CoChat
Sign Up
Cited by 42Treatment of Major DepressionNeurotransmitter Receptor Influence on BehaviorAlzheimer's disease research and treatments

APOE4 genotype exacerbates the depression-like behavior of mice during aging through ATP decline

Open access
Fang, Wenting, Xiao, Naian, Zeng, Guirong, Bi, Daode, Dai, Xiaoman, Mi, Xue, Ye, Qinyong, Chen, Xiaochun +1 more·2021·Translational Psychiatry
DOI 10.1038/s41398-021-01631-0PMC PMC8492798
Open this paper in CoChat — free accountOpen PDF

Abstract

Population-based studies reveal that apolipoprotein E ( APOE ) ε 4 gene allele is closely associated with late-life depression (LLD). However, its exact role and underlying mechanism remain obscure. The current study found that aged apoE4-targeted replacement (TR) mice displayed obvious depression-like behavior when compared with age-matched apoE3-TR mice. Furthermore, apoE4 increased stress-induced depression-like behaviors, accompanied by declines in the hippocampal 5-HT (1A) radioligand [18F] MPPF uptake evidenced by positron emission tomography (PET). In [18F]-fluorodeoxyglucose PET ([18F]-FDG PET) analyses, the FDG uptake in the prefrontal cortex, temporal cortex and hippocampus of apoE4-TR mice significantly declined when compared with that of apoE3-TR mice after acute stress. Further biochemical analysis revealed that ATP levels in the prefrontal cortex of apoE4-TR mice decreased during aging or stress process and ATP supplementation effectively rescued the depression-like behaviors of elderly apoE4-TR mice. In primary cultured astrocytes from the cortex of apoE-TR mice, apoE4, when compared with apoE3, obviously decreased the mitochondrial membrane potential, mitochondrial respiration, and glycolysis in a culture time-dependent manner. Our findings highlight that apoE4 is a potential risk factor of depression in elderly population by impairing the glucose metabolism, reducing ATP level, and damaging mitochondrial functions in astrocytes, which indicates that in clinical settings ATP supplementation may be effective for elderly depression patients with apoE4 carrier.

AI snapshot

Written from the paper’s full text.

TL;DR

In apoE4-targeted replacement mice, APOE4 exacerbated depression-like behavior during aging and after acute stress, with reduced hippocampal 5-HT radioligand uptake and regional glucose metabolism. ATP levels declined in the prefrontal cortex, and ATP supplementation rescued depression-like behaviors in elderly apoE4-TR mice, while apoE4 impaired astrocytic mitochondrial respiration, glycolysis, and membrane potential in long-term culture.

Key findings

  • Aged 18-month apoE4-TR mice showed lower sucrose consumption, longer tail-suspension immobility, and fewer rearings than age-matched apoE3-TR mice (n = 13–16); after forced swim stress, 8-month-old apoE4-TR mice had significantly longer immobility than apoE3-TR mice (n = 8–13), and lower hippocampal [18F]MPPF SUV mean values (n = 7–8).
  • [18F]-FDG PET SUV declined in prefrontal cortex, temporal cortex, and hippocampus after FST in both 3- and 8-month-old groups, with greater declines in apoE4-TR mice; 8-month-old apoE4-TR mice also had lower SUV than age-matched apoE3-TR mice without FST (n = 3 per group).
  • ATP in the prefrontal cortex was significantly lower in 18-month-old apoE4-TR mice than in age-matched apoE3-TR mice (n = 8–13) and in 8-month-old apoE4-TR mice after stress (n = 9); 7-day ATP supplementation (125 mg/kg/day, i.p.) increased prefrontal ATP (n = 6–7) and improved sucrose preference, open-field locomotion, and TST immobility in 18-month-old apoE4-TR mice (n = 10).
  • In primary cortical astrocytes cultured for 2 months, apoE4 expression reduced basal and maximal mitochondrial respiration and glycolysis rate/capacity versus apoE3 (N = 12–16) and increased the JC-1 monomer/aggregate ratio (N = 3); no significant differences were observed after 1 month of culture.

Methods

  • Male human apoE-TR homozygous mice on a C57BL/6J background were tested at 3, 8, and 18 months of age using sucrose preference, tail suspension, open field, and forced swim tests; ATP supplementation was given intraperitoneally once daily for 7 days.
  • Brain 5-HT1A and glucose metabolism were assessed by microPET/CT with [18F]MPPF and [18F]FDG, with SUV quantified in prefrontal cortex, temporal cortex, and hippocampus; ATP content was measured by bioluminescence assay.
  • Primary cortical astrocytes from newborn apoE-TR mice were cultured for 1 or 2 months, then analyzed with Seahorse XF96 for mitochondrial respiration and glycolysis and with JC-1 flow cytometry for mitochondrial membrane potential; statistics used SPSS 22.0 with mean ± SEM, two-way ANOVA with Tukey’s test, two-tailed Student’s t tests, or Mann–Whitney test as appropriate.

Limitations

  • The authors state that long-term cultured astrocytes cannot replace those in aged brains and that future research is needed to explore how apoE4 influences astrocyte function.
  • The authors note that elderly apoE4-TR mice were treated with ATP for only one week and behavioral tests were performed as soon as possible to prevent drug failure, with 24 h rest between the latter two behavioral tests.
  • Evident from the text: PET analyses used n = 3 per group, only male apoE-TR mice were studied, and no human clinical validation is reported.

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

Integrity signals

Registry

Crossref · 10.1038/s41398-021-01631-0

Cites

67 of 67 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

33 of 66 cited sources checked · 14 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    The APOE ε4 allele is associated with late-life depression in humans.

