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Cited by 21Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsAdvanced Neuroimaging Techniques and Applications

The DOI matches its Crossref record; 57 of the 59 references it cites were found in a registry or an index; 32 of the 53 sources its claims cite were checked for support.

Effects of APOE2 and APOE4 on brain microstructure in older adults: modification by age, sex, and cognitive status

Open access
Reas, Emilie T., Triebswetter, Curtis, Banks, Sarah J., McEvoy, Linda K.·2024·Alzheimer's Research & Therapy
DOI 10.1186/s13195-023-01380-wPMC PMC10782616
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Abstract

Background: APOE4 is the strongest genetic risk factor for sporadic Alzheimer’s disease (AD), whereas APOE2 confers protection. However, effects of APOE on neurodegeneration in cognitively intact individuals, and how these associations evolve with cognitive decline, are unclear. Furthermore, few studies have evaluated whether effects of APOE on neurodegenerative changes are modified by other AD key risk factors including age and sex. Methods: Participants included older adults (57% women; 77 ± 7 years) from the Rancho Bernardo Study of Health Aging and the University of California San Diego Alzheimer’s Disease Research Center, including 192 cognitively normal (CN) individuals and 33 with mild cognitive impairment. Participants underwent diffusion MRI, and multicompartment restriction spectrum imaging (RSI) metrics were computed in white matter, gray matter, and subcortical regions of interest. Participants were classified as APOE4 carriers,APOE2 carriers, and APOE3 homozygotes. Analysis of covariance among CN (adjusting for age, sex, and scanner) assessed differences in brain microstructure by APOE, as well as interactions between APOE and sex. Analyses across all participants examined interactions between APOE4 and cognitive status. Linear regressions assessed APOE by age interactions. Results: Among CN,APOE4 carriers showed lower entorhinal cortex neurite density than non-carriers, whereas APOE2 carriers showed lower cingulum neurite density than non-carriers. Differences in entorhinal microstructure by APOE4 and in entorhinal and cingulum microstructure by APOE2 were present for women only. Age correlated with lower entorhinal restricted isotropic diffusion among APOE4 non-carriers, whereas age correlated with lower putamen restricted isotropic diffusion among APOE4 carriers. Differences in microstructure between cognitively normal and impaired participants were stronger for APOE4-carriers in medial temporal regions, thalamus, and global gray matter, but stronger for non-carriers in caudate. Conclusions: The entorhinal cortex may be an early target of neurodegenerative changes associated with APOE4 in presymptomatic individuals, whereas APOE2 may support beneficial white matter and entorhinal microstructure, with potential sex differences that warrant further investigation.APOE modifies microstructural patterns associated with aging and cognitive impairment, which may advance the development of biomarkers to distinguish microstructural changes characteristic of normal brain aging,APOE-dependent pathways, and non-AD etiologies.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

In older adults, APOE4 was associated with lower entorhinal cortex neurite density among cognitively normal individuals, while APOE2 was associated with lower cingulum neurite density. APOE also modified age- and cognitive-status-related microstructural patterns, with several effects observed only in women.

Key findings

  • Among cognitively normal participants, APOE4 carriers had lower entorhinal cortex neurite density than non-carriers (F(1,187) = 4.46, p = 0.04); this difference was present in women (F(1,115) = 4.90, p = 0.03) but not men (F(1,69) = 0.25, p = 0.62).
  • Among cognitively normal participants, cingulum neurite density differed by APOE2 (F(2,185) = 5.42, p = 0.005), with lower neurite density for APOE2/3 than APOE3/3 and APOE4 carriers; this was present in women (F(2,114) = 6.33, p = 0.002) but not men (F(2,67) = 0.70, p = 0.50).
  • Age interacted with APOE4 for entorhinal restricted isotropic diffusion (p = 0.02), with older age correlated with lower RI among APOE4 non-carriers (p < 0.001) but not carriers (p = 0.88); APOE also interacted with age for putamen RI (p = 0.003), with age-related decline only in APOE4 carriers.
  • APOE4 interacted with cognitive status for hippocampal IF and HI (p < 0.05) and entorhinal HI (p = 0.004); differences were more pronounced for APOE4 carriers in medial temporal regions, thalamus, and global gray matter, but stronger for non-carriers in caudate.

Methods

  • Cross-sectional study of 225 older adults (139 Rancho Bernardo Study, 86 UC San Diego ADRC; 192 cognitively normal, 33 cognitively impaired; 57% women; mean age 76.5 ± 7.0 years) who completed diffusion MRI and had APOE genotype data.
  • Restriction spectrum imaging (RSI) metrics—restricted isotropic diffusion, neurite density, hindered isotropic diffusion, and isotropic free water—were computed in white matter, gray matter, and subcortical regions of interest, including entorhinal cortex, hippocampus, cingulum, and other limbic/association fibers.
  • Analyses used ANCOVA among cognitively normal participants adjusting for age, sex, and scanner; linear regressions tested APOE-by-age interactions; ANCOVAs across all participants tested APOE4-by-cognitive-status interactions, with Bonferroni correction for fibers/subcortical regions and FDR for cortical surface analyses.

Limitations

  • The paper states that AD biomarker characterization was not available for the full sample, precluding inclusion of amyloid and tau in statistical analyses; the study was cross-sectional; the sample was almost entirely non-Hispanic White; there were few APOE4 homozygotes and no APOE2 homozygotes; and RSI cannot directly image cell morphometry or establish physiological mechanisms.
  • The paper notes that sex-by-APOE interactions did not reach significance, so sex-stratified findings require replication in larger datasets.
  • The text makes evident that a priori entorhinal/hippocampal analyses did not adjust for multiple comparisons across regions, and whole-brain exploratory cortical surface analyses found no significant APOE differences, warranting caution about regional specificity.

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

Integrity signals

Registry

Crossref · 10.1186/s13195-023-01380-w

Cites

57 of 57 references verified0 citation errors · 0 not checkable

Statistics

Verification

Claims the paper makes

32 of 53 cited sources checked · 24 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Prior diffusion MRI studies have identified microstructural white matter abnormalities in cognitively normal older APOE4 carriers, including increased mean diffusivity and reduced fractional anisotropy or restricted diffusion.

