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Cited by 24Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

Plcg2M28L Interacts With High Fat/High Sugar Diet to Accelerate Alzheimer’s Disease-Relevant Phenotypes in Mice

Open access
Oblak, Adrian L., Kotredes, Kevin P., Pandey, Ravi S., Reagan, Alaina M., Ingraham, Cynthia, Perkins, Bridget, Lloyd, Christopher, Baker, Deborah +16 more·2022·Frontiers in Aging Neuroscience
DOI 10.3389/fnagi.2022.886575PMC PMC9263289

Published version of a preprint

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Abstract

Obesity is recognized as a significant risk factor for Alzheimer’s disease (AD). Studies have supported the notion that obesity accelerates AD-related pathophysiology in mouse models of AD. The majority of studies, to date, have focused on the use of early-onset AD models. Here, we evaluate the impact of genetic risk factors on late-onset AD (LOAD) in mice fed with a high fat/high sugar diet (HFD). We focused on three mouse models created through the IU/JAX/PITT MODEL-AD Center. These included a combined risk model with APOE4 and a variant in triggering receptor expressed on myeloid cells 2 ( Trem2 R47H ). We have termed this model, LOAD1. Additional variants including the M28L variant in phospholipase C Gamma 2 ( Plcg2 M28L ) and the 677C > T variant in methylenetetrahydrofolate reductase ( Mthfr 677C > T ) were engineered by CRISPR onto LOAD1 to generate LOAD1. Plcg2 M28L and LOAD1. Mthfr 677C > T . At 2 months of age, animals were placed on an HFD that induces obesity or a control diet (CD), until 12 months of age. Throughout the study, blood was collected to assess the levels of cholesterol and glucose. Positron emission tomography/computed tomography (PET/CT) was completed prior to sacrifice to image for glucose utilization and brain perfusion. After the completion of the study, blood and brains were collected for analysis. As expected, animals fed a HFD, showed a significant increase in body weight compared to those fed a CD. Glucose increased as a function of HFD in females only with cholesterol increasing in both sexes. Interestingly, LOAD1. Plcg2 M28L demonstrated an increase in microglia density and alterations in regional brain glucose and perfusion on HFD. These changes were not observed in LOAD1 or LOAD1. Mthfr 677C > T animals fed with HFD. Furthermore, LOAD1. Plcg2 M28L but not LOAD1. Mthfr 677C > T or LOAD1 animals showed transcriptomics correlations with human AD modules. Our results show that HFD affects the brain in a genotype-specific manner. Further insight into this process may have significant implications for the development of lifestyle interventions for the treatment of AD.

AI snapshot

Written from the paper’s full text.

TL;DR

In mice carrying late-onset Alzheimer’s disease (LOAD) risk variants, a 10-month high fat/high sugar diet (HFD) produced genotype-specific brain changes, with LOAD1.Plcg2M28L showing the strongest AD-relevant phenotypes. HFD interacted with Plcg2M28L to increase microglial density, alter brain glucose/perfusion, and align brain transcriptomes with human AD inflammatory modules, while LOAD1.Mthfr677C>T did not show these interactions.

Key findings

  • HFD from 2 to 12 months increased body weight regardless of genotype; cholesterol was elevated at 8 and 12 months in all HFD strains (p < 0.0001 at JAX and IU), while glucose increased with HFD in females only. Fasting glucose exceeded 240 mg/dL only in LOAD1 HFD and LOAD1.Plcg2M28L HFD mice.
  • LOAD1.Plcg2M28L females on HFD showed increased IBA1+ microglial density in cortex compared with LOAD1.Plcg2M28L on control diet; this was not seen in LOAD1.Mthfr677C>T. Brain IL-1β increased in HFD-fed LOAD1 mice, whereas LOAD1.Plcg2M28L mice had reduced brain IL-1β and IFN-γ regardless of diet and elevated plasma TNF-α in HFD males only.
  • The HFD × Plcg2M28L interaction positively correlated with human AD immune-related AMP-AD modules (Consensus Cluster B) and with inflammatory LOAD subtypes across ROSMAP, MSBB, and Mayo cohorts; no significant correlation was observed for HFD × Mthfr677C>T. PET/CT showed HFD mice overall had increased brain glucose uptake and perfusion versus control diet; 15 of 27 regions explained 80% of variance in glycolysis and 13 of 27 in blood flow.
  • No neuronal loss was detected, and LOAD1.Plcg2M28L HFD mice still lacked amyloid-beta plaques.