    “Population-based studies reveal that apolipoprotein E (APOE) ε4 gene allele is closely associated with late-life depression (LLD).”
    • Also stated in: § Introduction · hedged
      “APOE ε4 allele can potentially identify people at high risk for clinically significant depression [1–5]”
    Quote in the paperSubstantial claim2 of 5 sources checked
    • cites [1] Yen YC, Rebok GW, Gallo JJ, Yang MJ, Lung FW, Shih CH. ApoE4 allele is associated with late-life depression: a population-based study. Am J Geriatr Psychiatry. 2007;15:858–68. source
    • cites [2] Irwin MR, Olmstead R, Breen EC, Witarama T, Carrillo C, Sadeghi N, et al. Cognitive behavioral therapy and tai chi reverse cellular and genomic markers of inflammation in late-life insomnia: a randomized controlled trial. Biol Psychiatry. 2015;78:721–29. source

      The Introduction (page unavailable) links poor sleep and inflammatory markers to depression, but does not discuss APOE ε4. Searches of our copy for APOE ε4, apolipoprotein E, and a population-based genetic association found no passage addressing the claimed link with late-life depression. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [3] Zhao F, Yue Y, Jiang H, Yuan Y. Shared genetic risk factors for depression and stroke. Prog Neuropsychopharmacol Biol Psychiatry. 2019;93:55–70. source
    • cites [4] Li W, Ban C, Yue L, Sun L, Li X, Xiao S. Homozygosity in the APOE 3 polymorphism is associated with less depression and higher serum low-density lipoprotein in chinese elderly schizophrenics. Front Endocrinol. 2020;11:642. source
    • cites [5] Feng F, Lu SS, Hu CY, Gong FF, Qian ZZ, Yang HY, et al. Association between apolipoprotein E gene polymorphism and depression. J Clin Neurosci. 2015;22:1232–38. source
  • Premisecitation

    Astrocytic atrophy and decreased expression of the astrocyte biomarker GFAP have been documented in both animal depression models and autopsy specimens of depressed patients.

    “astrocytic atrophy and decreased expression of the astrocyte biomarker GFAP have been documented in both animal depression models and autopsy specimens of depressed patients [25]”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [25] Zhou X, Xiao Q, Xie L, Yang F, Wang L, Tu J. Astrocyte, a promising target for mood disorder interventions. Front Mol Neurosci. 2019;12:136. source

      The Human Data section (page unavailable) reports low GFAP levels in postmortem brain specimens from people with mood disorders and lower GFAP-immunoreactive astrocyte density in younger and mixed-age MDD groups. It does not establish astrocytic atrophy and decreased GFAP expression in both animal depression models and depressed patients; it also notes increased GFAP-immunoreactive density in late-onset depression. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
  • Interpretationcitation

    Dysregulation of extracellular ATP is involved in depression-like disorders in rodents.

    “Our data further validate that the dysregulation of extracellular ATP, a significant mediator of astrocyte-neuron communications [61, 62], is involved in depression-like disorders in rodents [24, 63, 64].”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [24] Cao X, Li LP, Wang Q, Wu Q, Hu HH, Zhang M, et al. Astrocyte-derived ATP modulates depressive-like behaviors. Nat Med. 2013;19:773–77. source
    • cites [63] Rietveld L, Stuss DP, McPhee D, Delaney KR. Genotype-specific effects of Mecp2 loss-of-function on morphology of Layer V pyramidal neurons in heterozygous female Rett syndrome model mice. Front Cell Neurosci. 2015;9:145. source

      The Introduction and Abstract discuss Rett syndrome and neuronal morphology, not extracellular ATP or depression-like disorders. Searches of our complete indexed copy for extracellular ATP and depression-like behavior found no passage addressing the claimed link in rodents. (LLM, conf=0.77)

      Experimental — accuracy not yet measured
    • cites [64] Cui QQ, Hu ZL, Hu YL, Chen X, Wang J, Mao L, et al. Hippocampal CD39/ENTPD1 promotes mouse depression-like behavior through hydrolyzing extracellular ATP. EMBO Rep. 2020;21:e47857. source
  • Premisecitation

    Compared with apoE3 at 3 months of age, apoE4 did not aggravate depression-like behaviors under chronic unpredictable mild stress (CUMS).

    “Our previous research has shown that compared with apoE3 at the age of 3 months, apoE4 did not aggravate the depression-like behaviors under chronic unpredictable mild stress (CUMS) [34].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [34] Lin LY, Zhang J, Dai XM, Xiao NA, Wu XL, Wei Z, et al. Early-life stress leads to impaired spatial learning and memory in middle-aged ApoE4-TR mice. Mol Neurodegener. 2016;11:51. source
  • Premisecitation

    The human apoE-TR homozygous male mice express human APOE3 or APOE4 under the mouse APOE promoter, replacing the endogenous mouse APOE.

    “The human apoE-TR homozygous male mice with the C57BL/6J background were purchased from Taconic (www.taconic.com), in which the expression of human APOE3 or APOE4 is controlled by the mouse APOE promoter, replacing the endogenous mouse APOE [26].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [26] Knouff C, Hinsdale ME, Mezdour H, Altenburg MK, Watanabe M, Quarfordt SH, et al. Apo E structure determines VLDL clearance and atherosclerosis risk in mice. J Clin Invest. 1999;103:1579–86. source
  • Classified as probably not a substantial claim. 33
  • May combine two claims. 13
  • The quote only partly states this claim. 1

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    In depression mice models, abnormal energy metabolism features have been documented, including abnormal glucose metabolism, elevated lactate levels, mitochondrial dysfunction, and abnormal ATP levels.