    “Diffusion MRI studies have identified microstructural white matter (WM) abnormalities in cognitively normal older APOE4 carriers, including increased mean diffusivity and reduced fractional anisotropy or restricted diffusion [3–5]”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [3] Adluru N, Destiche DJ, Lu SY-F, Doran ST, Birdsill AC, Melah KE, Okonkwo OC, Alexander AL, Dowling NM, Johnson SC, et al. White matter microstructure in late middle-age: effects of apolipoprotein E4 and parental family history of Alzheimer’s disease. NeuroImage Clin. 2014;4:730–42. source

      The Abstract Results and Discussion Summary report higher mean diffusivity in cognitively healthy older APOE4 carriers than in non-carriers. They do not report reduced fractional anisotropy or restricted diffusion in those carriers; lower axial diffusivity was observed in participants with parental family history who did not carry APOE4. Page numbers are unavailable in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [4] Cavedo E, Lista S, Rojkova K, Chiesa PA, Houot M, Brueggen K, Blautzik J, Bokde ALW, Dubois B, Barkhof F, et al. Disrupted white matter structural networks in healthy older adult APOE ε4 carriers – An international multicenter DTI study. Neuroscience. 2017;357:119–33. source
    • cites [5] Kljajevic V, Meyer P, Holzmann C, Dyrba M, Kasper E, Bokde ALW, Fellgiebel A, Meindl T, Hampel H, Teipel S. The ε4 genotype of apolipoprotein E and white matter integrity in Alzheimer’s disease. Alzheimers Dement. 2014;10(3):401–4. source
  • Premisecitation

    More recent investigations have interrogated cortical or subcortical gray matter with inconclusive findings.

    “more recent investigations have interrogated cortical or subcortical gray matter with inconclusive findings [9, 10].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [9] Mole JP, Fasano F, Evans J, Sims R, Kidd E, Aggleton JP, Metzler-Baddeley C. APOE-ε4-related differences in left thalamic microstructure in cognitively healthy adults. Sci Rep. 2020;10(1):19787. source
    • cites [10] Nir TM, Zhu AH, Gari IB, Dixon D, Islam T, Villalon-Reina JE, Medland SE, Thompson PM, Jahanshad N. Effects of ApoE4 and ApoE2 genotypes on subcortical magnetic susceptibility and microstructure in 27,535 participants from the UK Biobank. In: Biocomputing. 2022. edn.: 121–132. source

      The Methods and Discussion (pages unavailable in our copy) show that this study investigated subcortical gray matter, and the Discussion notes inconsistent effects on diffusion metrics and a need for replication. But it also reports an association between ApoE4 and higher subcortical iron burden; it does not characterize its overall findings as inconclusive or investigate cortical gray matter. (LLM, conf=0.81)

      Experimental — accuracy not yet measured
  • Premisecitation

    APOE is differentially associated with AD risk across populations.

    “APOE is differentially associated with AD risk across populations [16]”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [16] Neu SC, Pa J, Kukull W, Beekly D, Kuzma A, Gangadharan P, Wang L-S, Romero K, Arneric SP, Redolfi A, et al. Apolipoprotein E genotype and sex risk factors for Alzheimer disease: a meta-analysis. JAMA Neurol. 2017;74(10):1178–89. source
  • Premisecitation

    Entorhinal cortex is a site of preclinical neuropathological tau deposition that is elevated for APOE4 carriers.

    “The regional specificity of these findings aligns with evidence that entorhinal cortex is a site of preclinical neuropathological tau deposition that is elevated for APOE4 carriers [37] and predicts cognitive decline [38], and which undergoes accelerated atrophy in preclinical AD [39].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [37] Young CB, Johns E, Kennedy G, Belloy ME, Insel PS, Greicius MD, Sperling RA, Johnson KA, Poston KL, Mormino EC, et al. APOE effects on regional tau in preclinical Alzheimer’s disease. Mol Neurodegener. 2023;18(1):1. source
  • Premisecitation

    APOE2 confers greater protection against AD risk for women than men.

    “Women are more vulnerable to effects of APOE4 on memory decline [45] as well as risk for AD dementia [16] and neuropathology [46], and more limited data suggest that APOE2 also confers greater protection against AD risk for women than men [16].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [16] Neu SC, Pa J, Kukull W, Beekly D, Kuzma A, Gangadharan P, Wang L-S, Romero K, Arneric SP, Redolfi A, et al. Apolipoprotein E genotype and sex risk factors for Alzheimer disease: a meta-analysis. JAMA Neurol. 2017;74(10):1178–89. source
  • It may state two separate claims as one. 44
  • Probably not a substantial claim. 38

  • It may state two separate claims as one.

    Premisecitation

    The few diffusion MRI studies evaluating APOE2 have generated mixed findings, with one study observing higher WM fractional anisotropy among APOE2 carriers, yet others reporting null effects.

    “The few diffusion MRI studies evaluating APOE2 have similarly generated mixed findings, with one study observing higher WM fractional anisotropy among APOE2 carriers [14], yet others reporting null effects [7, 15].”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [14] Chiang GC, Zhan W, Schuff N, Weiner MW. White matter alterations in cognitively normal apoE epsilon2 carriers: insight into Alzheimer resistance? AJNR Am J Neuroradiol. 2012;33(7):1392–7. source
    • cites [7] Lacey C, Gawryluk J. White matter microstructure and cognitive functioning across healthy older adults with different APOE alleles. Alzheimers Dement. 2021;17(S1):e051190. source
    • cites [15] Nir TM, Zhu AH, Gari IB, Dixon D, Islam T, Villalon-Reina JE, Medland SE, Thompson PM, Jahanshad N. Effects of ApoE4 and ApoE2 genotypes on subcortical magnetic susceptibility and microstructure in 27,535 participants from the UK Biobank. Pac Symp Biocomput. 2022;27:121–32.

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

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Some reports indicate slower hippocampal atrophy among APOE2 carriers.

    “with some reports of slower hippocampal atrophy among APOE2 carriers [13].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [13] Chiang GC, Insel PS, Tosun D, Schuff N, Truran-Sacrey D, Raptentsetsang ST, Jack CR Jr, Aisen PS, Petersen RC, Weiner MW, et al. Hippocampal atrophy rates and CSF biomarkers in elderly APOE 2 normal subjects. Neurology. 2010;75(22):1976–81. source

  • Probably not a substantial claim. It may be too vague to check against evidence.

    Premisecitation

    Studies reporting sex-specific associations of APOE4 with WM integrity and stronger APOE-related differences in brain metabolism and cortical atrophy for women than men provide grounds for deeper exploration of sex differences.

    “studies reporting sex-specific associations of APOE4 with WM integrity [19] and stronger APOE-related differences in brain metabolism and cortical atrophy for women than men [20, 21] provide grounds for deeper exploration of sex differences in underlying cytoarchitecture.”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [19] Horgusluoglu-Moloch E, Wang M, Zhou X, Zeng Q, Zhang B. Sex and APOE genotype-specific white matter changes in Alzheimer’s disease. Alzheimers Dement. 2021;17(S1):e055755. source
    • cites [20] Sampedro F, Vilaplana E, de Leon MJ, Alcolea D, Pegueroles J, Montal V, Carmona-Iragui M, Sala I, Sánchez-Saudinos MB, Antón-Aguirre S, et al. APOE-by-sex interactions on brain structure and metabolism in healthy elderly controls. Oncotarget. 2015;6(29):26663–74. source
    • cites [21] Hobel Z, Isenberg AL, Raghupathy D, Mack W, Pa J. for the Alzheimer’s Disease Neuroimaging I, the Australian Imaging B, Lifestyle flagship study of a: APOE ɛ4 gene dose and sex effects on Alzheimer’s disease MRI biomarkers in older adults with mild cognitive impairment. J Alzheimers Dis. 2019;71:647–58. source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    APOE is multifunctional, with roles in lipid and glucose metabolism, neuroinflammation, amyloid and tau accumulation, and blood-brain barrier dysfunction.