Methods

  • Three congenic C57BL/6J strains were used: LOAD1 (APOE4/Trem2R47H), LOAD1.Plcg2M28L, and LOAD1.Mthfr677C>T. At 2 months, mice were randomized to control diet (6% fat) or HFD (45% fat, ResearchDiet D12451i) until 12 months; n = 10 per sex/genotype/diet unless specified, with NanoString n = 6 and PET n = 10 per sex/genotype/age.
  • Outcomes included longitudinal body weight, fasting blood glucose and cholesterol at 8 and 12 months, terminal PET/CT with 18F-FDG and 64Cu-PTSM plus autoradiography, brain histology (NeuN, Iba1), cytokine panel assay, and NanoString Mouse AD panel transcriptomics.
  • Analyses used mixed ANOVA for repeated measures, two-way ANOVA with Tukey’s post hoc tests, multiple regression for NanoString effects, Pearson correlations with human AMP-AD modules and LOAD subtypes, KEGG/GSEA, and PCA for imaging regions.

Limitations

  • Stated: the study was not designed to determine whether diet effects are reversible; the 45% fat HFD is somewhat extreme; B6 mice do not develop overt type 2 diabetes and detailed type 2 diabetic phenotypes were not assessed, so the authors cannot rule out that the HFD × Plcg2M28L interaction is due to differential type 2 diabetes susceptibility; the mice lack amyloid-beta plaques and neuronal loss, requiring additional perturbations or aging; findings need support from human and cell-based models given reported human/mouse microglia differences.
  • Evident: blood glucose levels differed between JAX and IU despite efforts to standardize housing, and microglia density data were not based on stereological analyses, which the paper notes makes them suggestive. PET/CT was not performed in LOAD1.Mthfr677C>T because no inflammatory transcriptomic interaction was found.

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

Integrity signals

Registry

Crossref · 10.3389/fnagi.2022.886575

Cites

76 of 76 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

30 of 47 cited sources checked · 14 supported · 3 flagged · accuracy not yet measured

  • Premisecitation

    Transcriptomic analyses of brain tissue from LOAD1.Plcg2M28L or LOAD1.Mthfr677C>T mice revealed increased alignment to brain transcriptomes from human patients with AD compared to B6 or LOAD1 controls.

    “Transcriptomic analyses of the brain tissue from LOAD1.Plcg2M28L or LOAD1.Mthfr677C > T mice revealed increased alignment to brain transcriptomes from human patients with AD compared to B6 or LOAD1 controls (Preuss et al., 2020).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Preuss et al., 2020 source

      The Results section describes comparing brain transcriptomes from APOE4 KI, Trem2*R47H, and combined-variant mice with human AD co-expression modules, including comparisons with B6 controls. Searches for LOAD1.Plcg2M28L and LOAD1.Mthfr677C>T found no passage reporting analyses of those mice or their increased alignment relative to B6 or LOAD1 controls. No page numbers were available in our copy. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
  • Premisecitation

    LOAD1 mice provided a sensitized background for assessing additional genetic and environmental risk factors.

    “Therefore, these mice provided a sensitized background for assessing additional genetic and environmental risk factors (Kotredes et al., 2021).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Kotredes et al., 2021 source
  • Premisecitation

    In LOAD1 mice and controls aged 24 months, age but not genotype was the major factor driving changes.

