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Cited by 111Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

APOE2 eases cognitive decline during Aging: Clinical and preclinical evaluations

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Shinohara, Mitsuru, Kanekiyo, Takahisa, Yang, Longyu, Linthicum, Duane, Shinohara, Motoko, Fu, Yuan, Price, Laura, Frisch‐Daiello, Jessica L. +3 more·2016·Annals of Neurology
DOI 10.1002/ana.24628PMC PMC5010530
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Abstract

Objective: Apolipoprotein E (apoE), a major cholesterol carrier in the brain, is associated with a strong risk for Alzheimer disease. Compared to the risky APOE4 gene allele, the effects of the protective APOE 2 gene allele are vastly understudied, and thus need to be further clarified. Methods: We reviewed National Alzheimer's Coordinating Center clinical records and performed preclinical experiments using human apoE‐targeted replacement (apoE‐TR) mice, which do not show amyloid pathology. Results: Clinically, the APOE2 allele was associated with less cognitive decline during aging. This effect was also seen in subjects with little amyloid pathology, or after adjusting for Alzheimer disease‐related pathologies. In animal studies, aged apoE2‐TR mice also exhibited preserved memory function in water maze tests. Regardless, apoE2‐TR mice showed similar or greater age‐related changes in synaptic loss, neuroinflammation, and oxidative stress compared to apoE3‐TR or apoE4‐TR mice. Interestingly, apoE concentrations in the cortex, hippocampus, plasma, and cerebrospinal fluid (CSF) were positively correlated with memory performance across apoE isoforms, where apoE2‐TR mice had higher apoE levels. Moreover, apoE2‐TR mice exhibited the lowest levels of cholesterol in the cortex, despite higher levels in CSF and plasma. These cholesterol levels were associated with apoE levels and memory performance across apoE isoforms. Interpretation: APOE2 is associated with less cognitive decline during aging. This can occur independently of age‐related synaptic/neuroinflammatory changes and amyloid accumulation. Higher levels of apoE and associated cholesterol metabolism in APOE2 carriers might contribute to this protective effect. Ann Neurol 2016;79:758–774

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  • After controlling for the presence and severity of Alzheimer disease neuropathology and comorbid pathologies, carrying the APOEε4 allele might still accelerate the rate of cognitive decline in the normal ageing-sporadic Alzheimer disease continuum, whereas carrying the APOEε2 allele might slow down cognitive decline.

    “However, after controlling for the presence and severity of AD neuropathology and comorbid pathologies, carrying the APOEε4 allele might still accelerate the rate of cognitive decline in the normal ageing-sporadic AD continuum, whereas carrying the APOEε2 allele might slow down cognitive decline47,77,80,81.”

    From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [77]

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  • The well-established association between APOE genotype and cognition - whereby APOEε4 accelerates age-related cognitive decline and APOEε2 delays it - is largely mediated by genotype-specific effects on Alzheimer disease neuropathological changes and, to a lesser extent, on comorbid pathologies.

    “The well-established association between APOE genotype and cognition — whereby APOEε4 accelerates age-related cognitive decline76 and APOEε2 delays it77 — is largely mediated by genotype-specific effects on AD neuropathological changes and, to a lesser extent, on comorbid pathologies46–48,78,79.”

    From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [77]

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Authors
Shinohara, M., Kanekiyo, T., Yang, L., Linthicum, D., Shinohara, M., Fu, Y., Price, L., Frisch‐Daiello, J. L., Han, X., Fryer, J. D., & Bu, G.
Affiliations
  • Mayo Clinic (US)
  • Sanford Burnham Prebys Medical Discovery Institute (US)
Corresponding author
Bu, Guojun
ORCID
Venue
Annals of Neurology
Publisher
Wiley
Published
2016-03-29
Volume
79
Issue
5
Pages
758-774
ISSN
  • 0364-5134 (ISSN-L)
  • 1531-8249
DOI
10.1002/ana.24628
PMC
PMC5010530
OpenAlex
W2290101922
Cited by
111
References
11
Citations by year
2026: 7 · 2025: 12 · 2024: 10 · 2023: 14 · 2022: 13 · 2021: 8 · 2020: 13 · 2019: 11 · 2018: 8 · 2017: 11 · 2016: 4
FWCI
9.11
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Annals of Neurology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
Funders
  • NIH (R01AG035355, R01AG027924, R01AG046205, RF1AG051504, P01NS074969, P50AG016574)
  • Alzheimer's Association and Cure Alzheimer's Fund
  • Alzheimer's Association
  • Japan Heart Foundation
  • Naito Foundation
  • BrightFocus Foundation
  • NIH National Institute on Aging (U01 AG016976)
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
APOE2, apolipoprotein E, cognitive decline, aging, Alzheimer's disease, APOE ε4, memory, synaptic loss, neuroinflammation, oxidative stress, cholesterol metabolism, cerebrospinal fluid, hippocampus, amyloid pathology

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