    “APOE is multifunctional, with roles in lipid and glucose metabolism, neuroinflammation, amyloid and tau accumulation, and blood-brain barrier dysfunction [2].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [2] Raulin A-C, Doss SV, Trottier ZA, Ikezu TC, Bu G, Liu C-C. ApoE in Alzheimer’s disease: pathophysiology and therapeutic strategies. Mol Neurodegener. 2022;17(1):72. source

  • Probably not a substantial claim. It may state two separate claims as one.

    Premisecitation

    Some studies have reported stronger effects of APOE4 on WM microstructure with age, whereas others observed no such interaction.

    “some studies have reported stronger effects of APOE4 on WM microstructure with age [3, 15, 18], whereas others observed no such interaction [8].”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [3] Adluru N, Destiche DJ, Lu SY-F, Doran ST, Birdsill AC, Melah KE, Okonkwo OC, Alexander AL, Dowling NM, Johnson SC, et al. White matter microstructure in late middle-age: effects of apolipoprotein E4 and parental family history of Alzheimer’s disease. NeuroImage Clin. 2014;4:730–42. source
    • cites [15] Nir TM, Zhu AH, Gari IB, Dixon D, Islam T, Villalon-Reina JE, Medland SE, Thompson PM, Jahanshad N. Effects of ApoE4 and ApoE2 genotypes on subcortical magnetic susceptibility and microstructure in 27,535 participants from the UK Biobank. Pac Symp Biocomput. 2022;27:121–32.

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

    • cites [18] Operto G, Molinuevo JL, Cacciaglia R, Falcon C, Brugulat-Serrat A, Suárez-Calvet M, Grau-Rivera O, Bargalló N, Morán S, Esteller M, et al. Interactive effect of age and APOE-ε4 allele load on white matter myelin content in cognitively normal middle-aged subjects. NeuroImage Clin. 2019;24:101983. source

  • It may state two separate claims as one.

    Findingcitation

    CI demonstrated widespread microstructural abnormalities compared to CN, with the strongest differences in entorhinal cortex IF and HI, and hippocampal RI; CI showed higher IF, and lower RI and HI, than CN.

    “As we previously reported in an overlapping sample [25], CI demonstrated widespread microstructural abnormalilties compared to CN (Additional file 1: Figure S2A), with the strongest differences in entorhinal cortex IF and HI, and hippocampal RI (p < 0.001); CI showed higher IF, and lower RI and HI, than CN.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [25] Reas ET, Hagler DJ Jr, White NS, Kuperman JM, Bartsch H, Cross K, Loi RQ, Balachandra AR, Meloy MJ, Wierenga CE, et al. Sensitivity of restriction spectrum imaging to memory and neuropathology in Alzheimer’s disease. Alzheimers Res Ther. 2017;9(1):55. source

      The Results section (page unavailable) reports lower neurite density (ND) across white matter in MCI and AD than in healthy controls, and higher entorhinal cortex isotropic free-water diffusion (IF). It does not report the claimed entorhinal HI or hippocampal RI differences, nor establish those measures as the strongest group differences; the paper analyzes ND and IF rather than RI and HI. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Premisecitation

    Lower amyloid burden has been observed among APOE2 carriers, but differences in tau or atrophy have been inconclusive.

    “Although lower amyloid burden has been observed among APOE2 carriers, differences in tau or atrophy have been inconclusive [11, 12]”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [11] Groot C. Multimodal imaging correlates of the protective APOE2 allele. Alzheimers Dement. 2020;16(S3):e039421. source
    • cites [12] Grothe MJ, Salvadó G, Groot C, Moscoso A, Gispert JD, Schöll M, Ossenkoppele R. Differential effects of APOE2 and APOE4 alleles on PET-measured amyloid-β and tau deposition in older individuals without dementia. Alzheimers Dement. 2020;16(S4):e040440. source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Higher brain network segregation may attenuate cortical tau propagation.

    “Higher brain network segregation may also attenuate cortical tau propagation [44].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [44] Steward A, Biel D, Brendel M, Dewenter A, Roemer S, Rubinski A, Luan Y, Dichgans M, Ewers M, Franzmeier N, et al. Functional network segregation is associated with attenuated tau spreading in Alzheimer’s disease. Alzheimers Dement. 2023;19(5):2034–46. source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    One DTI study identified higher fractional anisotropy for APOE2 carriers than APOE3 homozygotes within a small cluster of the posterior cingulum.

    “However, others reported no difference in WM integrity for APOE2 carriers [7, 15] and one DTI study identified higher fractional anisotropy for APOE2 carriers than APOE3 homozygotes within a small cluster of the posterior cingulum [14].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [14] Chiang GC, Zhan W, Schuff N, Weiner MW. White matter alterations in cognitively normal apoE epsilon2 carriers: insight into Alzheimer resistance? AJNR Am J Neuroradiol. 2012;33(7):1392–7. source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Thalamic atrophy in MCI and hypometabolism in APOE4 carriers have been observed.

    “The role of thalamic structure and function in AD appears complex and perhaps nonlinear, as thalamic atrophy in MCI [48] and hypometabolism in APOE4 carriers [49] have been observed, whereas others have reported increased thalamic volume [50] and hypermetabolism with amyloid pathology [51] among APOE4 carriers.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [48] Chételat G, Landeau B, Eustache F, Mézenge F, Viader F, de la Sayette V, Desgranges B, Baron JC. Using voxel-based morphometry to map the structural changes associated with rapid conversion in MCI: a longitudinal MRI study. Neuroimage. 2005;27(4):934–46. source
    • cites [49] Langbaum JBS, Chen K, Caselli RJ, Lee W, Reschke C, Bandy D, Alexander GE, Burns CM, Kaszniak AW, Reeder SA, et al. Hypometabolism in Alzheimer-affected brain regions in cognitively healthy Latino individuals carrying the apolipoprotein E ε4 allele. Arch Neurol. 2010;67(4):462–8. source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Entorhinal cortex undergoes accelerated atrophy in preclinical AD.

    “The regional specificity of these findings aligns with evidence that entorhinal cortex is a site of preclinical neuropathological tau deposition that is elevated for APOE4 carriers [37] and predicts cognitive decline [38], and which undergoes accelerated atrophy in preclinical AD [39].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [39] Miller MI, Younes L, Ratnanather JT, Brown T, Trinh H, Postell E, Lee DS, Wang M-C, Mori S, O’Brien R, et al. The diffeomorphometry of temporal lobe structures in preclinical Alzheimer’s disease. NeuroImage Clin. 2013;3:352–60. source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Age-related entorhinal atrophy is observed in the general population.

