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Cited by 55Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Apolipoprotein E as a β-amyloid-independent factor in Alzheimer’s disease

Open access
Wolf, Andrew B, Valla, Jon, Bu, Guojun, Kim, Jungsu, LaDu, Mary, Reiman, Eric M, Caselli, Richard J·2013·Alzheimer's Research & Therapy
DOI 10.1186/alzrt204PMC PMC3979087
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Abstract

APOE, which encodes apolipoprotein E, is the most prevalent and best established genetic risk factor for late-onset Alzheimer's disease. Current understanding of Alzheimer's disease pathophysiology posits an important role for apolipoprotein E in the disease cascade via its interplay with β-amyloid. However, evidence is also emerging for roles of apolipoprotein E in the disease process that are independent of β-amyloid. Particular areas of interest are lipid metabolism, tau pathology, neuroenergetics, neurodevelopment, synaptic plasticity, the neurovasculature, and neuroinflammation. The intent of this article is to review the literature in each of these areas.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that APOE/apolipoprotein E contributes to late-onset Alzheimer’s disease risk through β-amyloid-independent mechanisms involving lipid metabolism, tau pathology, neuroenergetics, neurodevelopment, synaptic plasticity, the neurovasculature, and neuroinflammation. It synthesizes evidence that apoE4 can exert both toxic gain-of-function and loss-of-function effects, while emphasizing that many mechanisms remain unresolved.

Key findings

  • APOE allele frequencies are approximately 10% for ε2, 70% for ε3, and 20% for ε4 in the US; compared with ε3 homozygotes, ε4 homozygotes have up to 15 times the risk and ε4 heterozygotes up to four times the risk for AD, while ε2 is associated with decreased risk.
  • apoE4 differs structurally from apoE3 by arginine at residues 112 and 158, is more prone to domain interaction, and undergoes neuron-specific proteolysis by AECE to generate apoE4∆272–299; this fragment can translocate to the cytosol, form tangle-like structures with phosphorylated tau, and impair mitochondrial function. Mice expressing high neuronal apoE4∆272–299 develop neurofibrillary tangles and die at 2 to 4 months, while lower expression causes learning and memory deficits at 6 to 7 months.
  • Cognitively normal late middle age (50 to 65 years) APOE ε4 homozygotes show reduced cerebral metabolic rate for glucose in parietal, prefrontal, and temporal regions; cognitively normal 20- to 39-year-old ε4 carriers also show decreased cerebral metabolic rate for glucose, and young-adult ε4 carriers show Complex IV deficits in the posterior cingulate cortex. Postmortem middle temporal gyrus tissue from middle-aged APOE ε4 carriers shows differential expression of 70 transcripts, 30 involved in oxidative mitochondrial function.
  • apoE4 has been linked to impaired blood–brain barrier integrity via an inflammatory CypA–NF-κB–matrix metalloproteinase pathway in pericytes, an effect not seen in apoE2 or apoE3 mice; apoE4 is also associated with increased glial activation, microglia/macrophages, T-cell invasion, and altered cytokine signaling (IL-1β, IL-6, TNFα) in mouse studies.

Methods

  • Design: narrative literature review; the stated intent is to review and assess research on β-amyloid-independent roles of apoE in AD across lipid metabolism, tau pathology, neuroenergetics, neurodevelopment, synaptic plasticity, the neurovasculature, and neuroinflammation.
  • Data/sample: no primary data are presented; the review cites human imaging and postmortem studies, cell culture experiments, and transgenic/knock-in mouse models.
  • Main analysis: qualitative synthesis of published findings, with no systematic search strategy, meta-analysis, or quantitative pooling described.

Limitations

  • The paper states that much of the reviewed work has been accomplished in a limited number of laboratories and encourages other investigators to replicate and extend the findings in existing and novel models.
  • The paper notes that the apoE4 domain interaction model has been challenged by alternative studies using mutated protein, possibly limiting physiological relevance; it also notes inconsistent mouse behavior outcomes and that the ε4 carrier versus noncarrier difference in hippocampal volumes has not been found consistently.
  • Evident from the text: as a narrative review, it does not use a systematic search or quantitative synthesis, and many mechanistic conclusions rely on animal or cell-culture models rather than confirmed human causal evidence.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1186/alzrt204

Cites

104 of 104 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 129 cited sources checked · 0 supported · 0 flagged

  • Premisenone given

    There is a growing body of evidence for roles of apoE in Alzheimer's disease risk that are independent of β-amyloid.

