Association of apolipoprotein E ϵ2 and vasculopathy in cerebral amyloid angiopathy
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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Human studies have linked APOE2 to greater CAA severity in some cohorts, and to CAA-related vasculopathic changes and hemorrhagic complications.
“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 [53]
APOEε2/ε4 individuals have a particularly high risk of intracerebral lobar haemorrhage in the presence of cerebral amyloid angiopathy, possibly because the APOEε2 allele has been associated with fibrinoid necrosis of the vessel wall.
“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 [56]
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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).”
BackgroundGenetic risk factors for spontaneous intracerebral haemorrhage
Carpenter, A., Singh, I. P., Gandhi, C. D., & Prestigiacomo, C. J. (2015) · Nature Reviews Neurology · doi:10.1038/nrneurol.2015.226 · Cited by 103 · see citing works
Quantitation of apoE Domains in Alzheimer Disease Brain Suggests a Role for apoE in Aß Aggregation
Cho, H. S., Hyman, B. T., Greenberg, S. M., & Rebeck, G. W. (2001) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/60.4.342 · Cited by 102 · see citing works
Self-citationCortical 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 · see citing works
Self-citationApolipoprotein 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 · see citing works
A novel AβPP mutation exclusively associated with cerebral amyloid angiopathy
Obici, L. P., Demarchi, A., de Rosa, G., Bellotti, V., Marciano, S., Donadei, S., Arbustini, E., Palladini, G. O., Diegoli, M., Genovese, E., et al. (2005) · Annals of Neurology · doi:10.1002/ana.20571 · Cited by 97 · see citing works
Spontaneous intracerebral hemorrhage: epidemiology and clinical presentation
Woo, D., & Broderick, J. P. (2002) · Neurosurgery Clinics of North America · doi:10.1016/s1042-3680(02)00011-6 · Cited by 95 · see citing works
McCarron, M. O., Nicoll, J. A. R., Ironside, J. W., Love, S., Alberts, M. J., & Bone, I. (1999) · Stroke · doi:10.1161/01.str.30.8.1643 · Cited by 92 · see citing works
Understanding the Pathophysiology of Cerebral Amyloid Angiopathy
Gatti, L., Tinelli, F., Scelzo, E., Arioli, F., Fede, G. D., Obici, L. P., Pantoni, L., Giaccone, G., Caroppo, P., Parati, E. A., et al. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21103435 · Cited by 91 · see citing works
“[59] and later supported by the finding that ε2 is associated with larger ICH-related haematoma volume and poorer functional outcome [60].”
ResultClinical diagnosis of cerebral amyloid angiopathy: Validation of the Boston Criteria
Smith, E. E., & Greenberg, S. M. (2003) · Current Atherosclerosis Reports · doi:10.1007/s11883-003-0048-4 · Cited by 88 · see citing works
Self-citationCortical 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 · see citing works
Self-citationApolipoprotein E Genotype Predicts Hematoma Expansion in Lobar Intracerebral Hemorrhage
Brouwers, H. B., Biffi, A., Ayres, A. M., Schwab, K. M., Cortellini, L., Romero, J. M., Rost, N. S., Viswanathan, A., Greenberg, S. M., Rosand, J. M., et al. (2012) · Stroke · doi:10.1161/strokeaha.111.643262 · Cited by 87 · see citing works
Self-citationApolipoprotein 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 · see citing works
“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].”
Farid, K., Charidimou, A., & Baron, J. (2017) · NeuroImage Clinical · doi:10.1016/j.nicl.2017.05.002 · Cited by 83 · see citing works
“…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).”