    “In contrast, entorhinal RI declined with age among APOE4 non-carriers, which may reflect aging-related neuronal loss or dystrophy among those with reduced genetic risk for AD, consistent with age-related entorhinal atrophy observed in the general population [41].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [41] Fjell AM, Walhovd KB, Fennema-Notestine C, McEvoy LK, Hagler DJ, Holland D, Brewer JB, Dale AM. One-year brain atrophy evident in healthy aging. J Neurosci. 2009;29(48):15223–31. source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Higher diastolic blood pressure has been observed in some cohorts.

    “Diastolic blood pressure was elevated for male APOE4 carriers relative to non-carriers, consistent with a documented susceptibility of APOE4 carriers to cardiovascular risk factors [54], including higher diastolic blood pressure observed in some cohorts [55–57].”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [55] Hestad KA, Engedal K, Whist JE, Farup PG. The effect of ApoE e4 on blood pressure in patients with and without depression. Neuropsychiatr Dis Treat. 2016;12:1365–70. source
    • cites [56] Stewart KC, Subramanian D, Neal UJ, Hanson AJ. APOE genotype influences postprandial blood pressure after high fat feeding in older adults. J Nutr Health Aging. 2019;23(5):408–13. source
    • cites [57] Sapkota B, Subramanian A, Priamvada G, Finely H, Blackett PR, Aston CE, Sanghera DK. Association of APOE polymorphisms with diabetes and cardiometabolic risk factors and the role of APOE genotypes in response to anti-diabetic therapy: results from the AIDHS/SDS on a South Asian population. J Diabetes Complications. 2015;29(8):1191–7. source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Various conditions including Parkinson's disease and psychiatric disorders are accompanied by striatal dysfunction.

    “APOE4 non-carriers demonstrated a distinct pattern of reduced striatal intracellular integrity (caudate RI) with cognitive impairment, which may point to AD-independent striatal contributions to clinical symptoms, as various conditions including Parkinson’s disease and psychiatric disorders are accompanied by striatal dysfunction [52, 53].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [52] Zhai S, Shen W, Graves SM, Surmeier DJ. Dopaminergic modulation of striatal function and Parkinson’s disease. J Neural Transm. 2019;126(4):411–22. source
    • cites [53] Karcher NR, Rogers BP, Woodward ND. Functional connectivity of the striatum in Schizophrenia and psychotic bipolar disorder. Biol Psychiatry Cogn Neurosci Neuroimaging. 2019;4(11):956–65. source

      The Introduction links striatal abnormalities and altered cortico-striatal connectivity to schizophrenia and other psychotic disorders. It does not address Parkinson’s disease, so this source supports only the psychiatric-disorders part of the attributed claim. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Increased thalamic volume and hypermetabolism with amyloid pathology have been reported among APOE4 carriers.

    “The role of thalamic structure and function in AD appears complex and perhaps nonlinear, as thalamic atrophy in MCI [48] and hypometabolism in APOE4 carriers [49] have been observed, whereas others have reported increased thalamic volume [50] and hypermetabolism with amyloid pathology [51] among APOE4 carriers.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [50] Cacciaglia R, Molinuevo JL, Falcón C, Brugulat-Serrat A, Sánchez-Benavides G, Gramunt N, Esteller M, Morán S, Minguillón C, Fauria K, et al. Effects of APOE-ε4 allele load on brain morphology in a cohort of middle-aged healthy individuals with enriched genetic risk for Alzheimer’s disease. Alzheimers Dement. 2018;14(7):902–12. source
    • cites [51] Johnson SC, Christian BT, Okonkwo OC, Oh JM, Harding S, Xu G, Hillmer AT, Wooten DW, Murali D, Barnhart TE, et al. Amyloid burden and neural function in people at risk for Alzheimer’s disease. Neurobiol Aging. 2014;35(3):576–84. source

      Results §3.3 reports greater medial-thalamic glucose metabolism in participants with indeterminate or positive amyloid burden than in amyloid-negative participants. The cohort was enriched for APOE4 carriers, but the analysis grouped participants by amyloid burden, not carrier status; the Discussion also reports no significant APOE-genotype association. The separate increased-volume finding is attributed to citation [50], not this paper. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Premisecitation

    Women are more vulnerable to effects of APOE4 on memory decline, risk for AD dementia, and neuropathology.

    “Women are more vulnerable to effects of APOE4 on memory decline [45] as well as risk for AD dementia [16] and neuropathology [46], and more limited data suggest that APOE2 also confers greater protection against AD risk for women than men [16].”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [45] Wang X, Zhou W, Ye T, Lin X, Zhang J. for Alzheimer’s Disease Neuroimaging I: sex difference in the association of APOE4 with memory decline in mild cognitive impairment. J Alzheimers Dis. 2019;69:1161–9. source
    • cites [16] Neu SC, Pa J, Kukull W, Beekly D, Kuzma A, Gangadharan P, Wang L-S, Romero K, Arneric SP, Redolfi A, et al. Apolipoprotein E genotype and sex risk factors for Alzheimer disease: a meta-analysis. JAMA Neurol. 2017;74(10):1178–89. source

      The Results report greater AD risk for APOE ε3/ε4 women than men at ages 65–75, and greater protection from AD for women with APOE ε2/ε3. But they found no sex difference in AD risk across ages 55–85, so the unqualified statement that women are more vulnerable to APOE4-associated AD risk overstates the finding. The memory-decline and neuropathology clauses carry other citations and are not judged here. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites [46] Altmann A, Tian L, Henderson VW, Greicius MD. Alzheimer’s Disease Neuroimaging Initiative I: sex modifies the APOE-related risk of developing Alzheimer disease. Ann Neurol. 2014;75(4):563–73. source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Entorhinal cortex tau deposition predicts cognitive decline.

    “The regional specificity of these findings aligns with evidence that entorhinal cortex is a site of preclinical neuropathological tau deposition that is elevated for APOE4 carriers [37] and predicts cognitive decline [38], and which undergoes accelerated atrophy in preclinical AD [39].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [38] Sperling RA, Mormino EC, Schultz AP, Betensky RA, Papp KV, Amariglio RE, Hanseeuw BJ, Buckley R, Chhatwal J, Hedden T, et al. The impact of amyloid-beta and tau on prospective cognitive decline in older individuals. Ann Neurol. 2019;85(2):181–93. source

      The Results report that greater entorhinal cortex tau was associated with greater decline in the memory composite. The Discussion qualifies this finding: tau-related memory decline was evident only in the Aβ-positive group. The unqualified claim does not convey that condition, and the paper did not find a significant association with executive-function decline. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Large-world connectivity of distal networks including projections of the cingulate with frontal and temporal cortex predominates in AD, accompanied by degraded rich hubs.