    “In the depression mice model, features of abnormal energy metabolism have also been documented, including abnormal glucose metabolism, elevated lactate levels, mitochondrial dysfunction, and abnormal ATP levels [19–22].”
    Quote in the paperSubstantial claim1 of 4 sources checked
    • cites [19] Tsankova NM, Berton O, Renthal W, Kumar A, Neve RL, Nestler EJ. Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nat Neurosci. 2006;9:519–25. source
    • cites [20] Eranti S, Mogg A, Pluck G, Landau S, Purvis R, Brown RG, et al. A randomized, controlled trial with 6-month follow-up of repetitive transcranial magnetic stimulation and electroconvulsive therapy for severe depression. Am J Psychiatry. 2007;164:73–81. source
    • cites [21] Tsankova NM, Kumar A, Nestler EJ. Histone modifications at gene promoter regions in rat hippocampus after acute and chronic electroconvulsive seizures. J Neurosci. 2004;24:5603–10. source

      The Introduction and Discussion describe histone modifications and gene expression after electroconvulsive seizures in rat hippocampus, not energy metabolism in depression mouse models. Searches for glucose metabolism, lactate, mitochondrial dysfunction, ATP, and energy metabolism found no passage addressing those features. Page numbers were not available in our copy. (LLM, conf=0.77)

      Experimental — accuracy not yet measured
    • cites [22] Dyrvig M, Hansen HH, Christiansen SH, Woldbye DP, Mikkelsen JD, Lichota J. Epigenetic regulation of Arc and c-Fos in the hippocampus after acute electroconvulsive stimulation in the rat. Brain Res Bull. 2012;88:507–13. source

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

    Premisecitation

    In stressful circumstances, APOE ε4 allele carriers are at increased risk of mental illness.

    “in stressful circumstances, APOE ε4 allele carriers are at an increased risk of mental illness [8, 9]”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [8] Yen YC, Rebok GW, Yang MJ, Lung FW. A multilevel analysis of the influence of Apolipoprotein E genotypes on depressive symptoms in late-life moderated by the environment. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32:479–86. source
    • cites [9] Dose J, Huebbe P, Nebel A, Rimbach G. APOE genotype and stress response - a mini review. Lipids Health Dis. 2016;15:121. source

      The Background section links APOE ε4 to increased risk of late-onset Alzheimer’s disease, and the Conclusion discusses its role in cellular stress responses. Neither passage establishes that carriers face increased risk of mental illness in stressful circumstances. Searches for mental illness, psychiatric conditions, and psychosocial stress found no passage addressing that claim. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    The apoE4 (1-272) fragment interacts directly with mitochondria, resulting in mitochondrial dysfunction and neurotoxicity.

    “apoE4 (1-272) fragment appears to interact directly with mitochondria, resulting in mitochondrial dysfunction and neurotoxicity [13]”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [13] Chang S, ran Ma T, Miranda RD, Balestra ME, Mahley RW, Huang Y. Lipid- and receptor-binding regions of apolipoprotein E4 fragments act in concert to cause mitochondrial dysfunction and neurotoxicity. Proc Natl Acad Sci USA. 2005;102:18694–99. source

  • Classified as probably not a substantial claim.

    Premisecitation

    APOE4 increases the sensitivity of cells to oxidative stress.

    “APOE4 increases the sensitivity of cells to oxidative stress”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [13] Chang S, ran Ma T, Miranda RD, Balestra ME, Mahley RW, Huang Y. Lipid- and receptor-binding regions of apolipoprotein E4 fragments act in concert to cause mitochondrial dysfunction and neurotoxicity. Proc Natl Acad Sci USA. 2005;102:18694–99. source

      The Abstract lists impairment of the antioxidative defense system among proposed apoE4-related mechanisms, which is consistent with greater vulnerability to oxidative stress. But the paper does not report a test showing that APOE4 increases cells’ sensitivity to oxidative stress; its cell experiments assess neurotoxicity and mitochondrial function, not responses to an oxidative challenge. (LLM, conf=0.78)

      Experimental — accuracy not yet measured

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

    Premisecitation

    In the central nervous system, apoE is mainly secreted by astrocytes, with different isoforms playing distinct roles in lipid metabolism and nervous system homeostasis.

    “In the central nervous system (CNS), apoE is mainly secreted by astrocytes, with different isoforms playing distinct roles in lipid metabolism and nervous system homeostasis [11, 12].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [11] Huang Y, Mahley RW. Apolipoprotein E: structure and function in lipid metabolism, neurobiology, and Alzheimer’s diseases. Neurobiol Dis. 2014;72:3–12. source
    • cites [12] Gong JS, Kobayashi M, Hayashi H, Zou K, Sawamura N, Fujita SC, et al. Apolipoprotein E (ApoE) isoform-dependent lipid release from astrocytes prepared from human ApoE3 and ApoE4 knock-in mice. J Biol Chem. 2002;277:29919–26. source

      The Discussion (page not provided) reports that apoE3-expressing astrocytes release more lipid than apoE4-expressing astrocytes and suggests a resulting difference in cholesterol supply to neurons, supporting the isoform-dependent lipid-metabolism point. The Results (page not provided) show apoE release from cultured astrocytes, but the paper does not establish that astrocytes are the main source of secreted apoE throughout the CNS. Its proposed effects on neuronal plasticity and regeneration are narrower than a general claim about nervous system homeostasis. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    The APOE ε4 allele is associated with severer depressive symptoms.