    “LOAD1 mice and controls were aged 24 months and data showed age but not genotype was the major factor-driving changes in LOAD1 mice (Kotredes et al., 2021).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Kotredes et al., 2021 source
  • Premisecitation

    Addition of a high fat/high sugar diet exacerbates Alzheimer's disease phenotypes in mouse models relevant to early-onset AD.

    “Also, the addition of an HFD exacerbated AD phenotypes in mouse models relevant to early-onset AD (Knight et al., 2014; Jones et al., 2019; Bracko et al., 2020; Robison et al., 2020; Jones et al., 2021).”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites Knight et al., 2014 source

      The Discussion (page unavailable) reports that a high-fat diet worsened memory deficits in 3xTgAD mice, supporting the high-fat-diet part of the citing sentence. The Methods describe the diet as high-fat, not high-fat/high-sugar; the quoted claim’s added sugar qualifier is unsupported. The Discussion also reports no increase in amyloid or tau deposition, so the exacerbation shown is cognitive rather than neuropathological. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites Jones et al., 2019 source

      The Discussion (page unavailable) reports that high-fat diets worsened cognitive deficits or AD pathology in some AD mouse models, which supports the general point. But this paper studied APOE knock-in mice, not an early-onset AD model, and found no robust diet-related behavioral effects in its own experiment. The cited passages also do not establish a high-sugar diet. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites Bracko et al., 2020 source

      The Discussion reports that a high-fat diet increased amyloid pathology, inflammation, and behavioral deficits in APP/PS1 mice. The Methods describe the diet as high-fat but do not establish the claim’s additional “high sugar” characterization; the verbatim citing sentence itself says only “HFD.” (LLM, conf=0.84)

      Experimental — accuracy not yet measured
  • Premisecitation

    Neuronal cell loss was not observed in LOAD1 mice, even at 24 months of age.

    “Neuronal cell loss was also not observed in LOAD1 mice, even at 24 months of age (Kotredes et al., 2021).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Kotredes et al., 2021 source
  • May combine two claims. 19
  • Classified as probably not a substantial claim. 37

  • May combine two claims.

    Study design and conductcitation

    All strains were validated using brain RNA-seq to confirm no off-target effects and no alterations in target transcript isoforms or expression levels.

    “All strains were validated using brain RNA-seq to confirm no off-target effects and no alterations in target transcript isoforms/expression levels (Kotredes et al., 2021).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Kotredes et al., 2021 source

      The paper reports brain RNA-seq in Materials and Methods (RNA-Sequencing Experimental Design), but it does not say that this confirmed an absence of off-target effects. More decisively, the Discussion reports that the Trem2*R47H mutation created a novel splice site and reduced Trem2 transcript levels by approximately 20%—the opposite of the claimed absence of changes in target isoforms or expression. Page numbers are not available in our copy. (LLM, conf=0.93)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

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

    Premisecitation

    Previous HFD studies have been associated with increased microglial activity in wild-type mice.

    “Previous HFD studies have been associated with increased microglial activity in wild-type mice (Rivera et al., 2013; Wanrooy et al., 2018).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites Rivera et al., 2013 source

      The Results (Figure 9; page unavailable) report significantly more Iba1-positive microglial cells in the hippocampi of HFD-fed rats, supporting the association with increased microglial activity. The cited study examined rats, not wild-type mice, so it does not support that population-specific part of the claim. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites Wanrooy et al., 2018 source

      The Results section (“Hyperglycemia increases microglia numbers and activates astrocytes”; page unavailable) reports increased hippocampal microglia in mice given STZ on a control diet, but not in either high-fat-diet group. The paper therefore does not support citing its HFD findings as evidence of increased microglial activity in wild-type mice; its measured outcome was microglial number rather than activity. (LLM, conf=0.78)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

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

    Premisecitation

    Although APOE4 and TREM2R47H are strong genetic risk factors for LOAD in humans, TREM2R47H may be reducing the effect of the APOE4 variant when present together.