    “Indeed, “large world” connectivity of distal networks including projections of the cingulate with frontal and temporal cortex [42] predominates in AD, accompanied by degraded “rich hubs,” localized networks of high connectivity [43].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [42] He Y, Chen Z, Evans A. Structural insights into aberrant topological patterns of large-scale cortical networks in Alzheimer’s disease. J Neurosci. 2008;28(18):4756–66. source

      The Interregional correlations of cortical thickness section reports increased correlations in AD between the cingulate and frontal and temporal regions. The Altered small-world configurations section reports longer network paths and a shift toward a more regular configuration, but does not establish that “large-world” connectivity predominates or that the correlations are anatomical projections. The separate “rich hubs” clause is cited to [43], not this paper. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [43] Drenthen GS, Backes WH, Freeze WM, Jacobs HIL, Verheggen ICM, van Boxtel MPJ, Hoff EI, Verhey FR, Jansen JFA. Rich-club connectivity of the structural covariance network relates to memory processes in mild cognitive impairment and Alzheimer’s disease. J Alzheimers Dis. 2022;89:209–17. source

  • It may state two separate claims as one.

    Findingown data

    Exploratory analyses revealed significant interactions for global gray matter RI, HI, and IF, thalamus RI and ND, and caudate RI, although whole-brain analyses revealed no significant localized interactions within cortical gray matter.

    “Exploratory analyses also revealed significant interactions for global gray matter RI, HI, and IF (p < 0.01), thalamus RI (p < 0.001) and ND (p = 0.009), and caudate RI (p = 0.003), although whole-brain analyses revealed no signifcant localized interactions within cortical gray matter.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    There was an effect of APOE2 on entorhinal HI for women but not men, reflecting lower HI for APOE2/3 than APOE3/3 and APOE4 women.

    “Similarly, there was an effect of APOE2 on entorhinal HI for women (F(2,114) = 4.43, p = 0.01) but not men (F(2,67) = 0.10, p = 0.90), reflecting lower HI for APOE2/3 than APOE3/3 and APOE4 women”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    Blood pressure did not differ by APOE4 among women.

    “for whom blood pressure did not differ by APOE4.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Sex by APOE interactions did not reach significance for cingulum ND, entorhinal HI, or any other measure.

    “However, sex by APOE interactions did not reach significance for cingulum ND (p = 0.28), entorhinal HI (p = 0.056), or any other measure.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Among CN, entorhinal ND differed by APOE4 only for women, not for men.

    “Sex-stratified analyses revealed that entorhinal ND differed by APOE4 only for women (F(1,115) = 4.90, p = 0.03) but not for men (F(1,69) = 0.25, p = 0.62)”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    After adjustment for cortical thickness or volume, the interactions for entorhinal cortex HI and hippocampal IF and HI were attenuated, driven by greater atrophy with cognitive impairment among APOE4 carriers.

    “After adjustment for cortical thickness or volume respectively, the interactions for entorhinal cortex HI (p = 0.14) and hippocampal IF (p = 0.16) and HI (p = 0.17) were attenuated, driven by greater atrophy with cognitive impairment among APOE4 carriers.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Among APOE4 carriers, CI exhibited lower gray matter RI and HI and higher IF, yet higher thalamic RI and ND, than CN.

    “Among APOE4 carriers, CI exhibited lower gray matter RI and HI and higher IF, yet higher thalamic RI and ND, than CN.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Among CN, age interacted with APOE4 for entorhinal cortex RI (p = 0.02), with older age correlated with lower RI for APOE4 non-carriers (p < 0.001) but not carriers (p = 0.88).

    “Age interacted with APOE4 for entorhinal cortex RI (p = 0.02), with correlations between older age and lower RI for APOE4 non-carriers (p < 0.001) but not carriers (p = 0.88) (Fig. 1B).”
    • Also stated in: § Results · plain
      “Age correlated with lower entorhinal restricted isotropic diffusion among APOE4 non-carriers”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    The difference in cingulum ND by APOE2 was present for women but not for men.

    “In sex-stratified analyses, this difference was present for women (F(2,114) = 6.33, p = 0.002) but not for men (F(2,67) = 0.70, p = 0.50)”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    APOE4 carriers exhibited lower entorhinal cortex HI and global gray matter ND and HI, as well as higher thalamic RI and ND, and global gray matter IF, than non-carriers.

    “APOE4 carriers exhibited lower entorhinal cortex HI and global gray matter ND and HI, as well as higher thalamic RI and ND, and global gray matter IF, than non-carriers (Additional file 1: Figure S2B).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    APOE4 interacted with cognitive status for hippocampal IF and HI, and for entorhinal HI.

    “APOE4 interacted with cognitive status for hippocampal IF and HI (p < 0.05), and for entorhinal HI (p = 0.004) (Additional file 1: Table S8, Additional file 1: Figure S2C).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    CI showed higher hippocampal IF and lower entorhinal cortex HI than CN among both APOE4 carriers and non-carriers, with more pronounced differences for carriers.

    “As shown in Fig. 3, CI showed higher hippocampal IF and lower entorhinal cortex HI than CN among both APOE4 carriers and non-carriers, with more pronounced differences for carriers.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Exploratory analyses revealed an interaction between APOE and age for putamen RI, with age-related decline present only for APOE4 carriers.

    “Exploratory analyses revealed an interaction between APOE and age for putamen RI (p = 0.003), with age-related decline present only for APOE4 carriers (Fig. 2B).”
    • Also stated in: § Results · plain
      “whereas age correlated with lower putamen restricted isotropic diffusion among APOE4 carriers.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    APOE2/3 participants did not differ from APOE2 non-carriers on any demographic or health factor.

    “APOE2/3 participants did not differ from APOE2 non-carriers on any demographic or health factor (Table 1).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    CI participants were more likely to be male and more highly educated than CN participants.

    “CI participants were more likely to be male and more highly educated than CN participants (p < 0.001; Additional file 1: Table S3).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    APOE4 carriers had higher diastolic blood pressure than non-carriers.

    “and had higher diastolic blood pressure (p = 0.009).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Widespread WM differences by cognitive status were observed and were not modified by APOE4.

    “However, widespread WM differences by cognitive status were observed, consistent with our prior findings in an overlapping sample [25], that were not modified by APOE4.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Participant age, sex, years of education, systolic blood pressure, BMI, or diabetes did not differ by APOE4.

    “Participant age, sex, years of education, systolic blood pressure, BMI, or diabetes did not differ by APOE4 (p > 0.05).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Entorhinal hindered diffusion was lower and hippocampal free water was higher for cognitively impaired participants across the full sample.

    “While entorhinal hindered diffusion was lower and hippocampal free water was higher for cognitively impaired participants across the full sample, these differences were accentuated among APOE4 carriers, consistent with their role as preclinical targets of AD neuropathology and neurodegeneration.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Adjustment for diastolic blood pressure slightly attenuated the difference in entorhinal ND by APOE4 in the sex-combined sample, but minimally affected this difference within women, who showed no difference in blood pressure by APOE, and did not alter any other APOE4 effects.

    “Concordantly, adjustment for diastolic blood pressure slightly attenuated the difference in entorhinal ND by APOE4 in the sex-combined sample, but minimally affected this difference within women, who showed no difference in blood pressure by APOE, and did not alter any other APOE4 effects.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    APOE4 carriers exhibited abnormal cortical gray matter and thalamic microstructure with MCI, patterns that were not present among non-carriers.

