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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These APOE4 pathway effects are consistent with reported roles of APOE4 in inflammation, synaptic impairment, MAPK1 signaling and downstream APP transcription, and early endosomes.
“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]
The Neuroinflammation and Synaptic function sections report APOE4-associated inflammatory activation and synaptic impairment. The Aβ production section reports greater APP transcription in human stem-cell-derived neurons exposed to APOE4, while noting conflicting mouse findings. The paper discusses intracellular endosomal compartments but does not identify early endosomes specifically, and the searched passages do not establish MAPK1 signaling as the pathway to APP transcription (pages unavailable in our copy). (LLM, conf=0.86)
Experimental — accuracy not yet measuredAPOE4 is associated with increased amyloid-β deposition, hyperphosphorylation and aggregation of tau, and accelerated cognitive decline.
“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]
The ‘APOE4 and Aβ pathology’ section (page unavailable) reports greater Aβ deposition in APOE4 carriers. The ‘Tau, α-synuclein and TDP43 proteinopathies’ section (page unavailable) reports increased tau phosphorylation in experimental models and more tau aggregates in people with two APOE4 alleles when Aβ pathology is present. The copy links APOE4 to earlier symptom onset, but the passages found do not establish accelerated cognitive decline; the claim also omits the condition on the human tau-aggregation finding. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe APOE4 polymorphism alters the accessibility of the lipid-binding region, interfering with APOE's cholesterol and lipid transport capacity.
“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]
The Biology of APOE section says APOE polymorphisms alter structure and lipid binding, and the Lipid transport section says APOE4 is less efficient at transporting lipids to neurons and reports impaired cholesterol efflux in APOE*ε4 homozygotes. But the paper does not say APOE4 alters access to the lipid-binding region or that this causes the transport impairment. Its Biology of APOE section instead describes lipid binding as increasing access to the receptor-binding region in a model of APOE3; page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAPOE4 is the strongest genetic determinant of late-onset AD, increasing risk in a gene dose-dependent manner, whereas APOE2 confers substantial protection.
“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]
The Introduction (page unavailable) reports that one APOE ε4 allele raises late-onset AD risk 3–4-fold and two raise it 9–15-fold, supporting the gene-dose claim. It also says ε2 is associated with decreased risk, but does not quantify that protection; it calls APOE a major risk determinant rather than establishing ε4 as the strongest genetic determinant. (LLM, conf=0.83)
Experimental — accuracy not yet measuredHaving the APOE ε4 coding mutation(s) increases Alzheimer's disease risk 3-15 fold.
“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]
The Introduction reports a 3–4-fold increase in late-onset Alzheimer’s disease risk with one APOE ε4 allele and a 9–15-fold increase with two. The cited 3–15-fold range matches, but the sentence omits the source’s late-onset qualifier. (LLM, conf=0.85)
Experimental — accuracy not yet measured
The PLCG2 P522R rare variant provides robust protection against AD (odds ratio ≈ 0.68).
“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]
The citation is attached to the comparison with one APOE2 allele. The Introduction (page unavailable) says APOE ε2 is associated with decreased Alzheimer’s disease risk, but our copy gives no evidence that its protection is comparable in magnitude to an odds ratio of approximately 0.68. Searches for PLCG2 P522R and that odds ratio found no supporting passage in this source. (LLM, conf=0.87)
Experimental — accuracy not yet measuredAPOE is the most important risk factor for AD and contributes significantly to risk of several other neurological and nonneurological disorders.
“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]
The Introduction calls APOE polymorphism a major risk determinant of late-onset AD and links APOE genotype to the risk of other neurological disorders, including dementia with Lewy bodies and Parkinson disease dementia. The Biology of APOE section links APOE2 to type III hyperlipoproteinaemia and APOE4 to pro-atherogenic changes. The paper does not establish that APOE is the *most important* risk factor for AD generally, or that it significantly affects the risk of *several* nonneurological disorders. (LLM, conf=0.84)
Experimental — accuracy not yet measuredA single copy of APOE-E4 confers ~3.7 times greater risk than APOE-E3, and homozygous APOE-E4/E4 carriers have ~12-15 times greater risk for developing AD.