    “and is associated with severer depressive symptoms [7]”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [7] Holmes SE, Esterlis I, Mazure CM, Lim YY, Ames D, Rainey-Smith S, et al. beta-Amyloid, APOE and BDNF genotype, and depressive and anxiety symptoms in cognitively normal older women and men. Am J Geriatr Psychiatry. 2016;24:1191–95. source

  • Classified as probably not a substantial claim.

    Premisecitation

    Previous studies reported that ATP decline is involved in the biological mechanism of MDD.

    “Previous studies have reported that ATP decline is involved in the biological mechanism of MDD [24, 31].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [24] Cao X, Li LP, Wang Q, Wu Q, Hu HH, Zhang M, et al. Astrocyte-derived ATP modulates depressive-like behaviors. Nat Med. 2013;19:773–77. source
    • cites [31] Culmsee C, Michels S, Scheu S, Arolt V, Dannlowski U, Alferink J. Mitochondria, microglia, and the immune system-how are they linked in affective disorders? Front Psychiatry. 2018;9:739. source

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

    Premisecitation

    Astrocytic apoE4 increases tau-induced synaptic loss and microglia phagocytosis of synaptic elements.

    “Studies have documented that astrocytic apoE4 increases tau-induced synaptic loss and microglia phagocytosis of synaptic elements [48]”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [48] Wang C, Xiong M, Gratuze M, Bao X, Shi Y, Andhey PS, et al. Selective removal of astrocytic APOE4 strongly protects against tau-mediated neurodegeneration and decreases synaptic phagocytosis by microglia. Neuron. 2021;109:1657–74. source

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

    Premisecitation

    ApoE4-expressing astrocytes affect glucose utilization, including increases in lactate synthesis, PPP flux, and de novo biosynthesis pathways.

    “and affect glucose utilization, including increases in lactate synthesis, PPP flux, and de novo biosynthesis pathways [54].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [54] Williams HC, Farmer BC, Piron MA, Walsh AE, Bruntz RC, Gentry MS, et al. APOE alters glucose flux through central carbon pathways in astrocytes. Neurobiol Dis. 2020;136:104742. source

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

    Premisecitation

    Changes in mitochondrial DNA and cell membrane permeability were found in both depression patients and animal models of depression.

    “Changes in mitochondrial DNA and cell membrane permeability were found in both depression patients and animal models of depression [32, 33].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [32] Tobe EH. Mitochondrial dysfunction, oxidative stress, and major depressive disorder. Neuropsychiatr Dis Treat. 2013;9:567–73. source

      The Animal studies section reports mtDNA defects in many patients with mood disorder and describes changes in mitochondrial membrane permeability in rats. But the rat experiment was a model of epilepsy, not depression, and the passage concerns a mitochondrial membrane rather than cell membrane permeability. The paper therefore does not establish both changes in both depression patients and animal models of depression. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [33] Caruso G, Benatti C, Blom J, Caraci F, Tascedda F. The many faces of mitochondrial dysfunction in depression: from pathology to treatment. Front Pharm. 2019;10:995. source

      The “Mitochondria and Depressive Disorders” section (page unavailable) reports elevated circulating cell-free mitochondrial DNA in patients with major depression and dissipated mitochondrial membrane potential in a mouse model. It does not report changes in mitochondrial DNA in the animal model or changes in cell membrane permeability in either group; membrane potential is a different measure. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Ca hyperactivity associated with ApoE4 is found in astrocytes from targeted replacement mice.

    “Ca hyperactivity associated with ApoE4 is found in astrocytes from targeted replacement mice [52].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [52] Larramona-Arcas R, González-Arias C, Perea G, Gutiérrez A, Vitorica J, García-Barrera T, et al. Sex-dependent calcium hyperactivity due to lysosomal-related dysfunction in astrocytes from APOE4 versus APOE3 gene targeted replacement mice. Mol Neurodegener. 2020;15:35. source

      The Discussion reports Ca2+ hyperactivity in astrocytes from APOE4 targeted replacement male mice, but not females. The claim omits that sex-specific limitation. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Depressive symptoms may be direct manifestations of AD pathophysiology at the preclinical stage, prior to the onset of mild cognitive impairment.

    “Depressive symptoms may be direct manifestations of AD pathophysiology at the preclinical stage, prior to the onset of mild cognitive impairment [37–39].”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [37] Solas M, Aisa B, Mugueta MC, Del Río J, Tordera RM, Ramírez MJ. Interactions between age, stress and insulin on cognition: implications for Alzheimer’s disease. Neuropsychopharmacology. 2010;35:1664–73. source

      The Introduction describes major depression as a risk factor for developing AD, not as a direct manifestation of preclinical AD pathophysiology. Searches for depressive symptoms as a prodrome and for mild cognitive impairment found no passage addressing whether symptoms occur before its onset. (LLM, conf=0.72)

      Experimental — accuracy not yet measured
    • cites [38] Herbert J, Lucassen PJ. Depression as a risk factor for Alzheimer’s disease: Genes, steroids, cytokines and neurogenesis - What do we need to know? Front Neuroendocrinol. 2016;41:153–71. source

      Section 1 (Epidemiological evidence; page not supplied) proposes that even early depression may reflect a progressive neuropathological process leading to AD, supporting the claim as a possibility. It does not establish that depressive symptoms occur before mild cognitive impairment; that specific timing is unsupported by the cited passages. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [39] Ismail Z, Elbayoumi H, Fischer CE, Hogan DB, Millikin CP, Schweizer T, et al. Prevalence of depression in patients with mild cognitive impairment: a systematic review and meta-analysis. JAMA Psychiatry. 2017;74:58–67. source

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

    Premisecitation

    There are approximately as many studies of APOE ε4 and depression that report positive results as those that find null results.