    “APOE4 carriers also exhibited abnormal cortical gray matter and thalamic microstructure with MCI, patterns that were not present among non-carriers.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    APOE4 carriers and CI participants were more likely to be positive for AD pathology (tau/Aβ42), and to have lower Aβ42/40 and higher p-tau than APOE4 non-carriers and CN participants.

    “APOE4 carriers and CI participants were more likely to be positive for AD pathology (tau/Aβ42, p < 0.05), and to have lower Aβ42/40 and higher p-tau than APOE4 non-carriers and CN participants (p < 0.01) (Additional file 1: Table S4).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Available biomarker data demonstrated more AD-like profiles (lower CSF amyloid and higher tau) for APOE4 carriers and CI participants.

    “Nevertheless, available biomarker data demonstrated more AD-like profiles (lower CSF amyloid and higher tau) for APOE4 carriers and CI participants, supporting the interpretation that these individuals were more likely to be in preclinical AD stages.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. It may state two separate claims as one.

    Premisecitation

    Limited evidence suggests that APOE4 may drive accelerated hippocampal atrophy and network disruption with MCI, though others report no modifying effect of APOE4 on WM microstructure in MCI.

    “limited evidence suggests that APOE4 may drive accelerated hippocampal atrophy and network disruption with MCI [22], though others report no modifying effect of APOE4 on WM microstructure in MCI [23].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [22] Ma C, Wang J, Zhang J, Chen K, Li X, Shu N, Chen Y, Liu Z, Zhang Z. Disrupted brain structural connectivity: pathological interactions between genetic APOE ε4 status and developed MCI condition. Mol Neurobiol. 2017;54(9):6999–7007. source
    • cites [23] Wang Z, Dai Z, Shu H, Liu D, Guo Q, He Y, Zhang Z. Cortical thickness and microstructural white matter changes detect amnestic mild cognitive impairment. J Alzheimers Dis. 2017;56:415–28. source

  • Probably not a substantial claim.

    Study design and conductnone given

    Analyses of RSI measures included covariates of age, sex, and scanner.

    “Analyses of RSI measures included covariates of age, sex, and scanner.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductcitation

    Cerebrospinal fluid was collected with standardized procedures, preanalytical preparation, and storage in accordance with recommended best practices.

    “A subset of ADRC participants (N = 70) underwent lumber puncture with standardized procedures, preanalytical preparation, and storage of cerebrospinal fluid in accordance with the recommended best practices [31].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] Vanderstichele H, Bibl M, Engelborghs S, Le Bastard N, Lewczuk P, Molinuevo JL, Parnetti L, Perret-Liaudet A, Shaw LM, Teunissen C, et al. Standardization of preanalytical aspects of cerebrospinal fluid biomarker testing for Alzheimer’s disease diagnosis: a consensus paper from the Alzheimer’s Biomarkers Standardization Initiative. Alzheimers Dement. 2012;8(1):65–73. source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    Cortical surface general linear models were corrected with the false discovery rate (FDR) method.

    “Cortical surface general linear models were corrected with the false discovery rate (FDR) method.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim.

    Study design and conductreasoning

    To account for multiple comparisons across eight fibers and four subcortical regions, significance was assessed using Bonferroni corrected thresholds set to p < 0.006 for WM fibers and p < 0.012 for subcortical regions.

    “to account for multiple comparisons across eight fibers and four subcortical regions, significance was assessed using Bonferroni corrected thresholds set to p < 0.006 for WM fibers and p < 0.012 for subcortical regions.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Carriers of the ε2 allele have an estimated 1.7 times decreased risk of AD.

    “whereas carriers of the protective ε2 allele have an estimated 1.7 times decreased risk [1]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, Myers RH, Pericak-Vance MA, Risch N, van Duijn CM. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA. 1997;278(16):1349–56. source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Study design and conductnone given

    Study procedures were approved by the University of California, San Diego Human Research Protections Program Board and participants provided informed written consent prior to participation.

    “Study procedures were approved by the University of California, San Diego Human Research Protections Program Board and participants provided informed written consent prior to participation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductown data

    After excluding six participants due to poor MRI data quality and three participants with APOE2/4 genotype due to conflicting risk effects of the ε2 and ε4 alleles, the final sample included 225 participants.

    “After excluding six participants due to poor MRI data quality and three participants with APOE2/4 genotype due to conflicting risk effects of the ε2 and ε4 alleles, the final sample included 225 participants”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Compared to ε3 homozygotes, individuals with one or two ε4 alleles have approximately 3 and 15 times increased risk of sporadic AD, respectively.

    “Compared to ε3 homozygotes, individuals with one or two ε4 alleles harbor approximately 3 and 15 times increased risk, respectively”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, Myers RH, Pericak-Vance MA, Risch N, van Duijn CM. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA. 1997;278(16):1349–56. source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    All raw and processed MR images were visually inspected for artifacts.

    “All raw and processed MR images were visually inspected for artifacts”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Study design and conductown data

    Because only a subset of participants (31% of the full sample) underwent lumbar puncture, cerebrospinal fluid measures are reported for AD biomarker characterization and were not incorporated into analyses.

    “Because only a subset of participants (31% of the full sample) underwent lumbar puncture, cerebrospinal fluid measures are reported for AD biomarker characterization and were not incorporated into analyses.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductown data

    Results were unchanged by further adjustment for diastolic blood pressure.

    “Results were unchanged by further adjustment for diastolic blood pressure.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Some studies reported no difference in WM integrity for APOE2 carriers.

    “However, others reported no difference in WM integrity for APOE2 carriers [7, 15] and one DTI study identified higher fractional anisotropy for APOE2 carriers than APOE3 homozygotes within a small cluster of the posterior cingulum [14].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [7] Lacey C, Gawryluk J. White matter microstructure and cognitive functioning across healthy older adults with different APOE alleles. Alzheimers Dement. 2021;17(S1):e051190. source
    • cites [15] Nir TM, Zhu AH, Gari IB, Dixon D, Islam T, Villalon-Reina JE, Medland SE, Thompson PM, Jahanshad N. Effects of ApoE4 and ApoE2 genotypes on subcortical magnetic susceptibility and microstructure in 27,535 participants from the UK Biobank. Pac Symp Biocomput. 2022;27:121–32.

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

  • It may state two separate claims as one.

    Interpretationown data

    APOE2 may support beneficial white matter and entorhinal microstructure, with potential sex differences that warrant further investigation.

    “whereas APOE2 may support beneficial white matter and entorhinal microstructure, with potential sex differences that warrant further investigation.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    APOE4 carriers have a documented susceptibility to cardiovascular risk factors.

