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Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies
Open accessAbstract
Polymorphism in the apolipoprotein E (APOE) gene is a major genetic risk determinant of late-onset Alzheimer disease (AD), with the APOE*ε4 allele conferring an increased risk and the APOE*ε2 allele conferring a decreased risk relative to the common APOE*ε3 allele. Strong evidence from clinical and basic research suggests that a major pathway by which APOE4 increases the risk of AD is by driving earlier and more abundant amyloid pathology in the brains of APOE*ε4 carriers. The number of amyloid-β (Aβ)-dependent and Aβ-independent pathways that are known to be differentially modulated by APOE isoforms is increasing. For example, evidence is accumulating that APOE influences tau pathology, tau-mediated neurodegeneration and microglial responses to AD-related pathologies. In addition, APOE4 is either pathogenic or shows reduced efficiency in multiple brain homeostatic pathways, including lipid transport, synaptic integrity and plasticity, glucose metabolism and cerebrovascular function. Here, we review the recent progress in clinical and basic research into the role of APOE in AD pathogenesis. We also discuss how APOE can be targeted for AD therapy using a precision medicine approach.
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“All these effects are consistent with reported roles of APOE4 in inflammation, synaptic impairment, MAPK1 signaling and downstream APP transcription, and early endosomes7,18.”
From APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes (2022) · cites this paper as [7]
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
“APOE4 is associated with increased amyloid-β deposition, hyperphosphorylation and aggregation of tau, and accelerated cognitive decline4–7.”
From APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes (2022) · cites this paper as [7]
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 APOE4 polymorphism alters the accessibility of the lipid-binding region, which interferes with its cholesterol and lipid transport capacity7.”
From APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes (2022) · cites this paper as [7]
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
“APOE4 is the strongest genetic determinant of late-onset AD, increasing risk in a gene dose-dependent manner, whereas APOE2 confers substantial protection 1 -5 .”
From APOE2 attenuates APOE4-associated amyloid pathology and related toxicity in a mouse model of Alzheimer’s disease (2026) · cites this paper as [3]
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
“having the APOE ɛ4 coding mutation(s) increases AD risk 3–15 fold [3]”
From Association of SPI1 haplotypes with altered SPI1 gene expression and Alzheimer’s disease risk (2022) · cites this paper as [3]
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The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“These include PLCG2 P522R rare variant (rs72824905) that provides robust protection against AD (odds ratio ≈ 0.68 [1, 4], comparable to having one APOE2 allele [5]”
From PLCγ2 deficiency compromises systemic immune tolerance and erodes myelin homeostasis while enhancing oxidative metabolism in the mouse brain (2026) · cites this paper as [5]
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 is the most important risk factor for AD and contributes significantly to the risk of developing several other neurological and nonneurological disorders (18).”
From Regulation of astrocyte lipid metabolism and ApoE secretion by the microglial oxysterol, 25-hydroxycholesterol (2023) · cites this paper as [18]
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
“A single copy of the APOE-E4 allele confers a ∼ 3.7 times greater risk than the common variant, APOE-E3, whereas homozygous APOE-E4/E4 carriers have a ∼12-15 times greater risk for developing AD.”
From Regulation of astrocyte lipid metabolism and ApoE secretion by the microglial oxysterol, 25-hydroxycholesterol (2023) · cites this paper as [18]
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 genotype is the strongest genetic risk factor for AD21, with APOE ε2 conferring protection from disease and APOE ε4 conferring higher risk, compared to the APOE ε3 allele”
From Clonal hematopoiesis is associated with protection from Alzheimer’s disease (2023) · cites this paper as [21]
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
“In line with this, binding to LDLR is required by ApoE to perform its downstream effector function (50–52).”
From Secreted Apoe rewires melanoma cell state vulnerability to ferroptosis (2024) · cites this paper as [51]
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
“Genome-wide association studies have consistently implicated immune-related pathways in AD susceptibility, particularly those involving microglial function [21,22].”