    “However, there is a growing body of literature supporting additional roles for apoE in AD risk, both via its normal physiological function and via pathogenic dysfunction that is independent of β-amyloid.”
    Quote in the paperSubstantial claim
  • Premisecitation

    APOE is the most prevalent and best-established genetic risk factor for late-onset, sporadic Alzheimer's disease.

    “The most prevalent and best-established genetic risk factor for late-onset, sporadic AD is APOE, encoding apolipoprotein E (apoE), first described in the early 1990s [1].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Premisecitation

    The LDL-receptor binding region (residues 136 to 150) is required for apoE4∆272-299 escape in Neuro-2a mouse neuroblastoma cultures.

    “The LDL-receptor binding region (residues 136 to 150), which is rich in positively-charged amino acids arginine, lysine, and histidine, is required for escape in Neuro-2a mouse neuroblastoma cultures [23].”
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  • Premisecitation

    The biochemical stability of apoE is dependent on C-terminal segments.

    “The biochemical stability of apoE is dependent on C-terminal segments [21,22].”
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  • Premisecitation

    Cognitively normal 20- to 39-year-old APOE ε4 carriers exhibit a significantly decreased cerebral metabolic rate for glucose in similar regions, decades ahead of any apparent pathology or cognitive defects.

    “Cognitively normal, 20-year-old to 39-year-old APOE ϵ4 carriers exhibit a significantly decreased cerebral metabolic rate for glucose in similar regions, in this case decades ahead of any apparent pathology or cognitive defects [33].”
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  • Classified as probably not a substantial claim. 11
  • May combine two claims. 34

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The role of APOE in Alzheimer's disease risk is frequently understood in the context of the interplay of apoE with β-amyloid.

    “Frequently, the role of APOE in AD risk is understood in the context of the interplay of apoE with β-amyloid, and this topic has been recently reviewed [2].”
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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    APOE has three common alleles in humans: APOE ε2 (US frequency ~10%), APOE ε3 (US frequency ~70%), and APOE ε4 (US frequency ~20%).

    “APOE has three common alleles in humans: APOE ϵ2 (US frequency ~10%), APOE ϵ3 (US frequency ~70%), and APOE ϵ4 (US frequency ~20%) [3].”
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    Premisecitation

    Additional studies found longitudinal declines in the cerebral metabolic rate for glucose and gene dose effects.

    “Additional studies found longitudinal declines in the cerebral metabolic rate for glucose [31] and gene dose effects [32].”
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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    apoE4 is associated with hyperlipidemia and heart disease.

    “Additionally, apoE is known to have significant impacts in the periphery, with apoE4 being associated with hyperlipidemia and heart disease [13].”
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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    apoE is highly expressed in the liver and brain, with the primary brain source being astrocytes, and in the brain is associated with high-density lipoprotein-like lipoproteins.

    “apoE is highly expressed in the liver and brain (with the primary brain source being astrocytes), and in the brain is associated with high-density lipoprotein-like lipoproteins [9].”
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  • May combine two claims.

    Premisecitation

    apoE is secreted and loaded with lipids via ABCA1 to form lipidated lipoprotein particles, and endocytosis occurs via apoE receptors LDL receptor primarily in glia and LDL receptor-related protein 1 primarily in neurons.

    “apoE is secreted and loaded with lipids via the ATP-binding cassette transporter (ABCA1) to form lipidated lipoprotein particles. Endocytosis of these particles occurs via interaction with apoE receptors, namely low-density lipoprotein (LDL) receptor (primarily in glia) and LDL receptor-related protein 1 (primarily in neurons) [10].”
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    Premisecitation

    Full-length apoE4 expressed in Neuro-2a cultures acts along with zinc to phosphorylate tau via the extracellular signal-regulated kinase pathway, and neuron-specific apoE4 expression in mice results in high levels of phosphorylated extracellular signal-regulated kinase and phosphorylated tau in the hippocampus.