    “there are approximately as many studies of APOE ε4 and depression that report positive results as those that find null results [2].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [2] Irwin MR, Olmstead R, Breen EC, Witarama T, Carrillo C, Sadeghi N, et al. Cognitive behavioral therapy and tai chi reverse cellular and genomic markers of inflammation in late-life insomnia: a randomized controlled trial. Biol Psychiatry. 2015;78:721–29. source

      The Methods and Results passages concern inflammatory markers in a late-life insomnia trial, while the References mention depression without addressing APOE ε4. Searches for APOE ε4, apolipoprotein E, and positive versus null depression findings found no passage in our copy comparing those studies. (LLM, conf=0.75)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Antidepressant effects of low-dose ketamine and transcranial magnetic stimulation can improve cerebral glucose metabolism in these regions.

    “Antidepressant effects of low-dose ketamine [56] and transcranial magnetic stimulation can improve the cerebral glucose metabolism in these regions [57–60].”
    Quote in the paperNot a substantial claim3 of 5 sources checked
    • cites [56] Lally N, Nugent AC, Luckenbaugh DA, Niciu MJ, Roiser JP, Zarate CA Jr. Neural correlates of change in major depressive disorder anhedonia following open-label ketamine. J Psychopharmacol. 2015;29:596–607. source

      The Abstract reports that reduced anhedonia after ketamine correlated with increased glucose metabolism in the hippocampus and dACC, but with decreased metabolism in the inferior frontal gyrus and OFC. The Discussion calls the imaging findings tentative because the ketamine study lacked a placebo control. Thus the paper supports an association between ketamine response and metabolic changes in specific regions, not a general claim that ketamine improves metabolism across the regions referred to; the sentence cites other sources for transcranial magnetic stimulation. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [57] Carlson PJ, Diazgranados N, Nugent AC, Ibrahim L, Luckenbaugh DA, Brutsche N, et al. Neural correlates of rapid antidepressant response to ketamine in treatment-resistant unipolar depression: a preliminary positron emission tomography study. Biol Psychiatry. 2013;73:1213–21. source

      The Results (page unavailable) report that low-dose ketamine changed regional glucose metabolism in participants with treatment-resistant depression, with increases in some regions and decreases in others; whole-brain metabolism did not change significantly. The source therefore supports a regional metabolic effect, but not a general claim that ketamine improved metabolism in the unspecified ‘these regions.’ Transcranial magnetic stimulation is cited to other sources in the sentence and is not assessed here. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [58] Chen MH, Li CT, Lin WC, Hong CJ, Tu PC, Bai YM, et al. Persistent antidepressant effect of low-dose ketamine and activation in the supplementary motor area and anterior cingulate cortex in treatment-resistant depression: A randomized control study. J Affect Disord. 2018;225:709–14. source
    • cites [59] Paillère Martinot ML, Martinot JL, Ringuenet D, Galinowski A, Gallarda T, Bellivier F, et al. Baseline brain metabolism in resistant depression and response to transcranial magnetic stimulation. Neuropsychopharmacology. 2011;36:2710–19. source

      The Introduction says high-frequency TMS aims to increase metabolism in prefrontal areas and notes its clinical effectiveness in treatment-resistant depression. But the study measured glucose metabolism before stimulation, not whether TMS improved it afterward; it therefore does not establish the claimed metabolic improvement. The ketamine claim is attached to a different citation and is not assessed here. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [60] Malizia AL. Receptor binding and drug modulation in anxiety. Eur Neuropsychopharmacol. 2002;12:567–74. source

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

    Premisecitation

    Patients suffering from AD are more prone to comorbid depression.

    “Patients suffering from AD are more prone to comorbid depression [40, 41]”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [40] Novais F, Starkstein S. Phenomenology of depression in Alzheimer’s disease. J Alzheimers Dis. 2015;47:845–55. source

      The available passages from our copy contain the title and bibliographic metadata, but no finding about whether patients with Alzheimer’s disease are more prone to depression. Searches for depression prevalence and comparisons with people without Alzheimer’s disease returned no relevant passage. (LLM, conf=0.73)

      Experimental — accuracy not yet measured
    • cites [41] Orgeta V, Tabet N, Nilforooshan R, Howard R. Efficacy of antidepressants for depression in Alzheimer’s disease: systematic review and meta-analysis. J Alzheimers Dis. 2017;58:725–33. source

      The Introduction says depression is one of the most common neuropsychiatric symptoms in AD and that up to 50% of patients experience depression or clinically significant depressive symptoms. It does not compare patients with AD to people without AD, so the claim that they are *more prone* to depression is not established by this source. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Astrocytes play a vital role in the pathophysiology of depression.

    “Astrocytes, the most abundant glial cells of the brain, play a vital role in the pathophysiology of depression [25]”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [25] Zhou X, Xiao Q, Xie L, Yang F, Wang L, Tu J. Astrocyte, a promising target for mood disorder interventions. Front Mol Neurosci. 2019;12:136. source

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    ApoE4 (1-272) fragments can directly interact with mitochondria, causing mitochondrial dysfunction and neurotoxicity.

