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Cited by 82Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Association of APOE e2 genotype with Alzheimer’s and non-Alzheimer’s neurodegenerative pathologies

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Goldberg, Terry E., Huey, Edward D., Devanand, D. P.·2020·Nature Communications
DOI 10.1038/s41467-020-18198-xPMC PMC7501268
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Abstract

The apolipoprotein E (APOE) gene contains both the major common risk variant for late onset Alzheimer’s disease (AD), e4, and the major neuroprotective variant, e2. Here we examine the association of APOE e2 with multiple neurodegenerative pathologies, leveraging the NACC v. 10 database of 1557 brains that included 130 e2 carriers and 679 e4 carriers in order to examine potential neuroprotective effects. For AD-related pathologies of amyloid plaques and Braak stage, e2 had large and highly significant protective effects contrasted with e3/e3 and e4 carriers with odds ratios of about 0.50 for e3 contrasts and 0.10 for e4 contrasts. When we separately examined e2/e4 carriers, risk for AD pathologies was similar to that of e4 carriers, not e2 carriers. For multiple fronto-temporal lobar pathologies and tauopathies, e2 was not significantly associated with pathology. In sum, we found that e2 was associated with large but circumscribed protective effects.

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  • Amyloid PET imaging results remain inconsistent, with some studies reporting attenuated or delayed amyloid deposition in APOE2/4 individuals relative to APOE3/4, whereas others have reported no significant difference between these genotypes.

    “Amyloid PET imaging results remain inconsistent, with some studies reporting attenuated or delayed amyloid deposition in APOE2/ 4 individuals relative to APOE3/4 44,45 , whereas others have reported no signi fi cant difference between these genotypes 46 .”

    From APOE2 attenuates APOE4-associated amyloid pathology and related toxicity in a mouse model of Alzheimer’s disease (2026) · cites this paper as [46]

    The Results (‘E2/e4 genotype’; page not provided) report that all e2/e4 versus e3/e4 contrasts were nonsignificant, including contrasts involving amyloid plaques. This supports the cited no-difference finding, but the study assessed postmortem pathology, not amyloid PET imaging, so it does not establish that finding for PET results. (LLM, conf=0.87)

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  • APOEε4 carriage has been independently associated with increased odds and severity of Lewy body pathology and TDP-43 pathology and with the presence of TDP-43-related hippocampal sclerosis in the scenario of a primary neuropathological diagnosis of Alzheimer disease.

    “Specifically, APOEε4 carriage has been independently associated with increased odds and severity of Lewy body pathology49,62 and TDP-43 pathology59,63,64 and with the presence of TDP-43-related hippocampal sclerosis63 in the scenario of a primary neuropathological diagnosis of AD.”

    From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [49]

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  • APOEε2 has been found to have both direct and indirect (through Aβ) protective effects against tangle pathology.

    “By contrast, APOEε2 has been found to have both direct and indirect (through Aβ) protective effects against tangle pathology48,49.”

    From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [49]

  • In a third study, the significance of the association between APOEε2 and primary tauopathy was lost when adjusting for Alzheimer disease neuropathological changes, suggesting a spurious association owing to the strength of the APOEε4-Alzheimer disease link.

    “and in a third study the significance of the association was lost when adjusting for AD neuropathological changes49, suggesting a spurious association owing to the strength of the APOEε4–AD link.”

    From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [49]

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Research works printed but not linked: 22

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Sorted by citations

Authors
Goldberg, T. E., Huey, E. D., & Devanand, D. P.
Affiliations
Columbia University Irving Medical Center (US)
Corresponding author
Goldberg, Terry E.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2020-09-18
Volume
11
Issue
1
Pages
4727-4727
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-020-18198-x
PMC
PMC7501268
OpenAlex
W3087075244
Cited by
82
References
11
Citations by year
2026: 13 · 2025: 13 · 2024: 16 · 2023: 12 · 2022: 17 · 2021: 10 · 2020: 1
FWCI
6.02
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Alzheimer's Coordinating Center (U01AG016976, P30 AG062421, P30 AG062715, P30 AG062429, P30 AG062422)
  • National Institutes of Health (AG028 383, 5p30ag062428-02, AG062421, AG049638, AG016573, AG016976, AG010124, AG023501, P30 AG062428–01, AG005138, AG005133, AG008017, AG010129, AG008051, AG005681, AG019610, AG035982, AG047270, AG047366, AG053760, AG010161, AG013854, AG025688, AG013846, AG062715, AG047266, AG005136, AG062429, AG062422, AG008702)
  • National Institute on Aging (AG062429, AG 005138, AG-028383, AG010133, AG 016976, P30AG053760, P30AG010129, P30AG010133, AG062421, AG-016573, AG008702, AG008051, P30-AG062428, P30AG049638, AG047366, AG-010124, P30AG028383, P30AG012300, AG-005133, AG 025688, AG-005136, AG062429-01, AG008017, P50AG005133, U01AG016976, AG-005146, AG-013854, AG035982, AG049638, P50AG005138, AG062715, R01AG062268, AG019610, AG-005142, AG010161, P30AG010124, AG047266, P50AG016573, AG062422-01, P50AG047366, AG010129, P30AG008017, P30 AG062428‐01, P30AG010161, P30AG008051, P50AG008702, AG023501, P30AG035982, AG013846, P50AG005681, P50AG005142, P50AG047270, P30AG019610, P50AG005146, AG047270, P30AG013846, P50AG005136, AG062422, P30AG013854, AG053760, P50AG025688, P50AG047266, AG005681, P30AG062429, P30AG066468, P30AG066462, P30AG066444, P30AG062422, P30AG066509, P30AG062715, U24AG072122, P30AG062421, P50AG023501)
  • National Institute of Mental Health (R01MH120794)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
apolipoprotein E, Alzheimer's disease, amyloid plaques, Braak stages, tauopathy, neuroprotection, APOE ε4, genetic risk variants
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Apolipoproteins E, Brain, Female, Genotype, Humans, Male, Logistic Models, Tauopathies, alpha-Synuclein, Apolipoprotein E4, Apolipoprotein E2, Frontotemporal Lobar Degeneration, Plaque, Amyloid

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