    “Full-length apoE4 expressed in Neuro-2a cultures acts along with zinc to phosphorylate tau via the extracellular signal-regulated kinase pathway, and neuron-specific apoE4 expression in mice results in high levels of phosphorylated extracellular signal-regulated kinase and phosphorylated tau in the hippocampus [24].”
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  • May combine two claims.

    Premisecitation

    apoE3 is effective at binding the microtubule-binding repeat region of tau, whereas apoE4 does not bind this region and thus may not be as effective at limiting formation of neurofibrillary tangles.

    “apoE3 is effective at binding the microtubule-binding repeat region of tau, the region responsible for the formation of paired helical filaments; apoE4 does not bind this region and thus may not be as effective at limiting formation of neurofibrillary tangles [25].”
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  • May combine two claims.

    Premisecitation

    The encoded apoE proteins differ at two amino acids: apoE2 has cysteine at residues 112 and 158, apoE3 has cysteine at residue 112 and arginine at residue 158, and apoE4 has arginine at residues 112 and 158.

    “The encoded proteins differ at two amino acids – apoE2 has cysteine at residues 112 and 158, apoE3 has cysteine at residue 112 and arginine at residue 158, and apoE4 has arginine at residues 112 and 158 [5].”
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  • May combine two claims.

    Premisecitation

    Although neurons take up astrocyte-secreted apoE, apoE proteolysis occurs in the neuronal secretory pathway and not in an endocytic pathway, indicating neuronal-source specificity.

    “Although neurons take up apoE secreted by astrocytes (the normal physiological process), this apoE proteolysis occurs in the neuronal secretory pathway and not in an endocytic pathway, which seems to indicate neuronal-source specificity to this event [20].”
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  • May combine two claims.

    Premisecitation

    Mice expressing neuronal apoE4∆272-299 at high levels develop neurofibrillary tangles and die at 2 to 4 months.

    “Mice expressing neuronal apoE4∆272–299 at high levels develop neurofibrillary tangles and die at 2 to 4 months.”
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    Premisecitation

    The location of residue 112 is thought to result in the side chain of arginine at residue 61 forming a salt bridge with glutamate at residue 255.

    “The location of this residue is thought to result in the side chain of the arginine at residue 61 (N-terminal domain) forming a salt bridge with the glutamate at residue 255 (C-terminal domain) [6].”
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    Premisecitation

    Neuronal apoE is upregulated in response to injury.

    “Neuronal apoE is known to be upregulated in response to injury [16,17].”
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  • May combine two claims.

    Premisecitation

    apoE is known to have effects on tau pathology, a hallmark of Alzheimer's disease, although the pathophysiology remains uncertain.

    “apoE is known to have effects on tau pathology, which is a hallmark of AD, although the pathophysiology remains uncertain.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Compared with APOE ε3 homozygotes, APOE ε4 homozygotes have up to 15 times the risk and APOE ε4 heterozygotes up to four times the risk for developing Alzheimer's disease.

    “When compared with persons homozygous for APOE ϵ3 (risk neutral), APOE ϵ4 homozygotes have up to 15 times the risk and APOE ϵ4 heterozygotes up to four times the risk for developing AD.”
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  • May combine two claims.

    Premisecitation

    apoE4 trafficking is impaired in the endoplasmic reticulum and Golgi apparatus in Neuro-2a cultures, and small-molecule apoE structure correctors can rescue this impairment.

    “Interestingly, apoE4 trafficking is impaired in the endoplasmic reticulum and Golgi apparatus in Neuro-2a cultures, and small-molecule apoE structure correctors can rescue this impairment [47].”
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  • May combine two claims.

    Interpretationreasoning

    Effects of apoE on neuroenergetics may represent a toxic gain of function leading to mitochondrial impairment, disrupted trafficking, or astrocyte damage and/or loss of antioxidant or other normal functions.

    “Taken together, effects of apoE on neuroenergetics may represent a toxic gain of function leading to mitochondrial impairment, disrupted trafficking, or astrocyte damage and/or loss of antioxidant or other normal functions (see Figure 1).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In Alzheimer's disease, oxidative stress is thought to be an early feature of pathophysiology.