    “Diastolic blood pressure was elevated for male APOE4 carriers relative to non-carriers, consistent with a documented susceptibility of APOE4 carriers to cardiovascular risk factors [54], including higher diastolic blood pressure observed in some cohorts [55–57].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [54] Song Y, Stampfer MJ, Liu S. Meta-analysis: apolipoprotein E genotypes and risk for coronary heart disease. Ann Intern Med. 2004;141(2):137–47. source

  • It may state two separate claims as one.

    Interpretationreasoning

    APOE4 carriers are particularly susceptible to preclinical neurodegenerative changes in medial temporal regions that progress with cognitive decline, whereas among APOE4 non-carriers, microstructural changes in these regions are more closely tied to aging than cognitive impairment.

    “Together, these findings support a model in which APOE4 carriers are particularly susceptible to preclinical neurodegenerative changes in medial temporal regions that progress with cognitive decline, whereas among APOE4 non-carriers, microstructural changes in these regions are more closely tied to aging than cognitive impairment.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Interpretationreasoning

    A pathological cascade originates with medial temporal neurodegeneration, followed by WM degeneration as neuropathology and associated cellular injury spreads throughout the cortex with disease progression.

    “These findings would be consistent with a pathological cascade that originates with medial temporal neurodegeneration, followed by WM degeneration as neuropathology and associated cellular injury spreads throughout the cortex with disease progression.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. It may be too vague to check against evidence.

    Interpretationreasoning

    These findings may advance the development of biomarkers to distinguish microstructural changes characteristic of normal brain aging, APOE-dependent pathways, and non-AD etiologies.

    “which may advance the development of biomarkers to distinguish microstructural changes characteristic of normal brain aging, APOE-dependent pathways, and non-AD etiologies.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim.

    Study design and conductreasoning

    A priori analyses did not adjust for multiple comparisons across regions.

    “Because of our hypothesis-driven focus on the entorhinal cortex and hippocampus in a priori analyses, these analyses did not adjust for multiple comparisons across regions.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Study design and conductown data

    Because education levels were higher among CI than CN, models were repeated with further adjustment for education, which did not alter results.

    “Because education levels were higher among CI than CN (Additional file 1: Table S3), models were repeated with further adjustment for education, which did not alter results.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Westlye and colleagues observed higher WM mean and radial diffusivity for APOE2 carriers than APOE3 homozygotes.

    “Consistent with our finding, Westlye and colleagues [8] observed higher WM mean and radial diffusivity for APOE2 carriers than APOE3 homozygotes.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Westlye LT, Reinvang I, Rootwelt H, Espeseth T. Effects of APOE on brain white matter microstructure in healthy adults. Neurology. 2012;79(19):1961–9. source

  • It may state two separate claims as one.

    Interpretationreasoning

    APOE genotype differentially regulates disease- and aging-related cytoarchitectural changes, such that APOE4 carriers undergo entorhinal neurodegeneration in preclinical and prodromal AD, with age-related striatal changes, whereas APOE4 non-carriers present with age-related entorhinal cortex microstructural abnormalities and striatal injury accompanying cognitive impairment.

    “Findings implicate differential regulation of disease- and aging-related cytoarchitectural changes by APOE genotype, such that APOE4 carriers undergo entorhinal neurodegeneration in preclinical and prodromal AD, with age-related striatal changes, whereas APOE4 non-carriers present with age-related entorhinal cortex microstructural abnormalities and striatal injury accompanying cognitive impairment”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    Patterns of microstructural abnormalities associated with mild cognitive impairment differed according to APOE4, serving as potential differential indicators of underlying etiology.

    “Patterns of microstructural abnormalities associated with mild cognitive impairment differed according to APOE4, serving as potential differential indicators of underlying etiology.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Study design and conductown data

    The sample almost entirely comprised non-Hispanic White participants and we were unable to account for racial/ethnic or ancestry differences.

    “Because the sample almost entirely comprised non-Hispanic White participants and we were unable to account for racial/ethnic or ancestry differences, findings may not generalize to non-white participants, considering effects of APOE are not uniform across racial groups.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Effects of APOE are not uniform across racial groups.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Study design and conductnone given

    RSI identifies diffusion patterns consistent with distinct tissue compartments, but cannot directly image cell morphometry or inform physiological mechanisms underlying microstructural properties.

    “Finally, it is important to highlight that RSI identifies diffusion patterns consistent with distinct tissue compartments, but cannot directly image cell morphometry or inform physiological mechanisms underlying microstructural properties.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: RSI identifies diffusion patterns consistent with distinct tissue compartments.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.

    Study design and conductnone given

    Accuracy of diffusion MRI measures relies on the validity of assumptions regarding cell architecture, as well as selection of protocol parameters.

    “As for all biophysical models, accuracy of diffusion MRI measures relies on the validity of assumptions regarding cell architecture, as well as selection of protocol parameters, which may complicate interpretability.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Study design and conductown data

    There were a small number of APOE4 homozygotes and no APOE2 homozygotes.

    “Given the small number of APOE4 homozygotes and lack of APOE2 homozygotes, further investigation is needed to probe allele dose effects.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    Microstructural signatures of APOE genotype emerge prior to cognitive impairment in patterns that may differ by sex, with entorhinal neurite loss as a potential preclinical AD biomarker, and WM microstructure associated with reduced AD risk.

    “Together, our findings indicate that microstructural signatures of APOE genotype emerge prior to cognitive impairment in patterns that may differ by sex, with entorhinal neurite loss as a potential preclinical AD biomarker, and WM microstructure associated with reduced AD risk.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    Associations of APOE4 with blood pressure may be stronger in men, in contrast to more pronounced associations between APOE and microstructural injury in women, such that blood pressure does not meaningfully account for the observed effects of APOE4.

    “Though sex differences in vascular effects of APOE remain poorly understood, these preliminary findings suggest that associations of APOE4 with blood pressure may be stronger in men, in contrast to more pronounced associations between APOE and microstructural injury in women, such that blood pressure does not meaningfully account for the observed effects of APOE4.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationreasoning

    APOE genotype may shape regionally specific patterns of cellular changes occurring with aging and neurodegenerative disease, with effects of normal aging predominating in the absence of pathogenic drivers.

    “APOE genotype may shape regionally specific patterns of cellular changes occurring with aging and neurodegenerative disease, with effects of normal aging predominating in the absence of pathogenic drivers.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductreasoning

    The cross-sectional nature of this study precludes tracking patterns of change or nonlinear dynamics of diffusion markers over time.

    “Furthermore, the cross-sectional nature of this study precludes tracking patterns of change or nonlinear dynamics of diffusion markers over time.”
    Quote in the paperNot a substantial claim
72 of 72

  • The paper relies on this without support.

    The entorhinal cortex and hippocampus are early targets of AD neuropathology and neurodegeneration.

    “identified based upon their early involvement in AD, including the entorhinal cortex and hippocampus, which are targets of early AD neuropathology and neurodegeneration”

  • The paper relies on this without support.

    The combined sample from the Rancho Bernardo Study and the UC San Diego ADRC is sufficiently homogeneous that cohort membership does not confound the associations between APOE and brain microstructure.