From Clonal Hematopoiesis of Indeterminate Potential as an Emerging Interdisciplinary Risk Factor in Alzheimer’s Disease: Current Evidence and Future Directions (2026) · cites this paper as [21]
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In the citing paper
“When activated, microglia, the resident immune cells of the central nervous system, play a central role in amyloid clearance, synaptic remodeling, and the regulation of inflammatory signaling within the brain [21].”
From Clonal Hematopoiesis of Indeterminate Potential as an Emerging Interdisciplinary Risk Factor in Alzheimer’s Disease: Current Evidence and Future Directions (2026) · cites this paper as [21]
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 gene is a known genetic risk factor for neurodegeneration and cardiovascular disease (CVD) [1, 2].”
From Characterization of APOE Christchurch carriers in 455,306 UK Biobank participants (2023) · 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.
In the citing paper
“apoE4 exacerbates amyloid pathology by promoting Aβ production and aggregation, and inhibiting Aβ clearance and degradation”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Yamazaki et al 2019
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
“apoE4 aggravates the tau pathology via promoting tau phosphorylation, aggregation, propagation, and tau-mediated neurodegeneration”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Yamazaki et al 2019
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
“LRP1 mediates and regulates the endocytosis of > 30 ligands, including apolipoprotein E (APOE) and amyloid-β (Aβ) [21–27]”
From LRP1 is a neuronal receptor for α-synuclein uptake and spread (2022) · cites this paper as [23]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Compared with APOE3, the APOE4 isoform increases AD risk and theAPOE2 isoform reduces AD risk.166”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [166]
The cited source says what the claim attributes to it.
In the citing paper
“APOE4 isoform may affects the development and progression of AD through multiple different pathways in which inflammatory regulation plays crucial role.166”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [166]
The cited source says what the claim attributes to it.
In the citing paper
“It is known that APOE is predominantly expressed in glial cells, particularly astrocytes and activated microglia, which play central roles in A β accumulation, clearance, and neuroin fl ammation 3,4 .”
From APOE2 attenuates APOE4-associated amyloid pathology and related toxicity in a mouse model of Alzheimer’s disease (2026) · cites this paper as [3]
The cited source says what the claim attributes to it.
In the citing paper
“Hyperphosphorylated forms of the microtubule-associated protein tau in neurons is a major hallmark of AD [2, 3].”
From CI-994 is a dual modulator of class I HDACs and Wnt/β-catenin signaling for the treatment of Alzheimer's disease (2026) · cites this paper as [3]
The cited source says what the claim attributes to it.
In the citing paper
“Multiple cohort studies have demonstrated that the APOE ε4 allele is a major genetic risk factor for AD”
From Blood PCSK9 Impacts Alzheimer's Disease Risk in an APOE Genotype‐Dependent Manner: A Prospective Cohort Study (2026) · cites this paper as [2]
The cited source says what the claim attributes to it.
In the citing paper
“while the three common isoforms (APOE2, APOE3, and APOE4) influence both amyloid‐β–dependent and independent pathways implicated in AD pathogenesis [1, 2].”
From Blood PCSK9 Impacts Alzheimer's Disease Risk in an APOE Genotype‐Dependent Manner: A Prospective Cohort Study (2026) · cites this paper as [2]
The cited source says what the claim attributes to it.
In the citing paper
“APOE plays a crucial role in the pathophysiology of AD, particularly in relation to Aβ and tau.43,44”
From Association of rare APOE missense variants with Alzheimer's disease in the Japanese population (2025) · cites this paper as [43]
The cited source says what the claim attributes to it.
In the citing paper
“Cerebrovascular dysfunction has been recognized as a major pathological process of AD”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Yamazaki et al 2019
The cited source says what the claim attributes to it.
In the citing paper
“with ApoE4-positive cells showing reduced function (Rawat et al., 2019; Yamazaki et al., 2019).”
From ApoE4 Impairs Neuron-Astrocyte Coupling of Fatty Acid Metabolism (2021) · cites this paper as Yamazaki et al., 2019
The cited source says what the claim attributes to it.
In the citing paper
“ApoE4 shows both loss-of-function and gain-of-toxic-function across various AD pathogenesis pathways (Yamazaki et al., 2019).”
From ApoE4 Impairs Neuron-Astrocyte Coupling of Fatty Acid Metabolism (2021) · cites this paper as Yamazaki et al., 2019
The cited source says what the claim attributes to it.