    “In AD, oxidative stress is thought to be an early feature of pathophysiology [49,50].”
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    Premisecitation

    Mice expressing human apoE4 display reduced neurogenesis, which is also apparent in apoE knockout mice.

    “Mice expressing human apoE4 display reduced neurogenesis, which is also apparent in apoE knockout mice [56].”
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    Premisecitation

    apoE4 binds the alpha and beta subunits of the F1 portion of ATP synthase in liver, although the functional consequences are unclear.

    “apoE4 binds the alpha and beta subunits of the F1 portion of ATP synthase in liver [41], although the functional consequences of this are unclear.”
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  • May combine two claims.

    Premisecitation

    apoE4 can induce endoplasmic reticulum stress in astrocytes, an effect that does not occur in neurons.

    “apoE4 can induce endoplasmic reticulum stress in astrocytes [46], an effect that does not occur in neurons [47].”
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    Premisecitation

    Human apoE4-expressing mice exhibit impairments in axonal transport and accumulate mitochondria in axonal dilations.

    “Human apoE4-expressing mice exhibit impairments in axonal transport and accumulate mitochondria in axonal dilations [38].”
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  • May combine two claims.

    Premisecitation

    Young APOE ε4 carriers display thinner entorhinal cortices than noncarriers and reduced hippocampal volumes compared with noncarriers and APOE ε2 carriers alone.

    “In volumetric studies utilizing magnetic resonance imaging, young APOE ϵ4 carriers display thinner entorhinal cortices than noncarriers [51] and reduced hippocampal volumes compared with both noncarriers [52] and APOE ϵ2 carriers alone [53].”
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    Premisecitation

    apoE4-expressing Neuro-2a and mouse primary neuron cultures have reduced expression of subunits for all electron transport chain complexes, and Complex IV respiratory function is significantly decreased.

    “apoE4-expressing Neuro-2a and mouse primary neuron cultures have reduced expression of subunits for all electron transport chain complexes [43]. Complex IV respiratory function is also significantly decreased.”
    Quote in the paperSubstantial claim0 of 1 sources checked
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    Premisecitation

    apoE4∆272-299 binds ubiquinol cytochrome c reductase core protein 2 and cytochrome CI of Complex III and cytochrome c oxidase subunit 4 isoform 1 of Complex IV, and this binding significantly reduced the respiratory function of both complexes.

    “In further study using Neuro-2a, apoE4∆272–299 demonstrated the ability to bind ubiquinol cytochrome c reductase core protein 2 and cytochrome CI of Complex III and cytochrome c oxidase subunit 4 isoform 1 of Complex IV of the electron transport chain. This binding significantly reduced the respiratory function of both complexes [42].”
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  • May combine two claims.

    Premisecitation

    apoE is associated with risk for cerebral amyloid angiopathy and other cerebrovascular conditions including cerebral hemorrhage and vascular dementia, in addition to Alzheimer's disease.

    “apoE is associated with risk for cerebral amyloid angiopathy and other cerebrovascular conditions including cerebral hemorrhage and vascular dementia, in addition to AD [80].”
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    Premisecitation

    apoE4 mice displayed increased loss of synaptic proteins and alterations in cytokine signaling (IL-1β, IL-6, and TNFα).

    “Interestingly, apoE4 mice also displayed increased loss of synaptic proteins and alterations in cytokine signaling (IL-1β, IL-6, and TNFα) [97].”
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    Premisecitation

    A non-Alzheimer's disease clinical diagnosis was more common in the hippocampal sparing group, but this did not appear to relate to APOE ε4 carrier status.

    “A non-AD clinical diagnosis (including the variant syndromes) was more common in the hippocampal sparing group, but this did not appear to relate to APOE ϵ4 carrier status (in contrast to van der Flier’s hypothesis).”
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    Interpretationcitation

    apoE2 and apoE3 suppress the CypA-NF-κB-matrix metalloproteinase pathway via LDL receptor-related protein 1, suggesting that apoE4 may impair the blood-brain barrier via a loss of function in comparison with the other isoforms.

    “Indeed, these proteins were shown to suppress the pathway via LDL receptor-related protein 1 [86], suggesting that apoE4 may impair the BBB via a loss of function in comparison with the other isoforms.”
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    Premisecitation

    apoE is involved in synaptogenesis via its cholesterol transport abilities and plays a role in maintaining the neural progenitor pool in the adult dentate gyrus.