Kirshner, H. S., & Bradshaw, M. (2015) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-015-0572-y · Cited by 83 · see citing works
ApoE isoform-specific effects on LTP: blockade by oligomeric amyloid-β1–42
Trommer, B. L., Shah, C., Yun, S. H., Gamkrelidze, G., Pasternak, E. S., Blaine Stine, W., Manelli, A., Sullivan, P., Pasternak, J. F., & LaDu, M. J. (2005) · Neurobiology of Disease · doi:10.1016/j.nbd.2004.08.011 · Cited by 82 · see citing works
“…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 · see citing works
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 · see citing works
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 · see citing works
Self-citationAdvances 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 · see citing works
Predictors of hematoma expansion predictors after intracerebral hemorrhage
Chen, S., Zhao, B., Wang, W., Shi, L., Reis, C., & Zhang, J. (2017) · Oncotarget · doi:10.18632/oncotarget.19366 · Cited by 71 · see citing works
Focal hemosiderin deposits and β‐amyloid load in the ADNI cohort
Kantarci, K., Gunter, J. L., Tosakulwong, N., Weigand, S. D., Senjem, M. L., Petersen, R. C., Aisen, P. S. S., Jagust, W. J., Weiner, M. W., Jack, C. R., et al. (2013) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2012.10.011 · Cited by 68 · see citing works
Gkanatsiou, E., Portelius, E., Toomey, C. E., Blennow, K., Zetterberg, H., Lashley, T., & Brinkmalm, G. (2019) · Neuroscience Letters · doi:10.1016/j.neulet.2019.02.033 · Cited by 66 · see citing works
Cerebral small vessel diseases: cerebral microangiopathies
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Carmona‐Iragui, M., Videla, L., Lleó, A., & Fortea, J. (2019) · Developmental Neurobiology · doi:10.1002/dneu.22709 · Cited by 64 · see citing works
Apolipoprotein E and central nervous system disorders: Reviews of clinical findings
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Cerebral amyloid angiopathy: diagnosis and potential therapies
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APOE and cortical superficial siderosis in CAA
Charidimou, A., Zonneveld, H. I., Shams, S., Kantarci, K., Shoamanesh, A., Hilal, S., Yates, P. A., Boulouis, G., Na, H. K., Pasi, M., et al. (2019) · Neurology · doi:10.1212/wnl.0000000000007818 · Cited by 60 · see citing works
Self-citationHemorrhagic stroke associated with the Iowa amyloid precursor protein mutation
Greenberg, S. M., Shin, Y., Grabowski, T. J., Cooper, G. E., Rebeck, G. W., Iglesias, S., Chapon, F., Tournier‐Lasserve, E., & Baron, J. (2003) · Neurology · doi:10.1212/01.wnl.0000050140.10044.a8 · Cited by 60 · see citing works
Self-citationGenetics of stroke: a review of recent advances
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Advances in molecular genetics and pathology of cerebrovascular disorders
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Esiri, M. M., Chance, S. A., Joachim, C. L., Warden, D. R., Smallwood, A., Sloan, C., Christie, S., Wilcock, G. K., & Smith, A. D. (2014) · Brain Pathology · doi:10.1111/bpa.12221 · Cited by 55 · see citing works
Racial differences in microbleed prevalence in primary intracerebral hemorrhage
Copenhaver, B. R., Hsia, A. W., Merino, J. G., Burgess, R. E., Fifi, J. T., Davis, L. A., Warach, S. J., & Kidwell, C. S. (2008) · Neurology · doi:10.1212/01.wnl.0000327524.16575.ca · Cited by 55 · see citing works
Verbeek, M. M., Nostrand, W. E. V., Otte‐Höller, I., Wesseling, P., & de Waal, R. M. W. (2000) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2000.tb06368.x · Cited by 55 · see citing works
Clinical considerations in early-onset cerebral amyloid angiopathy
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“Therefore, despite being rare, improving our understanding of disease processes in early-onset CAA subtypes might provide important mechanistic information for other, more commonly encountered, forms of CAA.”
InfluentialApolipoprotein E Genotype Regulates Amyloid-β Cytotoxicity
Wilhelmus, M. M. M., Otte‐Höller, I., Davis, J., Nostrand, W. E. V., de Waal, R. M. W., & Verbeek, M. M. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.4213-04.2005 · Cited by 54 · see citing works
“It has been suggested by Nicoll et al. (1997) and Greenberg et al. (1998) that both the 2 and 4 alleles are risk factors for CAArelated hemorrhages, the latter by increasing the vascular amyloid load and the former by increasing the susceptibility of the vessel for rupture.”
BackgroundClinical phenotype, atrophy, and small vessel disease in APOE ε2 carriers with Alzheimer disease
Groot, C., Sudre, C. H., Barkhof, F., Teunissen, C. E., van Berckel, B. N. M., Seo, S. W., Sebastien Ourselin, A., Scheltens, P., Cardoso, M. J., van der Flier, W. M., et al. (2018) · Neurology · doi:10.1212/wnl.0000000000006503 · Cited by 53 · see citing works
Cerebral amyloid angiopathy and related inflammatory disorders
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Prevalence and Natural History of Superficial Siderosis
Pichler, M. R., Vemuri, P., Rabinstein, A. A., Aakre, J. A., Flemming, K. D., Brown, R. D., Kumar, N., Kantarci, K., Kremers, W. K., Mielke, M. M., et al. (2017) · Stroke · doi:10.1161/strokeaha.117.018974 · Cited by 49 · see citing works
Martinez‐Lizana, E., Carmona‐Iragui, M., Alcolea, D. A., Gómez-Choco, M. J., Vilaplana, E., Sánchez‐Saudinós, M. B., Clarimón, J., Hernández‐Guillamón, M., Munuera, J., Gelpí, E., et al. (2015) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2015.25 · Cited by 47 · see citing works
Cerebral amyloid angiopathy in traumatic brain injury: association with apolipoprotein E genotype
Leclercq, P. D. (2005) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.2003.025528 · Cited by 46 · see citing works
Kim, S. E., Kim, H. J., Jang, H., Weiner, M. W., DeCarli, C. S., Na, D. L., & Seo, S. W. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231810490 · Cited by 42 · see citing works
- 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)
- Venue
- Neurology
- Published
- 1998-04
- Volume
- 50
- Issue
- 4
- Pages
- 961-965
- ISSN
- 0028-3878 (ISSN-L)
- 1526-632X
- 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 › Neurology › Intracerebral and Subarachnoid Hemorrhage Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › 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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