    “Available literature also shows that apoE4 (1-272) fragments can directly interact with mitochondria, causing mitochondrial dysfunction and neurotoxicity [13].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [13] Chang S, ran Ma T, Miranda RD, Balestra ME, Mahley RW, Huang Y. Lipid- and receptor-binding regions of apolipoprotein E4 fragments act in concert to cause mitochondrial dysfunction and neurotoxicity. Proc Natl Acad Sci USA. 2005;102:18694–99. source

  • May combine two claims.

    Premisecitation

    Astrocytes secrete adenosine ATP, which modulates depression-like behaviors.

    “and secrete adenosine ATP, which modulates depression-like behaviors [65, 66].”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [65] Xiong W, Cao X, Zeng Y, Qin X, Zhu M, Ren J, et al. Astrocytic epoxyeicosatrienoic acid signaling in the medial prefrontal cortex modulates depressive-like behaviors. J Neurosci. 2019;39:4606–23. source
    • cites [66] Ma J, Qi X, Yang C, Pan R, Wang S, Wu J, et al. Calhm2 governs astrocytic ATP releasing in the development of depression-like behaviors. Mol Psychiatry. 2018;23:883–91. source

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

    Premisecitation

    ApoE4-expressing astrocytes alter mitochondrial dynamics and function.

    “ApoE4-expressing astrocytes alter mitochondrial dynamics and function [53]”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [53] Schmukler E, Solomon S, Simonovitch S, Goldshmit Y, Wolfson E, Michaelson DM, et al. Altered mitochondrial dynamics and function in APOE4-expressing astrocytes. Cell Death Dis. 2020;11:578. source

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

    Premisecitation

    An early-life depression event elevates the subsequent AD risk.

    “An early-life depression event elevates the subsequent AD risk [34].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [34] Lin LY, Zhang J, Dai XM, Xiao NA, Wu XL, Wei Z, et al. Early-life stress leads to impaired spatial learning and memory in middle-aged ApoE4-TR mice. Mol Neurodegener. 2016;11:51. source

      The Background (page unavailable) says early-life depressive symptoms may increase the risk of cognitive impairment in old age. It does not establish that an early-life depressive episode increases subsequent Alzheimer’s disease risk; the AD-risk finding it discusses concerns late-onset depression together with APOE4. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

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

    Premisecitation

    ApoE4 disrupts intracellular lipid homeostasis.

    “ApoE4 disrupts intracellular lipid homeostais [50]”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [50] Sienski G, Narayan P, Bonner JM, Kory N, Boland S, Arczewska AA. et al., APOE4 disrupts intracellular lipid homeostasis in human iPSC-derived glia. Sci Transl Med. 2021;13:eaaz4564. source

  • Classified as probably not a substantial claim.

    Premisecitation

    Stimulation of ATP release in astrocytes produces an antidepressant effect.

    “while stimulation of ATP release in astrocytes produces an antidepressant effect [24]”
    • Also stated in: § APOE ε4 allele shows a culture-time-dependent damage to mitochondrial respiration and glycolysis of primary astrocytes · plain
      “stimulation of ATP release in astrocytes can bring about the antidepressant effect [24]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [24] Cao X, Li LP, Wang Q, Wu Q, Hu HH, Zhang M, et al. Astrocyte-derived ATP modulates depressive-like behaviors. Nat Med. 2013;19:773–77. source

  • Classified as probably not a substantial claim.

    Premisecitation

    Insufficient ATP release in astrocytes leads to depression-like behaviors.

    “Studies have shown that insufficient ATP release in astrocytes leads to depression-like behaviors”
    • Also stated in: § APOE ε4 allele shows a culture-time-dependent damage to mitochondrial respiration and glycolysis of primary astrocytes · plain
      “insufficient ATP release in astrocytes leads to depression-like behaviors”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [24] Cao X, Li LP, Wang Q, Wu Q, Hu HH, Zhang M, et al. Astrocyte-derived ATP modulates depressive-like behaviors. Nat Med. 2013;19:773–77. source

  • Classified as probably not a substantial claim.

    Premisecitation

    The APOE ε4 allele is associated with an earlier onset age of late-life depression.

    “forwarding the onset age of late-life depression (LLD) [6]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6] Butters MA, Sweet RA, Mulsant BH, Ilyas Kamboh M, Pollock BG, Begley AE, et al. APOE is associated with age-of-onset, but not cognitive functioning, in late-life depression. Int J Geriatr Psychiatry. 2003;18:1075–81. source

  • May combine two claims.

    Interpretationown data

    apoE4-TR mice show age-dependent declines in cerebral glucose metabolism, which is further significantly exacerbated under acute stress.

    “The above results indicate that apoE4-TR mice show age-dependent declines in cerebral glucose metabolism, which is further significantly exacerbated under acute stress.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    PET examination has reported decreased blood flow and impaired glucose metabolism in the caudate nucleus, anterior cingulate cortex, and prefrontal cortex of patients with depression.

    “PET examination has reported decreased blood flow and impaired glucose metabolism in the caudate nucleus, anterior cingulate cortex, and prefrontal cortex of patients with depression [14, 17].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [14] Videbech P. PET measurements of brain glucose metabolism and blood flow in major depressive disorder: a critical review. Acta Psychiatr Scand. 2000;101:11–20. source
    • cites [17] Drevets WC. Neuroimaging and neuropathological studies of depression: implications for the cognitive-emotional features of mood disorders. Curr Opin Neurobiol. 2001;11:240–49. source

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

    Premisecitation

    APOE4 is the strongest risk factor for late-onset Alzheimer's disease.

