The DOI matches its Crossref record.
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.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
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]
Citations
Cites
Still being checked.
Cited by
Sorted by citations
Items 101–162 of 162
Ghantasala, S., Pai, M. G. J., Biswas, D., Gahoi, N., Mukherjee, S., Manubhai, K. P., Nissa, M. U., Srivastava, A., Epari, S., Shetty, P. M., et al. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.548243 · Cited by 30
(ADNI), T. A. D. N. I., Valant, V., Keenan, B. T., Anderson, C. D., Shulman, J. M., Devan, W. J., Ayres, A. M., Schwab, K. M., Goldstein, J. N., Viswanathan, A., et al. (2012) · Translational Stroke Research · doi:10.1007/s12975-012-0161-1 · Cited by 30
Smith, E. E., Rosand, J. M., & Greenberg, S. M. (2006) · Magnetic Resonance Imaging Clinics of North America · doi:10.1016/j.mric.2006.06.002 · Cited by 29
Mastaglia, F. L., Byrnes, M. L., Johnsen, R. D., & Kakulas, B. A. (2003) · Journal of Clinical Neuroscience · doi:10.1016/s0967-5868(02)00317-x · Cited by 26
Apolipoprotein E genotype influences spatial distribution of cerebral microbleeds
Loehrer, E. A., Ikram, M. A., Akoudad, S., Vrooman, H. A., van der Lugt, A., Niessen, W. J., Albert Hofman, D., & Vernooij, M. W. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.09.012 · Cited by 24
Studies on the first described Alzheimer's disease amyloid β mutant, the Dutch variant
Levy, E., Prelli, F., & Frangione, B. (2006) · Journal of Alzheimer's Disease · doi:10.3233/jad-2006-9s337 · Cited by 24
Overlapping Protein Accumulation Profiles of CADASIL and CAA
Young, K. Z., Xu, G., Keep, S. G., Borjigin, J., & Wang, M. M. (2020) · American Journal Of Pathology · doi:10.1016/j.ajpath.2020.11.015 · Cited by 24
Ruzali, W. A. W., Kehoe, P. G., & Love, S. (2012) · Neuroscience Letters · doi:10.1016/j.neulet.2012.07.065 · Cited by 25
Self-citationSingh, B., Lavezo, J., Gavito-Higuera, J., Ahmed, F., Narasimhan, S. S., Brar, S. K., Cruz‐Flores, S., & Kraus, J. (2022) · Journal of Alzheimer s Disease Reports · doi:10.3233/adr-220055 · Cited by 24
Literature-related discovery: common factors for Parkinson’s Disease and Crohn’s Disease
Kostoff, R. N. (2014) · Scientometrics · doi:10.1007/s11192-014-1298-3 · Cited by 21
Current Management and Therapeutic Strategies for Cerebral Amyloid Angiopathy
Inoue, Y., Ando, Y., Misumi, Y., & Ueda, M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22083869 · Cited by 23
Jakubovic, R. Y. (2012) · Frontiers in Neurology · doi:10.3389/fneur.2012.00086 · Cited by 20
Multi‐pronged proteomic analysis to study the glioma pathobiology using cerebrospinal fluid samples
Gahoi, N., Malhotra, D., Moiyadi, A. V., Varma, S. G., Gandhi, M., & Srivastava, S. (2017) · PROTEOMICS - CLINICAL APPLICATIONS · doi:10.1002/prca.201700056 · Cited by 19
Hu, H., Wan, S., Hu, Y., Wang, Q., Li, H., & Zhang, N. (2025) · Annals of Medicine · doi:10.1080/07853890.2024.2445194 · Cited by 20
Eisenbaum, M., Pearson, A., Ortiz, C., Koprivica, M., Cembran, A., MULLAN, M. J., Crawford, F., Ojo, J. O., & Bachmeier, C. J. (2024) · Experimental Neurology · doi:10.1016/j.expneurol.2024.114702 · Cited by 18
Beyer, K., Lao, J. I., Latorre, P., & Ariza, A. (2005) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2005.tb06138.x · Cited by 14
APOE Genotype in Relation to Sporadic and Alzheimer-Related CAA
McCarron, M. O., & Nicoll, J. A. R. (2000) · Springer eBooks · doi:10.1007/978-94-017-1007-7_5 · Cited by 14
Self-citationAPOE polymorphisms influence longitudinal lipid trends preceding intracerebral hemorrhage
Phuah, C., Raffeld, M. R., Ayres, A. M., Gurol, M. E., Viswanathan, A., Greenberg, S. M., Biffi, A., Rosand, J. M., & Anderson, C. D. (2016) · Neurology Genetics · doi:10.1212/nxg.0000000000000081 · Cited by 13
Chapter 38 Intracerebral hemorrhage
Viswanathan, A., & Greenberg, S. M. (2008) · Handbook of clinical neurology · doi:10.1016/s0072-9752(08)93038-4 · Cited by 13
Greenberg, S. M. (2004) · Elsevier eBooks · doi:10.1016/b0-44-306600-0/50039-0 · Cited by 13
Chen, Y.-C., Lee‐Chen, G., Wu, Y., Hu, F.-J., Wu, H.-C., Kuo, H., Chu, C., Ryu, S., Chen, S., & Chen, C. (2009) · Clinica Chimica Acta · doi:10.1016/j.cca.2009.08.004 · Cited by 11
