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ApoE in Alzheimer’s disease: pathophysiology and therapeutic strategies
Open accessAbstract
Alzheimer’s disease (AD) is the most common cause of dementia worldwide, and its prevalence is rapidly increasing due to extended lifespans. Among the increasing number of genetic risk factors identified, the apolipoprotein E ( APOE ) gene remains the strongest and most prevalent, impacting more than half of all AD cases. While the ε4 allele of the APOE gene significantly increases AD risk, the ε2 allele is protective relative to the common ε3 allele. These gene alleles encode three apoE protein isoforms that differ at two amino acid positions. The primary physiological function of apoE is to mediate lipid transport in the brain and periphery; however, additional functions of apoE in diverse biological functions have been recognized. Pathogenically, apoE seeds amyloid-β (Aβ) plaques in the brain with apoE4 driving earlier and more abundant amyloids. ApoE isoforms also have differential effects on multiple Aβ-related or Aβ-independent pathways. The complexity of apoE biology and pathobiology presents challenges to designing effective apoE-targeted therapeutic strategies. This review examines the key pathobiological pathways of apoE and related targeting strategies with a specific focus on the latest technological advances and tools.
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“In humans, three major isoforms of APOE are lipidated in an isoform‐specific manner (ε2 > ε3 > ε4). 9 , 48”
From Deletion of miR-33, a regulator of the ABCA1–APOE pathway, ameliorates neuropathological phenotypes in APP/PS1 mice (2024) · cites this paper as [48]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“APOE binds to cell surface receptors, such as low‐density lipoprotein receptor (LDLR), LDLR‐related protein 1 (LRP1), very low‐density lipoprotein receptor (VLDLR), and apolipoprotein E receptor 2 (APOER2 or LRP8). 2 , 14 , 15”
From Deletion of neuronal Idol ameliorates Alzheimer's disease–related pathologies via APOE receptors (2025) · cites this paper as [2]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“Although mainly secreted by astrocytes, APOE is also expressed in microglia, neurons, and oligodendrocytes, particularly under injury and degenerative conditions. 2 , 13”
From Deletion of neuronal Idol ameliorates Alzheimer's disease–related pathologies via APOE receptors (2025) · cites this paper as [2]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“Genetic variants of many of the differentially expressed genes identified in this study, such as CLU and APOE, have been associated with increased Alzheimer’s disease risk58,59.”
From mTORC1 drives cell-autonomous astrocyte reactivity in tuberous sclerosis (2026) · cites this paper as [59]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The APOE-ε4 allele increases AD risk three- to eightfold compared to the neutral ε3 allele, while ε2 confers relative protection [154].”
From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [154]
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“ApoE influences AD pathogenesis through multiple pathways, such as (i) impaired clearance of Aβ by competing with receptor-mediated uptake (e.g., LRP1), (ii) modulation of tau phosphorylation and spread, and (iii) regulation of microglial activation.”
From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [154]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“APOE is multifunctional, with roles in lipid and glucose metabolism, neuroinflammation, amyloid and tau accumulation, and blood-brain barrier dysfunction [2].”
From Effects of APOE2 and APOE4 on brain microstructure in older adults: modification by age, sex, and cognitive status (2024) · cites this paper as [2]
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In the citing paper
“These efforts have resulted in identifying multiple mechanisms by which APOE influences AD‐related pathologies, including amyloid beta (Aβ) accumulation, tauopathy, neuroinflammation, and synaptic impairment. 2”
From Deletion of neuronal Idol ameliorates Alzheimer's disease–related pathologies via APOE receptors (2025) · cites this paper as [2]
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“as APOE is increasingly viewed not only as a risk locus, but also as a mechanistically actionable therapeutic axis in AD 2 .”
From Association of Rare APOE Missense Variants R189C and W276C With Risk of Alzheimer Disease (2026) · cites this paper as [2]
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In the citing paper
“Together, these data support a model in which C-terminal ApoE biology, including lipidation and self-association, is not merely correlative but is closely tied to pathogenesis and may inform future APOE-directed therapeutic strategies 2,17 .”
From Association of Rare APOE Missense Variants R189C and W276C With Risk of Alzheimer Disease (2026) · cites this paper as [2]
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In the citing paper
“Among these, the APOE gene plays a central role in modulating disease risk, primarily through its involvement in lipid transport, synaptic function, and amyloid-beta metabolism in the brain (Martens et al., 2022; Raulin et al., 2022).”
From Isogenic human stem cell models reveal mutation-dependent protective mechanisms of APOE3 Christchurch (2026) · cites this paper as Raulin et al., 2022
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“suggesting the distinct biochemical interactions influencing Aβ deposition or clearance [2, 3, 22, 23].”
From Astrocytic APOE3-Christchurch expression ameliorates brain amyloid-β pathology in 5xFAD mice (2026) · cites this paper as [2]
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In the citing paper
“In contrast, sporadic AD is strongly associated with polymorphisms in the APOE gene.”
From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [154]
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In the citing paper
“Recent work suggests that APOE variants not only modulate amyloid deposition but also reshape immune responses and lipid metabolism, positioning APOE at the nexus of amyloid, tau, and neuroinflammation [154].”
From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [154]
In the citing paper
“APOE exists in three isoforms, namely APOE2, APOE3, and APOE4, among which APOE4 isoform has been identified as the strongest genetic risk factor for late-onset AD.173”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [173]
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BackgroundCell type‐specific roles of APOE4 in Alzheimer disease
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Metadata
- Authors
- Raulin, A.-C., Doss, S. V., Trottier, Z. A., Ikezu, T. C., Bu, G., & Liu, C.-C.
- Affiliations
- Mayo Clinic in Florida (US)
- Corresponding author
- Bu, Guojun
- Liu, Chia-Chen
- ORCID
- Venue
- Molecular Neurodegeneration
- Published
- 2022-11-08
- Volume
- 17
- Issue
- 1
- Pages
- 72-72
- ISSN
- 1750-1326 (ISSN-L)
- PMC
- PMC9644639
- OpenAlex
- W4308572221
- Cited by
- 756
- References
- 317
- Citations by year
- 2026: 222 · 2025: 266 · 2024: 187 · 2023: 81
- FWCI
- 18.38
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Molecular Neurodegeneration (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- NIH Blueprint for Neuroscience Research (R37AG027924, RF1AG057181, U19AG069701, U19AG069701, R01AG062110)
- Cure Alzheimer’s Fund (Cure Alzheimer’s Fund)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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
- apolipoprotein E, Alzheimer's disease, APOE ε4, APOE isoforms, amyloid plaques, lipid transport, genetic risk factors
- MeSH terms
- Alleles, Alzheimer Disease, Apolipoproteins E, Humans, Amyloid beta-Peptides, Apolipoprotein E4, Plaque, Amyloid
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