    “It is well known that APOE4 is the strongest risk factor for late-onset Alzheimer’s disease [36].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36] Pericak-Vance MA, Bass MP, Yamaoka LH, Gaskell PC, Scott WK, Terwedow HA, et al. Complete genomic screen in late-onset familial Alzheimer disease. Evidence for a new locus on chromosome 12. JAMA. 1997;278:1237–41. source

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

    Premisecitation

    Astrocytic apoE is involved in the regulation of synaptic pruning, suggesting a key role for astrocytic apoE in synaptic integrity.

    “and that it is involved in the regulation of synaptic pruning, which suggests a key role for astrocytic apoE in synaptic integrity [49].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Chung WS, Verghese PB, Chakraborty C, Joung J, Hyman BT, Ulrich JD, et al. Novel allele-dependent role for APOE in controlling the rate of synapse pruning by astrocytes. Proc Natl Acad Sci USA. 2016;113:10186–91. source

  • The quote only partly states this claim.

    Interpretationown data

    Decline in ATP levels in the PFC contributes to depression-like behaviors of apoE4-TR mice regardless of aging or stress scenarios.

    “the decline in ATP levels in the PFC contributes to the depression-like behaviors of the apoE4-TR mice”
    Quote in the paperSubstantial claim

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

    Premisecitation

    In animal models of Alzheimer's disease, astrocytes undergo degeneration and atrophy at the early stages of pathological progression.

    “In animal models of Alzheimer’s disease (AD), astrocytes undergo degeneration and atrophy at the early stages of pathological progression [55].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] Rodríguez-Arellano JJ, Parpura V, Zorec R, Verkhratsky A. Astrocytes in physiological aging and Alzheimer’s disease. Neuroscience. 2016;323:170–82. source

  • May combine two claims.

    Interpretationown data

    ApoE4 plays an age-dependent role in depression and cognitive decline.

    “ApoE4 plays an age-dependent role in depression and cognitive decline”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Patients with major depressive disorder have decreased glucose metabolism in the prefrontal cortex (PFC), dorsal anterior cingulated cortex (dACC).

    “Accumulating evidence suggests that patients with major depressive disorder have decreased glucose metabolism in the prefrontal cortex (PFC), dorsal anterior cingulated cortex (dACC) [14].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Videbech P. PET measurements of brain glucose metabolism and blood flow in major depressive disorder: a critical review. Acta Psychiatr Scand. 2000;101:11–20. source

  • May combine two claims.

    Interpretationown data

    ApoE4 mediates declines in glucose metabolism and ATP level, which contributes to depression-like phenotypes during aging.

    “ApoE4 mediates the declines in glucose metabolism and ATP level, which contributes to the depression-like phenotypes during aging.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Depressed people often have impaired cognition.

    “depressed people often have impaired cognition [42–44].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [42] Culpepper L, Lam RW, McIntyre RS. Cognitive impairment in patients with depression: awareness, assessment, and management. J Clin Psychiatry. 2017;78:1383–94. source
    • cites [43] Knight MJ, Baune BT. Cognitive dysfunction in major depressive disorder. Curr Opin Psychiatry. 2018;31:26–31. source
    • cites [44] McIntyre RS, Xiao HX, Syeda K, Vinberg M, Carvalho AF, Mansur RB, et al. The prevalence, measurement, and treatment of the cognitive dimension/domain in major depressive disorder. CNS Drugs. 2015;29:577–89. source

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

    Premisecitation

    ApoE4 diminishes neurotrophic function of human iPSC-derived astrocytes.

    “and diminishes neurotrophic function of human iPSC-derived astrocytes [51].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] Zhao J, Davis MD, Martens YA, Shinohara M, Graff-Radford NR, Younkin SG, et al. APOE epsilon4/epsilon4 diminishes neurotrophic function of human iPSC-derived astrocytes. Hum Mol Genet. 2017;26:2690–700. source

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

    Study design and conductnone given

    Behavioral tests used double-blind tests.

    “In the behavioral tests, we used double-blind tests.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    apoE4 is a potential risk factor of depression in the elderly population by impairing glucose metabolism, reducing ATP level, and damaging mitochondrial functions in astrocytes.

    “Our findings highlight that apoE4 is a potential risk factor of depression in elderly population by impairing the glucose metabolism, reducing ATP level, and damaging mitochondrial functions in astrocytes”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Findings in apoE4-TR mice and mouse depression-like behaviors translate to elderly human depression and clinical ATP response.

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

    Study design and conductnone given

    Animals were divided into saline treatment group and ATP supplement group according to the random number table.

    “Animals were divided into saline treatment group and ATP supplement group according to the random number table.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

    Study design and conductnone given

    Long-term cultured astrocytes cannot replace those in aged brains.

    “Of course, the long-term cultured astrocytes cannot replace those in aged brains.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    APOE4 is a major genetic risk factor for cognitive impairment and depression in the elderly population.

    “Taken together, APOE4 is a major genetic risk factor for cognitive impairment and depression in the elderly population.”
    Quote in the paperSubstantial claim
40 of 40

  • The paper relies on this without support.

    Findings in apoE4-TR mice and mouse depression-like behaviors translate to elderly human depression and clinical ATP response.

    “which indicates that in clinical settings ATP supplementation may be effective for elderly depression patients with apoE4 carrier.”
    “Our findings highlight that apoE4 is a potential risk factor of depression in elderly population by impairing the glucose metabolism, reducing ATP level, and damaging mitochondrial functions in astrocytes”

  • The paper relies on this without support.

    The 18-month-old apoE4-TR mouse corresponds to an elderly human population.

    “the 18-month-old apoE4-TR mice”
    “elderly apoE4-TR mice”

  • The paper relies on this without support.