Harrigan, M. R., & Deveikis, J. P. (2018) · Contemporary medical imaging · doi:10.1007/978-3-319-66779-9_17 · Cited by 11
Wu, J., Liu, Z., Yao, M., Zhu, Y., Peng, B., & Ni, J. (2024) · Journal of Neurology · doi:10.1007/s00415-024-12451-9 · Cited by 11
In-vivo diagnosis of cerebral amyloid angiopathy: an updated review
Raposo, N., Périole, C., & Planton, M. (2023) · Current Opinion in Neurology · doi:10.1097/wco.0000000000001236 · Cited by 8
Lee, J. S., Lee, H., Park, S., Choe, Y. S., Park, Y. H., Cheon, B. K., Hahn, A., Ossenkoppele, R., Kim, H. J., Kim, S., et al. (2020) · Neurology · doi:10.1212/wnl.0000000000010811 · Cited by 8
Jang, D., Huh, P., & Lee, K. (2015) · Journal of neurosurgery · doi:10.3171/2015.5.jns142973 · Cited by 8
Genetics of primary intracerebral hemorrhage
Greenberg, S. M. (2002) · Journal of Stroke and Cerebrovascular Diseases · doi:10.1053/jscd.2002.129615 · Cited by 8
What Caused This Intracerebral Haemorrhage?
Warlow, C., van Gijn, J., Dennis, M. S., Wardlaw, J. M., Bamford, J., Hankey, G. J., Sandercock, P. A., Rinkel, G. J. E., Langhorne, P., Sudlow, C. L. M., et al. (2008) · Stroke · doi:10.1002/9780470696361.ch8 · Cited by 7
Association Between Interleukin-1A Polymorphism and Cerebral Amyloid Angiopathy–Related Hemorrhage
McCarron, M. O., Stewart, J., McCarron, P. A., Love, S., Vinters, H. V., Ironside, J. W., Mann, D. M. A., Graham, D. I., & Nicoll, J. A. R. (2003) · Stroke · doi:10.1161/01.str.0000089294.85447.1e · Cited by 6
Self-citationClassification, pathology, and basic aspects
Pantoni, L., & Gorelick, P. B. (2014) · Cambridge University Press eBooks · doi:10.1017/cbo9781139382694.002 · Cited by 5
Harrigan, M. R., & Deveikis, J. P. (2023) · Contemporary medical imaging · doi:10.1007/978-3-031-45598-8_17 · Cited by 4
Apolipoprotein E gene polymorphism influenced glycemic status among Malaysians
Rahman, K. M. H., Hossain, M. S., Haque, N., Razak, T. B. A., & Ahmad, H. (2019) · Biomedical Research and Therapy · doi:10.15419/bmrat.v6i7.557 · Cited by 4
Perez, C. M., Gong, Z., Yoo, C., Roy, D., Deoraj, A., & Felty, Q. H. (2023) · Molecular Neurobiology · doi:10.1007/s12035-023-03541-2 · Cited by 4
Relapsing cerebral amyloid angiopathy-related inflammation: the wax and the wane
Salam, S., Anandarajah, M., Al–Bachari, S., Pal, P., Sussman, J., & Hamdalla, H. H. M. (2017) · Practical Neurology · doi:10.1136/practneurol-2017-001599 · Cited by 5
Greenberg, S. M. (2009) · Cambridge University Press eBooks · doi:10.1017/cbo9780511691836.005 · Cited by 3
Bell, J. E., Becher, J., Keeling, J. W., & McIntosh, N. (2015) · Early Human Development · doi:10.1016/j.earlhumdev.2014.12.008 · Cited by 3
Ikeda, M., Okamoto, K., Suzuki, K., Takai, E., Kasahara, H., Furuta, N., Furuta, M., Tashiro, Y., Shimizu, C., TAKATAMA, S., et al. (2021) · Frontiers in Neurology · doi:10.3389/fneur.2021.645625 · Cited by 3
Cerebral microbleeds: Spatial distribution implications
Loehrer, E. A., Vernooij, M. W., & Ikram, M. A. (2014) · Translational Neuroscience · doi:10.2478/s13380-014-0217-7 · Cited by 3
β-amyloid wall deposit of temporal artery in subjects with spontaneous intracerebral haemorrhage
Tuttolomondo, A., Maugeri, R., Orlando, E., Giannone, A. G., Ciccia, F., Rizzo, A. G., Raimondo, D. D., Graziano, F., Pecoraro, R., Maida, C. D., et al. (2018) · Oncotarget · doi:10.18632/oncotarget.26165 · Cited by 3
Kase, C. S., Shoamanesh, A., Greenberg, S. M., & Caplan, L. R. (2015) · Elsevier eBooks · doi:10.1016/b978-0-323-29544-4.00028-1 · Cited by 3
Pathologic aspects of the hemorrhagic consequences of small vessel disease on the brain
Attems, J., & Jellinger, K. A. (2014) · Cambridge University Press eBooks · doi:10.1017/cbo9781139382694.005 · Cited by 2
Kase, C. S., Greenberg, S. M., Mohr, J. P., & Caplan, L. R. (2011) · Elsevier eBooks · doi:10.1016/b978-1-4160-5478-8.10029-6 · Cited by 2
Pathophysiology of Primary Intracerebral Hemorrhage: Insights into Cerebral Small Vessel Disease
Pasi, M., & Viswanathan, A. (2018) · Stroke revisited · doi:10.1007/978-981-10-1427-7_3 · Cited by 2
What caused this intracerebral hemorrhage?
