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Cited by 278Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

APOE in the bullseye of neurodegenerative diseases: impact of the APOE genotype in Alzheimer’s disease pathology and brain diseases

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Fernández-Calle, Rosalía, Konings, Sabine C., Frontiñán-Rubio, Javier, García-Revilla, Juan, Camprubí-Ferrer, Lluís, Svensson, Martina, Martinson, Isak, Boza-Serrano, Antonio +4 more·2022·Molecular Neurodegeneration
DOI 10.1186/s13024-022-00566-4PMC PMC9509584
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Abstract

ApoE is the major lipid and cholesterol carrier in the CNS. There are three major human polymorphisms, apoE2, apoE3, and apoE4, and the genetic expression of APOE4 is one of the most influential risk factors for the development of late-onset Alzheimer's disease (AD). Neuroinflammation has become the third hallmark of AD, together with Amyloid-β plaques and neurofibrillary tangles of hyperphosphorylated aggregated tau protein. This review aims to broadly and extensively describe the differential aspects concerning apoE. Starting from the evolution of apoE to how APOE's single-nucleotide polymorphisms affect its structure, function, and involvement during health and disease. This review reflects on how APOE's polymorphisms impact critical aspects of AD pathology, such as the neuroinflammatory response, particularly the effect of APOE on astrocytic and microglial function and microglial dynamics, synaptic function, amyloid-β load, tau pathology, autophagy, and cell–cell communication. We discuss influential factors affecting AD pathology combined with the APOE genotype, such as sex, age, diet, physical exercise, current therapies and clinical trials in the AD field. The impact of the APOE genotype in other neurodegenerative diseases characterized by overt inflammation, e.g., alpha- synucleinopathies and Parkinson's disease, traumatic brain injury, stroke, amyotrophic lateral sclerosis, and multiple sclerosis, is also addressed. Therefore, this review gathers the most relevant findings related to the APOE genotype up to date and its implications on AD and CNS pathologies to provide a deeper understanding of the knowledge in the APOE field.

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  • ApoE4 promotes AD pathology through toxic gain of function.

    “ApoE4 promotes AD pathology through toxic gain of function (74)”

    From Nuclear SphK2/S1P signaling is a key regulator of ApoE production and Aβ uptake in astrocytes (2024) · cites this paper as [74]

    The sections on amyloid-β load and tau pathology report that ApoE4 increases amyloid plaque burden and exacerbates tau-mediated pathology. However, the paper’s explicit description of a “toxic gain of function” refers to tau aggregation, not ApoE4, so it does not establish that specific mechanism for ApoE4. (LLM, conf=0.85)

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Authors
Fernández-Calle, R., Konings, S. C., Frontiñán-Rubio, J., García-Revilla, J., Camprubí-Ferrer, L., Svensson, M., Martinson, I., Boza-Serrano, A., Venero, J. L., Nielsen, H. M., Gouras, G. K., & Deierborg, T.
Affiliations
  • Lund University (SE)
  • University of Castilla-La Mancha (ES)
  • Stockholm University (SE)
ORCID
Venue
Molecular Neurodegeneration
Publisher
Springer Science and Business Media LLC
Published
2022-09-24
Volume
17
Issue
1
Pages
62-62
ISSN
1750-1326 (ISSN-L)
DOI
10.1186/s13024-022-00566-4
PMC
PMC9509584
OpenAlex
W4296949354
Cited by
278
References
159
Citations by year
2026: 54 · 2025: 112 · 2024: 60 · 2023: 50 · 2022: 2
FWCI
7.59
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Neurodegeneration (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RISalud Institutional Health Repository of Andalucía (submittedVersion, cc-by)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Deposito de Investigacion Universidad de Sevilla (University of Seville) (submittedVersion, cc-by-nc-nd)
  • Lund University Publications (Lund University) (submittedVersion)
Funders
  • The Strategic Research Area MultiPark (Multidisciplinary Research in neurodegenerative diseases), Lund University
  • The Swedish Alzheimer Foundation
  • The Swedish Brain Foundation
  • Crafoordska Stiftelsen
  • Demensförbundet
  • Greta och Johan Kocks stiftelser
  • Stiftelsen Olle Engkvist Byggmästare
  • Swedish Medical Research Council
  • Parkinsonfonden
  • A.E. Berger Foundation
  • Thurings Foundation
  • Swedish mental health foundation
  • Kungliga Fysiografiska Sällskapet i Lund
  • H2020 Marie Skłodowska-Curie Actions (721802)
  • Ministerio de Ciencia e Innovación (PID2021-124096OB-I00)
  • Junta de Andalucía (P18-RT-1372)
  • Universidad de Sevilla (US-1264806)
  • Lund University
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
apolipoprotein E, APOE ε4, Alzheimer's disease, APOE polymorphism, neuroinflammation, amyloid-beta, tau pathology, microglia, astrocytes, synaptic function, autophagy, intercellular communication, sex differences, neurodegenerative diseases, Parkinson's disease, synucleinopathies, traumatic brain injury, stroke, amyotrophic lateral sclerosis, multiple sclerosis
MeSH terms
Alzheimer Disease, Apolipoproteins E, Genotype, Humans, Amyloid beta-Peptides, tau Proteins, Neurodegenerative Diseases, Apolipoprotein E3, Apolipoprotein E4, Apolipoprotein E2, Plaque, Amyloid

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