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Cited by 231Barrier Structure and Function StudiesAlzheimer's disease research and treatmentsCerebrovascular and genetic disorders

The role of APOE in cerebrovascular dysfunction

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Tai, Leon M., Thomas, Riya, Marottoli, Felecia M., Koster, Kevin P., Kanekiyo, Takahisa, Morris, Alan W. J., Bu, Guojun·2016·Acta Neuropathologica
DOI 10.1007/s00401-016-1547-zPMC PMC4837016
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Abstract

The ε4 allele of the apolipoprotein E gene (APOE4) is associated with cognitive decline during aging, is the greatest genetic risk factor for Alzheimer's disease and has links to other neurodegenerative conditions that affect cognition. Increasing evidence indicates that APOE genotypes differentially modulate the function of the cerebrovasculature (CV), with apoE and its receptors expressed by different cell types at the CV interface (astrocytes, pericytes, smooth muscle cells, brain endothelial cells). However, research on the role of apoE in CV dysfunction has not advanced as quickly as other apoE-modulated pathways. This review will assess what aspects of the CV are modulated by APOE genotypes during aging and under disease states, discuss potential mechanisms, and summarize the therapeutic significance of the topic. We propose that APOE4 induces CV dysfunction through direct signaling at the CV, and indirectly via modulation of peripheral and central pathways. Further, that APOE4 predisposes the CV to damage by, and exacerbates the effects of, additional risk factors (such as sex, hypertension, and diabetes). ApoE4-induced detrimental CV changes include reduced cerebral blood flow (CBF), modified neuron-CBF coupling, increased blood-brain barrier leakiness, cerebral amyloid angiopathy, hemorrhages and disrupted transport of nutrients and toxins. The apoE4-induced detrimental changes may be linked to pericyte migration/activation, astrocyte activation, smooth muscle cell damage, basement membrane degradation and alterations in brain endothelial cells.

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  • The complexity of aged human brains, including inflammation and biomarker heterogeneity, is poorly recapitulated by preclinical models (largely rodent amyloid-transgenic mice), limiting translational predictivity.

    “The complexity of aged human brains, including inflammation and biomarker heterogeneity, is poorly recapitulated by preclinical models (largely rodent amyloid-transgenic mice), limiting translational predictivity [186].”

    From Targeted Nanoparticles for Drug Delivery Across the Blood–Brain Barrier in Early and Late Stages of Alzheimer's Disease: A Review (2026) · cites this paper as [186]

    The section on APOE-modulated neuroinflammation describes chronic inflammation as complex, and the AD/BBB section reports an opposite sex pattern for microbleeds in humans and APOE4/Aβ mice. These support a limited human–mouse difference, but the paper does not establish that preclinical models generally fail to recapitulate aged human brains or that biomarker heterogeneity limits their translational predictivity. No page numbers were available in our copy. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

  • ApoE may affect Alzheimer's disease pathogenesis through amyloid β-independent pathways.

    “In addition, ApoE may directly affect neuroinflammation, cerebral vascular integrity, metabolism, synaptic plasticity, and transcription through amyloid β-independent mechanisms [23,35,50].”

    From Apolipoprotein E metabolism and functions in brain and its role in Alzheimer's disease (2017) · cites this paper as [23]

  • ApoE affects cerebral vasculature by affecting cerebral blood flow, neuronal-vascular coupling, and BBB integrity.

    “ApoE affects cerebral vasculature by affecting cerebral blood flow, neuronal-vascular coupling, and BBB integrity [23].”

    From Apolipoprotein E metabolism and functions in brain and its role in Alzheimer's disease (2017) · cites this paper as [23]

  • In the periphery, ApoE has important implications in atherosclerosis and hyperlipoproteinemia, which also affect cerebral vasculature.

    “In the periphery, ApoE has important implications in atherosclerosis and hyperlipoproteinemia [3,23], which also affect cerebral vasculature.”

    From Apolipoprotein E metabolism and functions in brain and its role in Alzheimer's disease (2017) · cites this paper as [23]

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Cited by

Sorted by citations

Authors
Tai, L. M., Thomas, R., Marottoli, F. M., Koster, K. P., Kanekiyo, T., Morris, A. W. J., & Bu, G.
Affiliations
  • University of Illinois Chicago (US)
  • Mayo Clinic (US)
Corresponding author
Tai, Leon M.
ORCID
Venue
Acta Neuropathologica
Publisher
Springer Science and Business Media LLC
Published
2016-02-16
Volume
131
Issue
5
Pages
709-723
ISSN
  • 0001-6322 (ISSN-L)
  • 1432-0533
DOI
10.1007/s00401-016-1547-z
PMC
PMC4837016
OpenAlex
W2275281596
Cited by
231
References
21
Citations by year
2026: 22 · 2025: 33 · 2024: 23 · 2023: 28 · 2022: 21 · 2021: 20 · 2020: 23 · 2019: 23 · 2018: 17 · 2017: 15 · 2016: 6
FWCI
1.78
Type
journal article
Language
en
Open access
Licence
Locations
  • Acta Neuropathologica (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
Funders
  • National Institutes of Health (RF1AG051504, R01AG027924, R01AG035355, R01AG046205, P01AG030128, P01NS074969, and P50AG016574)
  • University of Illinois at Chicago (Start-up)
Topics
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Neurology › Cerebrovascular and genetic disorders
Keywords
apolipoprotein E, APOE ε4, cerebrovascular dysfunction, cerebral blood flow, cerebral amyloid angiopathy, pericytes, astrocytes, smooth muscle cells, brain endothelial cells, aging, hypertension, diabetes mellitus, Alzheimer's disease, cognitive decline, basement membrane degradation
MeSH terms
Apolipoproteins E, Cerebrovascular Circulation, Cerebrovascular Disorders, Humans, Genetic Predisposition to Disease

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