Current insights into apolipoprotein E and the immune response in Alzheimer's disease

Lin, Peter Bor‐Chian; Holtzman, David M.

doi:10.1111/imr.13414

Cited by 19Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

Current insights into apolipoprotein E and the immune response in Alzheimer's disease

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Lin, Peter Bor‐Chian, Holtzman, David M.·2024·Immunological Reviews

DOI 10.1111/imr.13414PMC PMC11578782

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Abstract

Summary: Alzheimer's disease (AD) is a progressive neurological disorder and the most common cause of dementia. Genetic analyses identified apolipoprotein E ( APOE ) as the strongest genetic risk for late‐onset AD. Studies have shown that ApoE modulates AD pathogenesis in part by influencing amyloid‐β (Aβ) deposition. However, ApoE also appears to regulate elements of AD via regulation of innate immune response, especially through microglial and astrocyte activation. In model systems, it also regulates changes in T‐cells. This review focuses on the key findings that have advanced our understanding of the role of ApoE in the pathogenesis of AD and the current view of innate immune response regulated by ApoE in AD, while discussing open questions and areas for future research.

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The Apoe-App interaction is crucial for the metabolism and clearance of Aβ.
“The Apoe-App interaction is crucial for the metabolism and clearance of Aβ, a key pathological hallmark of AD.”
From Cell signaling pathways discovery from multi-modal data (2025) · cites this paper as Lin & Holtzman 2024
The “ApoE and amyloid-β pathology” section says ApoE likely influences Aβ aggregation and clearance, and discusses Aβ uptake and degradation by microglia. It does not establish that an ApoE–APP interaction is responsible for Aβ metabolism or clearance; APP appears as part of mouse-model descriptions, not as the interacting mechanism claimed. (LLM, conf=0.86)
Experimental — accuracy not yet measured
These pathways highlight how neuronal and glial interactions modulate microglial activity through Apoe, App, Trem2, and Lrp1.
“These pathways highlight how neuronal and glial interactions modulate microglial activity through Apoe, App, Trem2, and Lrp1 [Krasemann et al., 2017; Lin & Holtzman 2024; Shinohara et al., 2017].”
From Cell signaling pathways discovery from multi-modal data (2025) · cites this paper as Lin & Holtzman 2024
The ‘ApoE and tau pathology’ section reports that ApoE from different cell types modulates microglial activity, including reduced microglial synaptic phagocytosis after astrocytic ApoE4 depletion. The review also cites a TREM2–APOE microglial pathway, but its discussion of APP is in mouse models, and it identifies LRP1 as an ApoE receptor rather than showing that APP and LRP1 mediate the claimed neuronal–glial modulation of microglia. No page numbers are available in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measured
Trem2 interacts with Apoe to regulate phagocytosis, survival, and inflammatory responses of microglia.
“Trem2, expressed on microglia, interacts with Apoe to regulate phagocytosis, survival, and inflammatory responses of microglia [Yeh et al., 2016; Lin & Holtzman 2024].”
From Cell signaling pathways discovery from multi-modal data (2025) · cites this paper as Lin & Holtzman 2024
The References section names a TREM2–APOE pathway affecting microglial phenotype, and the ‘ApoE and tau pathology’ section reports that removing astrocytic APOE4 reduced microglial synaptic phagocytosis. Our copy does not establish that TREM2 interacts with ApoE to regulate microglial survival or the full set of functions claimed; it also does not connect TREM2 specifically to the reported phagocytosis result. No page numbers were available in our copy. (LLM, conf=0.79)
Experimental — accuracy not yet measured
The Apoe-Trem2 axis plays a significant role in modulating microglial responses to Aβ and other neuroinflammatory signals.
“The Apoe-Trem2 axis plays a significant role in modulating microglial responses to Aβ and other neuroinflammatory signals.”
From Cell signaling pathways discovery from multi-modal data (2025) · cites this paper as Lin & Holtzman 2024
The sections on amyloid-β pathology and AD-related innate immunity describe ApoE-dependent changes in microglial responses to Aβ and tau. The paper cites a study of the TREM2–APOE pathway when discussing microglial states, but its own discussion does not explicitly establish that the combined axis modulates responses to Aβ and other neuroinflammatory signals. (LLM, conf=0.78)
Experimental — accuracy not yet measured
Apoe influences Aβ aggregation and deposition by affecting App processing and Aβ clearance.
“Apoe influences Aβ aggregation and deposition by affecting App processing and Aβ clearance [Lin & Holtzman 2024].”
From Cell signaling pathways discovery from multi-modal data (2025) · cites this paper as Lin & Holtzman 2024
The “ApoE and amyloid-β pathology” section says ApoE affects Aβ plaque deposition, likely through Aβ fibrillogenesis and clearance. It does not say ApoE does so by affecting APP processing; references to APP mouse models do not establish that mechanism. (LLM, conf=0.88)
Experimental — accuracy not yet measured

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[77]Holtzman DM, Fagan AM, Mackey B, Apolipoprotein E facilitates neuritic and cerebrovascular plaque formation in an Alzheimer's disease model. Ann Neurol. 2000; 47(6): 739– 747. 10852539
[111]Chemparathy A, Guen YL, Chen S, APOE loss-of-function variants: Compatible with longevity and associated with resistance to Alzheimer's Disease pathology. medRxiv. 2023. PMC10994769 38301647

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Authors: Lin, P. B., & Holtzman, D. M.
Affiliations: Washington University in St. Louis (US)
Corresponding author: Holtzman, David M.
ORCID: Lin, Peter Bor‐Chian
Holtzman, David M.
Venue: Immunological Reviews
Publisher: Wiley
Published: 2024-10
Volume: 327
Issue: 1
Pages: 43-52
ISSN: 0105-2896 (ISSN-L)
1600-065X
DOI: 10.1111/imr.13414
PMC: PMC11578782
OpenAlex: W4403734490
Cited by: 19
References: 115
Citations by year: 2026: 15 · 2025: 4
FWCI: 1.08
Type: journal article
Language: en
Open access: green
pmc.ncbi.nlm.nih.gov
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor, 23 d)
Locations: Immunological Reviews (publishedVersion)
PubMed (publishedVersion)
PubMed Central (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
Funders: Cure Alzheimer's Fund
Tau Consortium
JPB Foundation
National Institute on Aging (1U19AG069701)
National Institute of Neurological Disorders and Stroke (RF1NS090934)
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, Alzheimer's disease, innate immune response, amyloid-beta deposition, microglial activation, astrocyte activation, T cell regulation, genetic risk, pathogenesis
MeSH terms: Alzheimer Disease, Animals, Apolipoproteins E, Astrocytes, Humans, Immunity, Innate, T-Lymphocytes, Amyloid beta-Peptides, Microglia, Genetic Predisposition to Disease

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Current insights into apolipoprotein E and the immune response in Alzheimer's disease

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