Radmanesh, F., & Rosand, J. M. (2019) · Wiley eBooks · doi:10.1002/9781118492390.ch8 · Cited by 1
Gregoire, S. M. (2014) · UCL Discovery (University College London) · Cited by 1
Charidimou, A. (2015) · UCL Discovery (University College London) · Cited by 1
Chen, K., Chen, Y., Ren, Y., Wang, Z., Huang, Y., Pan, M., Li, Z., Casey, M. C., Qiao, W., Shi, J., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-78407-x
Switzer, A. R. (2014) · Libraries and Cultural Resources (University of Calgary) · doi:10.11575/prism/28634
Measurement of Aβ Uptake by Cerebrovascular Smooth Muscle Cells
Ruzali, W. A. W., & Love, S. (2015) · Springer eBooks · doi:10.1007/978-94-017-9716-0_8
Self-citationGenetics of Sporadic Cerebral Amyloid Angiopathy
Rannikmäe, K., & Sudlow, C. L. M. (2014) · InTech eBooks · doi:10.5772/58870 · Cited by 1
Genetic associations with brain microbleeds review and meta-analyses
Paternoster, L., Cordonnier, C., Thijs, V., Salman, R. A., & Sudlow, C. L. M. (2011)
Intracerebral Hemorrhage: Evidence-Based Medicine, Diagnosis, Treatment, and Complications
Washington, C. W., Hassan, A. N., & Zipfel, G. J. (2013) · Springer eBooks · doi:10.1007/978-1-4471-5226-2_25
Angiopathie amyloïde cérébrale : un diagnostic difficile en réanimation
Grèze, J., Bouzat, P., Grand, S., Payen, J., & Detante, O. (2011) · Annales Françaises d Anesthésie et de Réanimation · doi:10.1016/j.annfar.2011.07.016
Intracranial haemorrhage: the solution offered by recombinant factor VIIa
Micieli, G., Cavallini, A. M., & Marcheselli, S. (2007) · Springer eBooks · doi:10.1007/88-470-0351-2_10
Longitudinal Serum Lipid Trends and APOE in Primary Intracerebral Hemorrhage
Phuah, C. (2016) · Digital Access to Scholarship at Harvard (DASH) (Harvard University)
Angiopatia amiloide cerebrale sporadica
Puy, L., Hochart, A., Moulin, S., & Cordonnier, C. (2020) · EMC - Neurologia · doi:10.1016/s1634-7072(20)44005-x
Cerebral amyloid angiopathy : new insights from transgenic mice
Herzig, M. C. (2004) · edoc (University of Basel) · doi:10.5451/unibas-003642738
杨, 玉. (2023) · Advances in Clinical Medicine · doi:10.12677/acm.2023.134984
Zhang, C., Huang, L.-Y., Feng, Y., Tan, C., Tan, L., & Xu, W. (2025) · Journal of the American Heart Association · doi:10.1161/jaha.125.043446
Walker, L., Simpson, H., Thomas, A. J., & Attems, J. (2024) · Figshare · doi:10.6084/m9.figshare.26681218
Wu, H.-Y., Hou, J., Huang, L.-Y., Tan, L., & Xu, W. (2026) · Biological Psychiatry Global Open Science · doi:10.1016/j.bpsgos.2026.100773
Iatrogenic cerebral amyloid angiopathy: a scoping review
Ikeda, S., Hamaguchi, T., Hirano, T., Yagita, Y., Koga, M., Ihara, M., Nakajima, M., Itabashi, R., Shindo, A., Kudo, K., et al. (2026) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2026-339381
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