“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]
The Introduction says one APOE ε4 allele increases late-onset AD risk 3–4-fold, consistent with approximately 3.7-fold. For two alleles, it reports 9–15-fold, not the claimed 12–15-fold, and limits these estimates to late-onset AD. (LLM, conf=0.90)
Experimental — accuracy not yet measuredAPOE genotype is the strongest genetic risk factor for AD, with APOE ε2 conferring protection and APOE ε4 conferring higher risk compared to APOE ε3.
“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]
The Introduction identifies APOE as a major risk determinant of late-onset AD and says ε2 is associated with decreased risk and ε4 with increased risk relative to ε3. It does not establish that APOE is the strongest genetic risk factor for AD generally; its risk-factor framing is specifically about late-onset AD. (LLM, conf=0.85)
Experimental — accuracy not yet measuredBinding to LDLR is required by ApoE to perform its downstream effector function.
“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]
The Biology of APOE section says APOE redistributes lipids through binding to cell-surface receptors and identifies LDLR as one major receptor. It also identifies LRP1 as a major receptor, so the paper does not establish that binding specifically to LDLR is required for APOE’s downstream functions. Page numbers are unavailable in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredGenome-wide association studies have consistently implicated immune-related pathways in AD susceptibility, particularly those involving microglial function.
“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]
The Neuroinflammation section (page unavailable in our copy) links microglial immune function to AD and reports that a rare TREM2 variant is associated with increased AD risk. It does not say that genome-wide association studies have consistently implicated immune-related pathways; the evidence it presents is narrower than that claim. (LLM, conf=0.84)
Experimental — accuracy not yet measuredMicroglia play a central role in amyloid clearance, synaptic remodeling, and regulation of inflammatory signaling within the brain.
“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]
The Aβ clearance section describes microglial uptake and degradation of amyloid, and Neuroinflammation says microglia play a central role in the brain’s immune response and describes their proinflammatory activation. The Synaptic function section discusses APOE-related synaptic changes but does not attribute synaptic remodeling to microglia, so that part of the claim is unsupported. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe APOE gene is a known genetic risk factor for neurodegeneration and cardiovascular disease.
“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]
The Introduction identifies APOE ε4 as a genetic risk factor for Alzheimer disease and discusses associations with other neurodegenerative conditions. The Biology of APOE section links APOE4 to pro-atherogenic changes, but the cited passages do not establish the broader claim that APOE is a genetic risk factor for cardiovascular disease. (LLM, conf=0.84)
Experimental — accuracy not yet measuredApoE4 exacerbates amyloid pathology by promoting Aβ production and aggregation, and inhibiting Aβ clearance and degradation.
“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
The Aβ clearance section reports less efficient clearance and degradation with APOE4, and the Formation of Aβ fibrils section reports enhanced initial seeding. The Aβ production section reports increased production in human-derived neurons but conflicting mouse findings; it does not establish the claim’s unqualified production effect. Page numbers were not available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredApoE4 aggravates tau pathology via promoting tau phosphorylation, aggregation, propagation, and tau-mediated neurodegeneration.
“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
The section “Tau, α-synuclein and TDP43 proteinopathies” (page unavailable) reports increased tau phosphorylation with APOE4 and greater tau-mediated brain atrophy in one mouse model. It also reports more tau aggregates in APOE4 homozygotes only when Aβ pathology is present, and describes a different mouse model with more severe tau pathology under APOE2. The copy does not establish that APOE4 promotes tau propagation, so the unqualified list of effects overstates the source. (LLM, conf=0.87)
Experimental — accuracy not yet measuredCompared with APOE3, the APOE4 isoform increases AD risk and the APOE2 isoform reduces AD risk.