    “However, data now suggest that although APOE4 and TREM2R47H are strong genetic risk factors for LOAD in humans, TREM2R47H may be reducing the effect of the APOE4 variant when present together (Kotredes et al., 2021).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Kotredes et al., 2021 source

      The Discussion states the opposite direction of effect: APOEε4 suppresses effects associated with Trem2*R47H, including its transcriptional and inflammatory responses in the mouse models. The paper also reports emerging evidence that APOEε4 carriers may not have increased AD risk from Trem2*R47H; it does not say Trem2*R47H reduces the effect of APOEε4. (LLM, conf=0.88)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

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

    Premisecitation

    Metabolic syndrome increases the risk for Type 2 diabetes, cardiovascular disease, and Alzheimer's disease.

    “Metabolic syndrome increases the risk for Type 2 diabetes and cardiovascular disease, and AD (Kivipelto et al., 2001; Luchsinger et al., 2004; Cordain et al., 2005; Whitmer et al., 2008).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites Kivipelto et al., 2001 source
    • cites Luchsinger et al., 2004 source
    • cites Cordain et al., 2005 source

      The Glycemic load and Glycemic index sections link metabolic syndrome and insulin resistance with coronary heart disease and type 2 diabetes. The paper does not address Alzheimer’s disease in the passages found, so it does not support that part of the claim. Page numbers were not available in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Early dysregulation of inflammation in APOE4 brains could predispose to CNS damage from various insults, including diet, and later results in increased CNS damage normally associated with the APOE4 genotype.

    “A second study concluded that early dysregulation of inflammation in APOE4 brains could predispose to CNS damage from various insults, including diet, and later results in the increased CNS damage normally associated with the APOE4 genotype (Jones et al., 2021).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Jones et al., 2021 source

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

    Interpretationown data

    These data are consistent with the induction of diet-induced obesity (DIO) that has been previously reported for B6 mice.

    “These data are consistent with the induction of diet-induced obesity (DIO) that has been previously reported for B6 mice (Wanrooy et al., 2018).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Wanrooy et al., 2018 source

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

    Premisecitation

    Many individuals are likely to develop LOAD due to a combination of genetic and environmental factors.

    “Studies also suggest that genetic factors may only contribute between 50 and 70% of the risk for LOAD, meaning many individuals are likely to develop LOAD due to a combination of genetic and environmental factors (Kawahara et al., 2017; Sarkar et al., 2019; Rahman et al., 2020; Kim et al., 2021).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites Kawahara et al., 2017 source
    • cites Sarkar et al., 2019 source

      The Introduction (page unavailable) says that Alzheimer’s disease has a multifactorial etiology and links environmental metal exposure to AD. It does not specifically address late-onset Alzheimer’s disease (LOAD), establish a combined genetic-and-environmental risk for individuals, or give the cited 50–70% genetic-risk estimate. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites Rahman et al., 2020 source

  • Classified as probably not a substantial claim.

    Premisecitation

    Obesity increases the risk for late-onset Alzheimer's disease (LOAD) and other dementias.

    “Studies have shown that diet, obesity, cardiovascular diseases, hypertension, physical activity, diabetes, educational attainment, smoking, and traumatic brain injury increase the risk for LOAD and other dementias (Ebbert et al., 2014; Baumgart et al., 2015; Xu et al., 2015; Wajman et al., 2018).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Ebbert et al., 2014 source

      The Introduction and Abstract > Methods describe genetic risk alleles and LOAD prediction, not obesity. A search for obesity, body mass index, and lifestyle risk factors found no passage in our copy linking obesity to LOAD or other dementias. (LLM, conf=0.72)

      Experimental — accuracy not yet measured
    • cites Baumgart et al., 2015 source

      Section 3.2, “Mid-life obesity,” reports that mid-life obesity is associated with increased dementia risk. The claim omits that age qualifier and states an increase in risk more definitively than the paper does: the same section notes that obesity in later life may be associated with reduced risk, while Section 2 describes evidence for modifiable factors and dementia as inconclusive. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites Xu et al., 2015

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

  • Classified as probably not a substantial claim.