    “apoE has also been shown to be involved in synaptogenesis via its cholesterol transport abilities [67] and plays a role in maintaining the neural progenitor pool in the adult dentate gyrus [68].”
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    Premisecitation

    In humans, APOE ε4 homozygotes and APOE ε4 carriers exhibit declines in memory earlier than APOE ε4 noncarriers, and before age 60, while remaining free of clinically significant memory loss.

    “In humans, APOE ϵ4 homozygotes and APOE ϵ4 carriers exhibit declines in memory (as assessed by neuropsychological testing) earlier than APOE ϵ4 noncarriers, and before age 60, while remaining free of clinically significant memory loss [27,74-76].”
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    Premisecitation

    apoE knockout mice demonstrate deficiencies in blood-brain barrier integrity and an increased rate of decline in blood-brain barrier integrity with age.

    “apoE knockout mice demonstrate deficiencies in BBB integrity [83] and also demonstrate an increased rate of decline in BBB integrity with age [84].”
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  • May combine two claims.

    Premisecitation

    apoE4 is linked to deficits in β-amyloid clearance, and blood-brain barrier breakdown in Alzheimer's disease is most prominent in patients who are carriers of APOE ε4.

    “apoE4 in particular has been linked to deficits in β-amyloid clearance, and BBB breakdown in AD is most prominent in patients who are carriers of APOE ϵ4 [82].”
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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Microtubule depolymerization associated with apoE-tau interaction is thought to be important to apoE4 effects on neurite outgrowth.

    “Microtubule depolymerization associated with apoE–tau interaction is thought to be important to apoE4 effects on neurite outgrowth [64].”
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  • May combine two claims.

    Premisecitation

    apoE4 is believed to sequester apolipoprotein E receptor 2, leading to impairment of reelin signaling and synaptic plasticity, which is not seen with apoE3 and apoE2.

    “Interestingly, apoE4 is also believed to sequester apolipoprotein E receptor 2, leading to impairment of reelin signaling and synaptic plasticity, which is not seen with apoE3 and apoE2 [73].”
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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning

    Metabolically associated alterations in brain imaging, such as fluorodeoxyglucose positron emission tomography signal, could also be driven by cerebrovascular changes.

    “Notably, metabolically associated alterations in brain imaging (for example, in fluorodeoxyglucose positron emission tomography signal), such as those discussed earlier, could also be driven by cerebrovascular changes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In apoE mice, apoE4 (in comparison with apoE2 and apoE3) was associated with increased glial activation, increased levels of microglia and macrophages, and increased T-cell invasion in response to lipopolysaccharide.

    “In a recent study in apoE mice, apoE4 (in comparison with apoE2 and apoE3) was associated with increased glial activation, increased levels of microglia and macrophages, and increased T-cell invasion in response to lipopolysaccharide [97].”
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    Premisecitation

    apoE is involved in the inflammatory response and has been shown to modulate the expression of several cytokines in vitro and in vivo.

    “apoE is known to be involved in the inflammatory response, and has been shown to modulate the expression of several cytokines in vitro and in vivo[93].”
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    Premisecitation

    A large amount of work has focused on the role of inflammation in Alzheimer's disease, including interactions with apoE.

    “A large amount of work has focused on the role of inflammation in AD [91], including interactions with apoE [92].”
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    Premisecitation

    apoE plays a role in oligodendrogenesis, and brain imaging studies show white-matter differences in carriers of different APOE isoforms.

    “In addition to these neuronal effects, apoE plays a role in oligodendrogenesis [79] – a number of brain imaging studies show white-matter differences in carriers of different APOE isoforms [28].”
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    Premisecitation

    apoE is known to be involved in antigen presentation and modulation of nitric oxide production.

    “Additionally, apoE is known to be involved in antigen presentation and modulation of nitric oxide production [100-103].”
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    • cites [103]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

41 of 41

  • The paper relies on this without support.

    Well-conceived therapeutic strategies based upon the amyloid cascade hypothesis have failed to achieve significant disease modification.