“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]
APOE4 isoform may affect the development and progression of AD through multiple different pathways in which inflammatory regulation plays a crucial role.
“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]
APOE is predominantly expressed in glial cells, particularly astrocytes and activated microglia, which play central roles in Aβ accumulation, clearance, and neuroinflammation.
“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]
Hyperphosphorylated forms of tau in neurons is a major hallmark of AD.
“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 APOE ε4 allele is a major genetic risk factor for Alzheimer's disease.
“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 <i>APOE</i> Genotype‐Dependent Manner: A Prospective Cohort Study (2026) · cites this paper as [2]
The three common APOE isoforms (APOE2, APOE3, and APOE4) influence both amyloid-β-dependent and independent pathways implicated in Alzheimer's disease pathogenesis.
“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 <i>APOE</i> Genotype‐Dependent Manner: A Prospective Cohort Study (2026) · cites this paper as [2]
APOE plays a crucial role in the pathophysiology of AD, particularly in relation to Aβ and tau.
“APOE plays a crucial role in the pathophysiology of AD, particularly in relation to Aβ and tau.43,44”
From Association of rare <i>APOE</i> missense variants with Alzheimer's disease in the Japanese population (2025) · cites this paper as [43]
Cerebrovascular dysfunction is a major pathological process of AD.
“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
ApoE4-positive cells show reduced cholesterol transport function.
“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
ApoE4 shows both loss-of-function and gain-of-toxic-function across various Alzheimer's disease pathogenesis pathways.
“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
Cerebral glucose hypometabolism occurs in both the early stage of AD and epilepsy.
“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
A specific ApoE4 fragment, ApoE4[Δ(166-299)], promotes the cellular uptake of extracellular Aβ42 and results in increased oxidative stress, similar to the effect of L28P.
“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]
The “APOE4 and Aβ pathology > Aβ clearance” section discusses Aβ uptake by cells expressing APOE4, but does not address the ApoE4[Δ(166–299)] fragment or increased oxidative stress. Searches for the fragment, L28P, and oxidative stress found no passage establishing the claimed effect. The reported findings for APOE4-expressing astrocytes cannot establish what this specific fragment does. (LLM, conf=0.76)
Experimental — accuracy not yet measuredAPOE is the most significant known risk factor for sporadic Alzheimer's disease.
“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
ApoE4 exhibits the strongest receptor binding and is considered a high-risk allele, while ApoE2 exhibits the weakest receptor binding and is considered protective.
“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
APOE affects tau pathogenesis and tau-mediated neurodegeneration.
“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]
Meningeal lymphatic endothelial cells from 6-month-old 5xFAD mice show altered expression of genes tied to exocytosis, phospholipase D signaling, and low-density lipoprotein response.
“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]
Thirty-nine Alzheimer's disease-associated genes lie within the 10th percentile of highly expressed genes in meningeal lymphatic endothelial cells, including Apoe, which is among the few highly expressed genes shared by all three cell types.
“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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BackgroundMolecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease
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“These findings align with clinical and basic research, https://doi.org/10.1038/s41591-024-03340-9 which suggests that APOE ε4 primarily increases Alzheimer’s disease risk by causing earlier amyloid pathology in the brain 21,22 .”
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Self-citation<i>APOE</i> ε4 associates with microglial activation independently of Aβ plaques and tau tangles
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“Co-dominant and additive effects of APOE4 alleles in the EC In terms of AD susceptibility, one copy of APOE4 confers a ~3-fold increased risk, while two copies of APOE4 confers a ~12-fold increased risk of developing AD [14].”
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“The coding mutation APOE (cid:4) 4 is the most well-accepted AD risk genetic factor: having the APOE (cid:4) 4 coding mutation(s) increases AD risk 3–15 fold [3].”
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- 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
- Health Sciences › Medicine › Physiology › 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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