    Premisecitation

    Chronic inflammation greatly increases the risk for LOAD.

    “Chronic inflammation has been shown to greatly increase the risk for LOAD (Furman et al., 2019).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Furman et al., 2019 source

      The section “Systemic chronic inflammation and non-communicable disease risk” lists neurodegenerative diseases among the risks associated with systemic chronic inflammation. It also reports lower Alzheimer’s disease risk among rheumatoid arthritis patients treated with etanercept. Neither passage establishes that chronic inflammation greatly increases the risk of late-onset Alzheimer’s disease (LOAD) specifically; page numbers are not available in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Behavioral deficits were not observed due to HFD, suggesting that metabolic responses to HFD are dependent on both sex and APOE genotype.

    “Behavioral deficits were not observed due to HFD, suggesting that metabolic responses to HFD are dependent on both sex and APOE genotype.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Jones et al., 2019 source

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

    Study design and conductcitation

    PET images were corrected for radionuclide decay, tissue attenuation, detector dead-time loss, and photon scatter.

    “In all cases, images were corrected for radionuclide decay, tissue attenuation, detector dead-time loss, and photon scatter according to the manufacturer’s methods (Krishnamoorthy et al., 2018).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Krishnamoorthy et al., 2018 source

      In Materials and Methods (NEMA NU-4 evaluation; page unavailable), the paper says CT data were used for PET attenuation and scatter corrections and that images were reconstructed with all available PET data corrections. Scanner Calibrations (page unavailable) describes a dead-time correction. Our copy does not explicitly identify radionuclide-decay correction or establish that the citing study applied every listed correction in all cases. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

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

    Premisecitation

    With HFD, male APOE4 mice were more susceptible to metabolic disturbances, including glucose intolerance, compared to APOE3 mice.

    “In one study, Jones et al. (2019) found that with HFD, male APOE4 mice were more susceptible to metabolic disturbances, including glucose intolerance when compared to APOE3 mice.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Jones et al., 2019 source

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

    Premisecitation

    Genetic factors may contribute only between 50 and 70% of the risk for LOAD.

    “Studies also suggest that genetic factors may only contribute between 50 and 70% of the risk for LOAD, meaning many individuals are likely to develop LOAD due to a combination of genetic and environmental factors (Kawahara et al., 2017; Sarkar et al., 2019; Rahman et al., 2020; Kim et al., 2021).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites Kawahara et al., 2017 source
    • cites Sarkar et al., 2019 source

      The Introduction (page not provided) says that the etiology of Alzheimer’s disease is multifactorial, which supports the broad point that factors beyond genetics may be involved. It does not give a 50–70% estimate for genetic risk or specifically address late-onset Alzheimer’s disease (LOAD); searches for those terms found no supporting passage. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites Rahman et al., 2020 source

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

    Premisecitation

    B6 mice homozygous or heterozygous for Mthfr677C>T show reduced enzyme activity in both the liver and brain, elevated levels of homocysteine, cerebral blood flow deficits, reduced collagen 4 in the brain, and neurovascular damage by electron microscopy.

    “Supporting a role for MTHFR in the cerebrovascular function, B6 mice homozygous or heterozygous for Mthfr677C > T show reduced enzyme activity in both the liver and brain, elevated levels of homocysteine, cerebral blood flow deficits, reduced collagen 4 in the brain, and neurovascular damage by electron microscopy (Reagan et al., 2021).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Reagan et al., 2021 source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

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

    Premisecitation

    E4FAD (APOE4+5xFAD) mice show increased amyloid deposition, specifically more compact plaques, compared to E3FAD (APOE3+5xFAD) mice.