    “yet well-conceived therapeutic strategies based upon the amyloid cascade hypothesis have failed to achieve significant disease modification.”

  • The paper relies on this without support.

    Much of the work on apoE in Alzheimer’s disease has been accomplished in a limited number of laboratories.

    “Notably, much of this work has been accomplished in a limited number of laboratories.”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • APOE4 is associated with increased Aβ deposition, but its influence on metabolic pathways may contribute to AD risk independently of Aβ.

    “As such, APOE4 is associated with increased Aβ deposition but accumulating evidence suggests that its influence on metabolic pathways may contribute to disease risk independently of Aβ [3][4][5][6][7] .”

    From APOE4-drives brain bioenergetic shifts independent of Alzheimer’s disease pathology (2026) · cites this paper as [5]

    The Review’s Introduction describes APOE4-related changes in lipid metabolism and cerebral energy metabolism, including effects reported without a contribution from fibrillar Aβ; this supports the hedged claim that metabolic pathways may contribute independently to AD risk. It also links APOE4 to impaired Aβ clearance, but the passages do not explicitly establish increased Aβ deposition in APOE4 carriers. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • APOE4 increases Alzheimer's disease susceptibility and APOE2 offers protection.

    “The three primary APOE isoforms (APOE2, APOE3, and APOE4) have distinct effects on AD onset and age-related progression, with APOE4 increasing susceptibility and APOE2 offering protection (Corder et al., 1993; Saunders et al., 1993; Wolf et al., 2013).”

    From Isogenic human stem cell models reveal mutation-dependent protective mechanisms of APOE3 Christchurch (2026) · cites this paper as Wolf et al., 2013

  • APOE4 expression has deleterious effects on numerous Aβ-independent pathways, including lipid metabolism, tau pathology, bioenergetics, neuronal development, synaptic plasticity, the neuro-vasculature, and neuro-inflammation.

    “APOE4 expression has also been shown to have deleterious effects on numerous Aβ-independent pathways, including lipid metabolism, tau pathology, bioenergetics, neuronal development, synaptic plasticity, the neuro-vasculature, and neuro-inflammation”

    From APOE4 is Associated with Differential Regional Vulnerability to Bioenergetic Deficits in Aged APOE Mice (2020) · cites this paper as [15]

Cites

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Authors
Wolf, A. B., Valla, J., Bu, G., Kim, J., LaDu, M., Reiman, E. M., & Caselli, R. J.
Affiliations
  • University of Colorado Anschutz (US)
  • Midwestern University (US)
  • Mayo Clinic in Florida (US)
  • University of Illinois Chicago (US)
  • Translational Genomics Research Institute (US)
  • Mayo Clinic in Arizona (US)
Corresponding author
Caselli, Richard J
ORCID
Venue
Alzheimer's Research & Therapy
Publisher
Springer Science and Business Media LLC
Published
2013
Volume
5
Issue
5
Pages
38
ISSN
1758-9193 (ISSN-L)
DOI
10.1186/alzrt204
PMC
PMC3979087
OpenAlex
W2098752510
Semantic Scholar
93d0069a40b8c410e8d877e06e0d98b3152bfa1f
Cited by
55
References
104
Citations by year
2026: 2 · 2025: 3 · 2024: 1 · 2023: 2 · 2022: 1 · 2021: 3 · 2020: 7 · 2019: 2 · 2018: 5 · 2017: 11 · 2016: 4 · 2015: 8 · 2014: 5 · 2012: 1
FWCI
3.47
Type
journal article
Language
en
Open access
Locations
  • Alzheimer s Research & Therapy (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (submittedVersion)
  • PubMed Central (submittedVersion)
  • Figshare (submittedVersion, cc-by)
  • Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
Funders
  • National Institutes of Health (5r01ag027924-16)
  • National Institute on Aging (R01AG035355, R01-AG027924, P01 AG030128, RF1AG046205, R01AG046205)
  • National Institute of General Medical Sciences (T32GM008497)
  • 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, Alzheimer's disease, amyloid-beta, genetic risk factors, lipid metabolism, tau pathology, neuroenergetics, brain development, synaptic plasticity, neurovasculature, neuroinflammation

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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-17.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-17.

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.

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