    ApoE is mainly expressed in astrocytes in normal adult human brain.

    “ApoE is mainly expressed in astrocytes in normal adult human brain.”

  • The paper relies on this without support.

    Mitochondria are the main organelles that produce ATP.

    “Mitochondria are the main organelles that produce ATP.”

  • The paper relies on this without support.

    Depression and AD are strongly associated.

    “Depression and AD are strongly associated.”

  • The paper relies on this without support.

    Glucose is the major energy source for the brain and is metabolized into ATP via glycolysis, the tricarboxylic acid (TCA) cycle and the electron transport chain (ETC).

    “Normally, glucose is the major energy source for the brain and is metabolized into ATP via glycolysis, the tricarboxylic acid (TCA) cycle and the electron transport chain (ETC).”

  • The paper relies on this without support.

    Astrocytes are the most abundant glial cells of the brain.

    “Astrocytes, the most abundant glial cells of the brain”
7 of 7

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 age-dependent impairments in cerebral glucose metabolism independent of Aβ accumulation and reduces ATP production in mouse prefrontal cortex.

    “APOE4 is associated with age-dependent impairments in cerebral glucose metabolism independent of Aβ accumulation (Jagust et al., 2012) and reduces ATP production in mouse prefrontal cortex (Fang et al., 2021).”

    From APOE4 reduces hippocampal expression of phosphoglycerate kinase 1 and sodium potassium pump to enhance seizure susceptibility in mice (2026) · cites this paper as Fang et al., 2021

    The Results section on ATP supplementation reports lower prefrontal-cortex ATP concentrations in 18-month-old apoE4 mice and in 8-month-old apoE4 mice after stress, compared with age-matched apoE3 mice. This supports an ATP decline under those conditions, but the paper measures ATP levels rather than ATP production directly. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Some studies found that APOE4 reduced glycolysis, whereas others observed a shift from oxidative to glycolytic metabolism in APOE4 cells with higher glycolytic activity in APOE4 than APOE3.

    “Some studies found that APOE4 reduced glycolysis [28,39], whereas others observed a shift from oxidative to glycolytic metabolism in APOE4 cells with higher glycolytic activity in APOE4 than APOE3 [40,41,42].”

    From APOE4 Increases Energy Metabolism in APOE-Isogenic iPSC-Derived Neurons (2024) · cites this paper as [39]

  • The effects of APOE on OCR and ECAR in APOE4 astrocytes were not prominent after 1 month but became evident after 2 months of culture.

    “Similarly, Fang and colleagues found that the effects of APOE on OCR and ECAR in APOE4 astrocytes were not prominent after 1 month but became evident after 2 months of culture (Fang et al., 2021).”

    From APOE genotype-dependent differences in human astrocytic energy metabolism (2025) · cites this paper as Fang et al., 2021

  • APOE4 is associated with cortical ATP decline and age-dependent impairments in cerebral glucose uptake and metabolism independent of Aβ accumulation.

    “APOE4 is previously shown to be associated with cortical ATP decline (Fang et al., 2021) and age-dependent impairments in cerebral glucose uptake and metabolism independent of Aβ accumulation (Jagust et al., 2012).”

    From APOE4 reduces hippocampal expression of phosphoglycerate kinase 1 and sodium potassium pump to enhance seizure susceptibility in mice (2026) · cites this paper as Fang et al., 2021

  • Many contradictory results on the impact of APOE on energy metabolism have been published.

    “In general, many contradictory results on the impact of APOE on energy metabolism have been published.”

    From APOE4 Increases Energy Metabolism in APOE-Isogenic iPSC-Derived Neurons (2024) · cites this paper as [39]

    The Introduction describes reports of reduced brain glucose metabolism in APOE ε4 carriers, and the Results and Discussion describe this study’s age- or culture-dependent findings. None of those passages says that many published findings on APOE and energy metabolism contradict one another; searches for contradictory or inconsistent findings did not locate such a discussion. (LLM, conf=0.72)

    Experimental — accuracy not yet measured

Cites

Flagged first, then by citations

3 of the 70 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

Authors
Fang, W., Xiao, N., Zeng, G., Bi, D., Dai, X., Mi, X., Ye, Q., Chen, X., & Zhang, J.
Affiliations
Fujian Medical University (CN)
Corresponding author
  • Chen, Xiaochun
  • Zhang, Jing
ORCID
Venue
Translational Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2021-10-05
Volume
11
Issue
1
Pages
507-507
ISSN
2158-3188 (ISSN-L)
DOI
10.1038/s41398-021-01631-0
PMC
PMC8492798
OpenAlex
W3201680124
Cited by
42
References
70
Citations by year
2026: 5 · 2025: 13 · 2024: 11 · 2023: 7 · 2022: 6
FWCI
3.50
Type
journal article
Language
en
Update notices
correction (2021-11-28)
Open access
Licence
Locations
  • Translational Psychiatry (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Natural Science Foundation of China (81401149, 81871068, 81671352, 2018Y9095, 2018Y9057, 91232709)
Topics
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
APOE ε4, geriatric depression, depression-like behavior, aging, glucose metabolism, astrocytes, mitochondrial dysfunction, mitochondrial membrane potential, mitochondrial respiration, glycolysis, stress-induced depression, 18F-FDG PET, APOE3
MeSH terms
Adenosine Triphosphate, Aged, Animals, Depression, Genotype, Humans, Mice, Transgenic, Mice, Apolipoprotein E4

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 2026-11-02.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-11-02.

Cited sources are checked by gpt-6-sol.

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 ›

Are you an author, or do you see a problem with this page? Request a review