    “Previous studies support this, with E4FAD (APOE4+5xFAD) mice showing increased amyloid deposition, specifically more compact plaques, compared to E3FAD (APOE3+5xFAD) mice (Youmans et al., 2012).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Youmans et al., 2012 source

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

    Premisecitation

    Reduced PLCG2 gene expression drives distinct transcriptional phenotypes of microglia in the presence of amyloid pathology.

    “A previous study has reported that reduced PLCG2 gene expression alters microglial phenotypes in 5XFAD mice, affects plaque pathology, and drives distinct transcriptional phenotypes of microglia in the presence of amyloid pathology (Tsai et al., 2021).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Tsai et al., 2021 source

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

    Premisecitation

    The role of PLCG2 has not yet been comprehensively explored.

    “However, the role of PLCG2 has not yet been comprehensively explored (Tsai et al., 2021; Maguire et al., 2021).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites Tsai et al., 2021 source
    • cites Maguire et al., 2021 source

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

    Premisecitation

    Reduced PLCG2 gene expression alters microglial phenotypes in 5XFAD mice.

    “A previous study has reported that reduced PLCG2 gene expression alters microglial phenotypes in 5XFAD mice, affects plaque pathology, and drives distinct transcriptional phenotypes of microglia in the presence of amyloid pathology (Tsai et al., 2021).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Tsai et al., 2021 source

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

    Premisecitation

    Reduced PLCG2 gene expression affects plaque pathology in 5XFAD mice.

    “A previous study has reported that reduced PLCG2 gene expression alters microglial phenotypes in 5XFAD mice, affects plaque pathology, and drives distinct transcriptional phenotypes of microglia in the presence of amyloid pathology (Tsai et al., 2021).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Tsai et al., 2021 source

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

    Findingown data

    Blood glucose levels were slightly lower in all mice housed at JAX compared to IU.

    “In general, blood glucose levels were slightly lower in all mice housed at JAX (Figure 1D) compared to IU (Figure 1E) which may be due to differences in environment, despite efforts to standardize housing conditions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    LOAD1.Plcg2M28L mice demonstrated an increase in microglia density and alterations in regional brain glucose and perfusion on HFD.

    “Interestingly, LOAD1.Plcg2M28L demonstrated an increase in microglia density and alterations in regional brain glucose and perfusion on HFD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The increase in microglia density and alterations in regional brain glucose and perfusion were not observed in LOAD1 or LOAD1.Mthfr677C>T animals fed HFD.

    “These changes were not observed in LOAD1 or LOAD1.Mthfr677C > T animals fed with HFD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Multiple immune-related pathways were upregulated and synaptic associated pathways, such as GABAergic synapse, and axon guidance were downregulated in the presence of HFD and interaction between HFD and Plcg2M28L.

    “Multiple immune-related pathways were upregulated and synaptic associated pathways, such as GABAergic synapse, and axon guidance were downregulated in the presence of HFD and interaction between HFD and Plcg2M28L (Supplementary Figure 1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    This study revealed an increase in microgliosis in the hippocampus of LOAD1.Plcg2M28L mice, but not in LOAD1.Mthfr677C>T.

    “Consistent with the transcriptomic changes, this study revealed an increase in microgliosis in the hippocampus of LOAD1.Plcg2M28L mice, but not in LOAD1.Mthfr677C > T.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In LOAD1.Plcg2M28L mice, plasma IL-1β was reduced in males and plasma IFN-γ was reduced in females.

    “However, there was a reduction in IL-1β (LOAD1.Plcg2M28L males) and IFN-γ (LOAD1.Plcg2M28L females)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The effects were stronger in females as we observed a significant positive correlation with immune modules associated with the PHG brain region in females, which was not significant in male mice.

    “However, the effects were stronger in females as we observed a significant positive correlation (p < 0.05) with immune modules associated with the PHG brain region as well in females, which was not significant (p > 0.05) in male mice.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The second principal component accounts for 25% of the total variance and separated Mthfr677C > T and interaction between HFD and Plcg2M28L factors from other factors.

