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Cited by 149Alzheimer's disease research and treatmentsLipoproteins and Cardiovascular HealthCholesterol and Lipid Metabolism

Beyond the CNS: The many peripheral roles of APOE

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Martínez-Martínez, Ana B., Torres-Perez, Elena, Devanney, Nicholas, Del Moral, Raquel, Johnson, Lance A., Arbones-Mainar, Jose M.·2020·Neurobiology of Disease
DOI 10.1016/j.nbd.2020.104809PMC PMC7195217
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Abstract

Apolipoprotein E (APOE) is a multifunctional protein synthesized and secreted by multiple mammalian tissues. Although hepatocytes contribute about 75% of the peripheral pool, APOE can also be expressed in adipose tissue, the kidney, and the adrenal glands, among other tissues. High levels of APOE production also occur in the brain, where it is primarily synthesized by glia, and peripheral and brain APOE pools are thought to be distinct. In humans, APOE is polymorphic, with three major alleles (ε2, ε3, and ε4). These allelic forms dramatically alter APOE structure and function. Historically, the vast majority of research on APOE has centered on the important role it plays in modulating risk for cardiovascular disease and Alzheimer's disease. However, the established effects of this pleiotropic protein extend well beyond these two critical health challenges, with demonstrated roles across a wide spectrum of biological conditions, including adipose tissue function and obesity, metabolic syndrome and diabetes, fertility and longevity, and immune function. While the spectrum of biological systems in which APOE plays a role seems implausibly wide at first glance, there are some potential unifying mechanisms that could tie these seemingly disparate disorders together. In the current review, we aim to concisely summarize a wide breadth of APOE-associated pathologies and to analyze the influence of APOE in the development of several distinct disorders in order to provide insight into potential shared mechanisms implied in these various pathophysiological processes.

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  • ApoE binds a wide range of cellular receptors, including LDLR, LRP1, LRP2, LRP8, and VLDLR, which mediate the cellular uptake of apoE-containing lipoprotein particles.

    “ApoE binds a wide range of cellular receptors, including the LDL receptor (LDLR), the LDL receptor-related proteins (LRP) LRP1, LRP2, and LRP8, and the very low-density-lipoprotein receptor (VLDLR), which mediate the cellular uptake of the apoE-containing lipoprotein particles6).”

    From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [6]

    The ‘Lipid transport and metabolism’ section (page unavailable) says APOE promotes lipoprotein-particle internalization through LDL-receptor-family receptors, and the ‘Liver’ section describes APOE binding to LDLR. Our copy does not identify LRP1, LRP2, LRP8 and VLDLR as the specific receptors mediating that uptake, so it supports the mechanism but not the full receptor list. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Individuals homozygous for the APOEε2 allele have an increased risk of reduced fertility.

    “individuals homozygous for the APOEε2 allele also have an increased risk of reduced fertility76”

    From Variant-to-function mapping of late-onset Alzheimer’s disease GWAS signals in human microglial cell models implicates <i>RTFDC1</i> at the <i>CASS4</i> locus (2024) · cites this paper as [76]

    The Fertility section (page unavailable) says the ε2 allele appears to have the worst reproductive efficiency across the populations discussed, but cautions that offspring counts have confounding factors. It does not establish an increased risk specifically for people homozygous for APOEε2. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Martínez-Martínez, A. B., Torres-Perez, E., Devanney, N., Del Moral, R., Johnson, L. A., & Arbones-Mainar, J. M.
Affiliations
University of Kentucky (US)
ORCID
Venue
Neurobiology of Disease
Publisher
Elsevier BV
Published
2020-05
Volume
138
Pages
104809
ISSN
0969-9961 (ISSN-L)
DOI
10.1016/j.nbd.2020.104809
PMC
PMC7195217
OpenAlex
W3007638452
Cited by
149
References
18
Citations by year
2026: 27 · 2025: 31 · 2024: 21 · 2023: 19 · 2022: 27 · 2021: 17 · 2020: 7
FWCI
2.23
Type
journal article
Language
en
Open access
Licence
Locations
  • Neurobiology of Disease (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Zaguan (University of Zaragoza Repository) (submittedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Gobierno de Aragón
  • National Institute on Aging
  • National Institute of General Medical Sciences
  • Instituto de Salud Carlos III
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Keywords
apolipoprotein E, APOE polymorphism, adipose tissue, obesity, metabolic syndrome, diabetes mellitus, fertility, longevity, immune function, cardiovascular disease, Alzheimer's disease, pleiotropy, shared pathophysiological mechanisms
MeSH terms
Alleles, Apolipoproteins E, Brain, Diabetes Mellitus, Female, Genotype, Humans, Longevity, Male, Obesity, Metabolic Syndrome

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