    “Participants included older adults (57% women; 77 ± 7 years) from the Rancho Bernardo Study of Health Aging and the University of California San Diego Alzheimer’s Disease Research Center”

  • The paper relies on this without support.

    WM ND is influenced by various tissue properties, which may be reduced with lower axonal density or myelination, which presents a significant barrier to water diffusion.

    “WM ND is influenced by various tissue properties, which may be reduced with lower axonal density or myelination, which presents a significant barrier to water diffusion.”

  • The paper relies on this without support.

    Effects of APOE are not uniform across racial groups.

    “considering effects of APOE are not uniform across racial groups.”

  • The paper relies on this without support.

    RSI identifies diffusion patterns consistent with distinct tissue compartments.

    “RSI identifies diffusion patterns consistent with distinct tissue compartments, but cannot directly image cell morphometry or inform physiological mechanisms underlying microstructural properties.”
5 of 5

Statistics recomputed

Every reported test result, recomputed from its test statistic and degrees of freedom. A result shows as not adding up only once an independent check has confirmed it.

  • ConsistentF(1, 182) = 5.87reported p = .02 · recomputed p = .016

    “F(1,182) = 5.87, p = .02”

  • ConsistentF(2, 221) = 0.72reported p = .49 · recomputed p = .488

    “F(2,221) = 0.72, p = .49”

  • ConsistentF(2, 188) = 0.74reported p = .48 · recomputed p = .478

    “F(2,188) = 0.74, p = .48”

  • Consistentχ²(2) = 0.21reported p = .9 · recomputed p = .900

    “X2(2) = 0.21, p = .90”

  • Consistentχ²(2) = 2.03reported p = .36 · recomputed p = .362

    “X2(2) = 2.03, p = .36”

  • ConsistentF(2, 221) = 2.15reported p = .12 · recomputed p = .119

    “F(2,221) = 2.15, p = .12”

  • ConsistentF(2, 188) = 0.71reported p = .49 · recomputed p = .493

    “F(2,188) = 0.71, p = .49”

  • ConsistentF(2, 215) = 1.38reported p = .25 · recomputed p = .254

    “F(2,215) = 1.38, p = .25”

  • ConsistentF(2, 182) = 1.29reported p = .28 · recomputed p = .278

    “F(2,182) = 1.29, p = .28”

  • ConsistentF(2, 215) = 3.49reported p = .03 · recomputed p = .032

    “F(2,215) = 3.49, p = .03”

  • ConsistentF(2, 182) = 3.43reported p = .03 · recomputed p = .034

    “F(2,182) = 3.43, p = .03”

  • ConsistentF(2, 217) = 0.9reported p = .41 · recomputed p = .408

    “F(2,217) = 0.90, p = .41”

  • ConsistentF(2, 184) = 0.38reported p = .68 · recomputed p = .684

    “F(2,184) = 0.38, p = .68”

  • Consistentχ²(2) = 0.59reported p = .74 · recomputed p = .745

    “X2(2) = 0.59, p = .74”

  • Consistentχ²(2) = 0.63reported p = .73 · recomputed p = .730

    “X2(2) = 0.63, p = .73”

  • Consistentχ²(2) = 17.86reported p < .001 · recomputed p < .001

    “X2(2) = 17.86, p < .001”

  • ConsistentF(1, 187) = 4.46reported p = .04 · recomputed p = .036

    “F(1,187) = 4.46, p = .04”

  • ConsistentF(1, 185) = 4.39reported p = .04 · recomputed p = .038

    “F(1,185) = 4.39, p = .04”

  • ConsistentF(1, 115) = 4.9reported p = .03 · recomputed p = .029

    “F(1,115) = 4.90, p = .03”

  • ConsistentF(1, 69) = 0.25reported p = .62 · recomputed p = .619

    “F(1,69) = 0.25, p = .62”

  • ConsistentF(1, 186) = 2.23reported p = .14 · recomputed p = .137

    “F(1,186) = 2.23, p = .14”

  • ConsistentF(1, 114) = 3.6reported p = .06 · recomputed p = .060

    “F(1,114) = 3.60, p = .06”

  • ConsistentF(2, 185) = 5.42reported p = .005 · recomputed p = .005

    “F(2,185) = 5.42, p = .005”

  • ConsistentF(2, 114) = 6.33reported p = .002 · recomputed p = .002

    “F(2,114) = 6.33, p = .002”

  • ConsistentF(2, 67) = 0.7reported p = .5 · recomputed p = .500

    “F(2,67) = 0.70, p = .50”

  • ConsistentF(2, 114) = 4.43reported p = .01 · recomputed p = .014

    “F(2,114) = 4.43, p = .01”

  • ConsistentF(2, 67) = 0.1reported p = .9 · recomputed p = .905

    “F(2,67) = 0.10, p = .90”

  • ConsistentF(2, 112) = 7.53reported p < .001 · recomputed p < .001

    “F(2,112) = 7.53, p < .001”

28 of 28

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Self-check results appear here once an independent check has confirmed them.

Citations

Cites

Flagged first, then by citations

2 of the 59 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Nir TM, Zhu AH, Gari IB, Dixon D, Islam T, Villalon-Reina JE, Medland SE, Thompson PM, Jahanshad N. Effects of ApoE4 and ApoE2 genotypes on subcortical magnetic susceptibility and microstructure in 27,535 participants from the UK Biobank. Pac Symp Biocomput. 2022;27:121–32.

Cited by

Sorted by citations

Related

Metadata

Authors
Reas, E. T., Triebswetter, C., Banks, S. J., & McEvoy, L. K.
Affiliations
  • University of California San Diego (US)
  • Kaiser Permanente Washington Health Research Institute (US)
Corresponding author
Reas, Emilie T.
ORCID
Venue
Alzheimer's Research & Therapy
Publisher
Springer Science and Business Media LLC
Published
2024-01-11
Volume
16
Issue
1
Pages
7-7
ISSN
1758-9193 (ISSN-L)
DOI
10.1186/s13195-023-01380-w
PMC
PMC10782616
OpenAlex
W4390748077
Cited by
21
References
59
Citations by year
2026: 11 · 2025: 6 · 2024: 4
FWCI
4.97
Type
journal article
Language
en
Open access
Licence
Locations
  • Alzheimer s Research & Therapy (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Institute on Aging (R01 AG062483)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced Neuroimaging Techniques and Applications
Keywords
APOE2, APOE ε4, APOE3, Alzheimer's disease risk, brain microstructure, entorhinal cortex, cingulum, neurite density, sex differences, age effects, mild cognitive impairment, white matter, gray matter, subcortical structures, diffusion MRI
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Brain, Cognition, Female, Humans, Male, Apolipoprotein E4, Apolipoprotein E2, Cognitive Dysfunction

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.

A language model drew the claims from the paper on 2026-10-11, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).

A second model labelled each claim on 2026-10-11 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).

Cited sources are checked with a language model’s help (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 ›

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