 · 2015: 15 · 2014: 9 · 2013: 15 · 2012: 12
FWCI: 7.43
Type: journal article
Language: en
Open access: closed
Locations: Neurology (publishedVersion)
PubMed (publishedVersion)
Funders: Chinese Academy of Agricultural Sciences
National Institute on Aging (AG14473, AG 12406, AG00725)
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 ε4, intracerebral hemorrhage, vasculopathy, amyloid-beta deposition, postmortem brain
MeSH terms: Age Factors, Aged, Aged, 80 and over, Amyloidosis, Apolipoproteins E, Cerebral Arteries, Cerebral Hemorrhage, Genotype, Humans, Middle Aged, Cohort Studies, Apolipoprotein E2

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Association of apolipoprotein E ϵ2 and vasculopathy in cerebral amyloid angiopathy

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