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Cited by 19Alzheimer's disease research and treatmentsIntracerebral and Subarachnoid Hemorrhage ResearchDementia and Cognitive Impairment Research

Associations of APOE e2 genotype with cerebrovascular pathology: a postmortem study of 1275 brains

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Goldberg, Terry E, Huey, Edward D, Devanand, Davangere P·2021·Journal of Neurology, Neurosurgery & Psychiatry
DOI 10.1136/jnnp-2020-323746PMC PMC11299059
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Abstract

Objective: We assessed the association of apolipoprotein E (APOE) genotype with cerebrovascular disease (CVD) in a large neuropathological database maintained by the National Alzheimer’s Coordinating Center (NACC). Such a comprehensive investigation of APOE and CVD pathology has not heretofore been conducted. We focused on APOE e2, an established neuroprotective genetic variant against Alzheimer’s disease. Methods: To implement these objectives APOE associations in the NACC database of 1275 brains with 11 CVD pathologies, including old and recent infarcts, haemorrhages, cerebral amyloid angiopathy (CAA) and arteriosclerosis, were examined. These pathologies were uniformly and semiquantitatively measured across 39 Alzheimer’s Disease Center sites. We used χ2 statistics and ordinal regression to assess the significance of associations and Bonferroni corrected for multiple comparisons. Results: Of the cases, 98 were e2/e3 or e2/e2 genotypes (‘e2’ carriers), 621 were e3 homozygotes (‘e3’ group), and 556 were e4/e3 (442) or e4/e4 (114) genotypes (‘e4’ group). Results indicated that the APOE e4 allele significantly increased risk for CAA. After stratification by CAA presence/absence, we found that in those cases in which CAA was present, APOE e2 significantly increased risk for gross haemorrhage. All other associations were negative. Conclusions: In this, the largest study of APOE e2 effects on pathologically verified CVD, e2 was not protective against any CVD pathology compared with e3 homozygotes, including CAA. Regarding the latter pathology, e4 was associated with increases in its severity. Furthermore, and perhaps unexpectedly, e2 significantly increased risk of acute/subacute gross haemorrhage in the presence of CAA. Thus, there were limits to e2 neuroprotection against amyloidosis, despite its known and large protective effects against diffuse and neuritic amyloid plaques compared with e3/e3 and e4 carriers in this very collection.

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  • 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 [50]

    The Results (Gross hemorrhages; page unavailable) associate APOE ε2 with increased acute gross haemorrhage when CAA is present. But the Methods (Statistical Approach; page unavailable) explicitly exclude ε2/ε4 individuals from those analyses, so the finding does not establish particularly high risk for that genotype. The paper also says its gross-haemorrhage measure does not specifically identify lobar intracerebral haemorrhage. The vessel-wall explanation is attached to other citations in the citing sentence. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • Relative to APOEε3 homozygotes, APOEε2/ε4 carriers have greater Aβ plaque burden, increased cerebral amyloid angiopathy severity and increased odds of macroinfarcts, whereas differences in tangle burden are conflicting.

    “However, relative to APOEε3 homozygotes, APOEε2/ε4 carriers have greater Aβ plaque burden54, increased CAA severity50 and increased odds of macroinfarcts55, whereas differences in tangle burden are conflicting49,54.”

    From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [50]

    The Results (CAA section; page unavailable) report that APOE ε2/ε4 carriers had CAA more often than ε3 homozygotes (76% versus 49%). They do not report a severity comparison for those two genotypes, so the cited finding supports increased CAA frequency, not the claimed increased severity. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Compared with APOEε3 homozygosis, APOEε4 carriage has been independently associated with increased cerebrovascular burden in the form of gross macro infarcts in some studies, but not others.

    “Compared with APOEε3 homozygosis, APOEε4 carriage has been independently associated with increased cerebrovascular burden in the form of gross (macro) infarcts in some studies55, but not others50, whereas APOEε2 is associated with more severe ischaemic small vessel disease in the form of arteriolosclerosis, especially in individuals aged 90 years and older55.”

    From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [50]

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Cites

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Research works printed but not linked: 17

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Authors
Goldberg, T. E., Huey, E. D., & Devanand, D. P.
Affiliations
Columbia University Irving Medical Center (US)
Corresponding author
Goldberg, Terry E
ORCID
Venue
Journal of Neurology, Neurosurgery & Psychiatry
Publisher
BMJ
Published
2020-11-04
Volume
92
Issue
1
Pages
7-11
ISSN
  • 0022-3050 (ISSN-L)
  • 1468-330X
DOI
10.1136/jnnp-2020-323746
PMC
PMC11299059
OpenAlex
W3097327024
Cited by
19
References
5
Citations by year
2026: 2 · 2025: 3 · 2024: 5 · 2023: 2 · 2022: 4 · 2021: 2 · 2020: 1
FWCI
1.35
Type
journal article
Language
en
Open access
Locations
  • Journal of Neurology Neurosurgery & Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Columbia University Irving Medical Center (N/A)
  • National Institute on Aging (R01AG051346)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Neurology › Intracerebral and Subarachnoid Hemorrhage Research
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
APOE ε4, APOE genotype, cerebrovascular disease, cerebral amyloid angiopathy, hemorrhage, infarction, arteriosclerosis, neuroprotection, Alzheimer's disease, amyloidosis, genetic risk

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