In the citing paper
“Importantly, cerebral glucose hypometabolism occurs in both the early stage of AD (Christian et al., 2020; Yamazaki et al., 2019) and epilepsy (McDonald et al., 2018; Patel, 2018).”
From APOE4 reduces hippocampal expression of phosphoglycerate kinase 1 and sodium potassium pump to enhance seizure susceptibility in mice (2026) · cites this paper as Yamazaki et al., 2019
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In the citing paper
“We also found that LECs isolated from the meninges of 6-month-old 5xFAD mice showed significant changes in the expression of genes involved in processes such as exocytosis, phospholipase D signaling, and response to low-density lipoprotein (Extended Data Fig. 1f–k), suggesting that meningeal Aβ deposition might affect meningeal LECs early on through deleterious processes previously implicated in”
From Meningeal lymphatics affect microglia responses and anti-Aβ immunotherapy (2021) · cites this paper as [15]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“a specific ApoE4 fragment, ApoE4[Δ(166-299)], has previously been found to promote the cellular uptake of extracellular Aβ42 and resulted in increased oxidative stress [28], similar to the effect of L28P.”
From Investigation of the independent role of a rare APOE variant (L28P; APOE*4Pittsburgh) in late-onset Alzheimer disease (2023) · cites this paper as [28]
Experimental — accuracy not yet measuredIn the citing paper
“APOE is the most significant known risk factor for sporadic Alzheimer’s disease”
From APOE3 Christchurch modulates β-catenin/Wnt signaling in iPS cell-derived cerebral organoids from Alzheimer’s cases (2024) · cites this paper as Yamazaki et al., 2019
In the citing paper
“ApoE4 exhibits the strongest receptor binding and is considered a high-risk allele, while ApoE2 exhibits the weakest receptor binding and is considered protective (Yamazaki et al., 2019).”
From APOE3 Christchurch modulates β-catenin/Wnt signaling in iPS cell-derived cerebral organoids from Alzheimer’s cases (2024) · cites this paper as Yamazaki et al., 2019
In the citing paper
“APOE also affects tau pathogenesis and tau-mediated neurodegeneration [468].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [468]
In the citing paper
“In fact, 39 AD-associated genes were found within the 10th percentile of highly expressed genes in meningeal LECs, including Apoe, which is intrinsically linked to altered risk for late onset AD15,31 and was one of the few highly expressed genes found at the intersection between all three cell types (Extended Data Fig. 9o).”
From Meningeal lymphatics affect microglia responses and anti-Aβ immunotherapy (2021) · cites this paper as [15]
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Metadata
- Authors
- Yamazaki, Y., Zhao, N., Caulfield, T. R., Liu, C.-C., & Bu, G.
- Affiliations
- Mayo Clinic in Florida (US)
- Corresponding author
- Bu, Guojun
- Venue
- Nature Reviews Neurology
- Published
- 2019-07-31
- Volume
- 15
- Issue
- 9
- Pages
- 501-518
- ISSN
- 1759-4758 (ISSN-L)
- 1759-4766
- PMC
- PMC7055192
- OpenAlex
- W2965401191
- Cited by
- 1,425
- References
- 318
- Citations by year
- 2026: 191 · 2025: 259 · 2024: 233 · 2023: 242 · 2022: 200 · 2021: 172 · 2020: 124 · 2019: 4
- FWCI
- 14.75
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Reviews Neurology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- National Institute on Aging (RF1AG051504, R01AG027924, R37AG027924, RF1AG057181, RF1AG046205, R01AG035355)
- National Institute of Neurological Disorders and Stroke (P01NS074969)
- 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, APOE ε4, Alzheimer's disease, APOE polymorphism, amyloid-beta, tau pathology, neurodegeneration, microglial activation, lipid transport, synaptic plasticity, glucose metabolism, cerebrovascular function, precision medicine
- MeSH terms
- Alzheimer Disease, Apolipoproteins E, Brain, Humans, Polymorphism, Genetic, Amyloid beta-Peptides, Genetic Predisposition to Disease, Plaque, Amyloid
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