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Cited by 62Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsCognitive Abilities and Testing

APOE ε2ε4 genotype, incident AD and MCI, cognitive decline, and AD pathology in older adults

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Oveisgharan, Shahram, Buchman, Aron S., Yu, Lei, Farfel, Jose, Hachinski, Vladimir, Gaiteri, Chris, De Jager, Philip L., Schneider, Julie A. +1 more·2018·Neurology
DOI 10.1212/wnl.0000000000005677PMC PMC5996834
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Abstract

Objective To examine the association of the APOE ε2ε4 genotype with incident Alzheimer disease (AD), mild cognitive impairment (MCI), cognitive decline, and AD pathology in older adults. Methods We used data from 2,151 older adults of European ancestry who were free of dementia at baseline and underwent structured annual clinical evaluation in a longitudinal study for incident AD and MCI, and cognitive decline. Postmortem examination in decedents documented pathologic AD and quantified β-amyloid and neurofibrillary tangles. Participants were stratified into 4 groups based on APOE genotyping: ε2ε4, ε4 (ε4ε4, ε4ε3), ε2 (ε2ε2, ε2ε3), with ε3ε3 carriers serving as the reference group. We used Cox proportional hazards models to examine the association of APOE genotype with incident AD and MCI. Linear mixed-effect models were used to examine the association with cognitive decline. Logistic and linear regression models were used to examine AD pathology. All the models controlled for age, sex, and education. Results Of the 2,151 participants included in this study, ε2ε4 accounted for 2.1%, ε3/4 and 4/4 21.8%, ε2/3 and 2/2 14.0%, and ε3ε3 62.1%. We did not observe a difference in the risk of AD for ε2ε4 compared to ε3ε3. In cases without cognitive impairment at baseline, ε2ε4 carriers had an increased risk of incident MCI (hazard ratio 2.13, 95% confidence interval 1.34–3.39, p = 0.002) and a faster rate of cognitive decline (estimate −0.047, SE 0.018, p = 0.008) compared to ε3ε3 carriers. In decedents (n = 1,100), ε2ε4 showed a 3-fold increased odds of pathologic AD and a higher β-amyloid load than ε3ε3. Conclusion APOE ε2ε4 genotype in older adults is associated with risk of MCI, cognitive decline, and a greater burden of AD pathology, especially β-amyloid.

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  • The two cohorts (ROS and MAP) used uniform data collection, making it feasible to combine data across them to examine associations of clinical data with brain pathologies.

    “With uniform data collection, it is feasible to combine data across the two cohorts to examine associations of clinical data with brain pathologies, as done in many of our prior studies [4,45].”

    From Sex differences in Alzheimer’s disease and common neuropathologies of aging (2018) · cites this paper as [45]

  • 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 [54]

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References 28 · Cited by 62

Research works printed but not linked: 23

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Authors
Oveisgharan, S., Buchman, A. S., Yu, L., Farfel, J., Hachinski, V., Gaiteri, C., De Jager, P. L., Schneider, J. A., & Bennett, D. A.
Affiliations
  • Broad Institute (US)
  • From Rush Alzheimer's Disease Center (S.O., A.S.B., L.Y., J.F., C.G., J.A.S., D.A.B.) and Departments of Neurological Sciences (A.S.B., L.Y., J.A.S., D.A.B.) and Pathology (J.F., J.A.S.), Rush University Medical Center, Chicago, IL; Shariati Hospital (S.O.), Tehran University of Medical Sciences, Iran; Department of Geriatrics (J.F.), University of Sao Paulo Medical School, Brazil; University Hospital (V.H.), University of Western Ontario, London, Canada; Broad Institute (P.L.D.J.), Cambridge, MA;...
ORCID
Venue
Neurology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2018-06-12
Volume
90
Issue
24
Pages
e2127-e2134
ISSN
  • 0028-3878 (ISSN-L)
  • 1526-632X
DOI
10.1212/wnl.0000000000005677
PMC
PMC5996834
OpenAlex
W2799622011
Cited by
62
References
28
Citations by year
2026: 7 · 2025: 6 · 2024: 8 · 2023: 9 · 2022: 7 · 2021: 9 · 2020: 7 · 2019: 8 · 2018: 1
FWCI
4.92
Type
journal article
Language
en
Open access
Locations
  • Neurology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (UL1TR000430)
  • National Institute on Aging (R01AG043379, R01AG017917, R01AG056352, R01AG050631, R01AG042210, R01AG048108, RF1AG022018, R01AG052488, P01AG014449, U01AG046152, R01AG057911, R01AG053446, R01AG033570, R01AG015819, P30AG010161, RF1AG048056, R01AG040039, R01AG047976, RF1AG054057, R01AG054058, U01AG046161, R01AG054476, RF1AG015819, RF1AG036042, R01AG033678, R01AG034374, R01AG022018)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK099269)
  • National Institute of Neurological Disorders and Stroke (R01NS084965, UH2NS100599, R01NS078009, R01NS089674)
  • National Center for Advancing Translational Sciences
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Social Sciences › Psychology › Experimental and Cognitive Psychology › Cognitive Abilities and Testing
Keywords
Alzheimer's disease, mild cognitive impairment, cognitive decline, Alzheimer disease pathology, amyloid-beta, neurofibrillary tangles, older adults, genetic risk
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Brain, Female, Genotype, Humans, Male, Risk Factors, Genetic Predisposition to Disease, Apolipoprotein E4, Cognitive Dysfunction

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