    “The second principal component accounts for 25% of the total variance and separated Mthfr677C > T and interaction between HFD and Plcg2M28L factors from other factors (Supplementary Figure 2).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Some of those changes were observed in this study.

    “Some of those changes were observed in this study (Figure 1).”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Autoradiography provided secondary confirmation of the in vivo PET images.

    “To provide secondary confirmation of the in vivo PET images, and to quantify tracer uptake regionally, the brains were extracted post rapid decapitation, gross sectioned along the midline, slowly frozen on dry ice, then embedded in cryomolds with optimal cutting temperature (OCT) compound (Tissue-Tek).”
    Quote in the paperNot a substantial claim

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

    Study design and conductreasoning

    These data are not collected based on stereological analyses and are therefore suggestive of a reduced density of IBA1+ cells.

    “These data are not collected based on stereological analyses and are therefore suggestive of a reduced density of IBA1+ cells.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Unless specified, n = 10 for each sex, genotype, and diet were used.

    “Unless specified, n = 10 for each sex, genotype, and diet were used.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Experimental cohorts were randomized into two groups at 2 months of age.

    “At 2 months of age (mos), experimental cohorts were randomized into two groups: Group 1 continued on CD ad libitum and Group 2 was provided with ResearchDiet® feed D12451i (45% of high fat; 35% of carbohydrates, HFD3) ad libitum.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    Pathways were determined to be significant after multiple testing corrections (FDR adjusted p < 0.05).

    “Pathways were determined to be significant after multiple testing corrections (FDR adjusted p < 0.05).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    These data suggest HFD-induced features of some metabolic syndrome, potentially in a sex-specific manner, but independent of genotype.

    “Collectively, these data suggest HFD-induced features of some metabolic syndrome, potentially in a sex-specific manner, but independent of genotype.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Where possible, all housing and procedures were standardized and aligned across sites.

    “Where possible, all housing and procedures were standardized and aligned across sites.”
    Quote in the paperNot a substantial claim

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

    Study design and conductcitation

    PET and CT images were co-registered using a mutual information-based normalized entropy algorithm and mapped to stereotactic mouse brain coordinates.

    “Post-acquisition, all PET and CT images were co-registered using a mutual information-based normalized entropy algorithm (Studholme et al., 1998) with 12 degrees of freedom and mapped to stereotactic mouse brain coordinates (Franklin and Paxinos, 2013).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Studholme et al., 1998 source
    • cites Franklin and Paxinos, 2013

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

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

    Study design and conductown data

    Findings were confirmed using autoradiography.

    “Findings were confirmed using autoradiography.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    A detailed assessment of Type 2 diabetic phenotypes was not performed here.

    “However, a detailed assessment of Type 2 diabetic phenotypes was not performed here.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Our study was not designed to determine whether the changes are reversible.

    “However, our study was not designed to determine whether the changes are reversible.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Recent in vivo imaging studies have suggested that microglia displayed higher glucose uptake than neurons and astrocytes.

    “Recent in vivo imaging studies have suggested that microglia displayed higher glucose uptake than neurons and astrocytes (Xiang et al., 2021).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Xiang et al., 2021 source

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

    Premisecitation

    Variations in MTHFR, particularly the Mthfr677C>T variant, are associated with cardiovascular diseases, AD, and vascular dementia.

    “Variations in MTHFR, particularly the Mthfr677C > T variant, are associated with cardiovascular diseases, AD, and vascular dementia (Liu et al., 2010; Liew and Gupta, 2015; Rai, 2017).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Liu et al., 2010 source
    • cites Liew and Gupta, 2015 source
    • cites Rai, 2017 source

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationown data

    Additional pathways/processes need to be perturbed, likely in combination with extended aging, to further align these models to human LOAD.

    “Also, neuronal loss was not detected in LOAD1.Plcg2M28L mice on an HFD, at least in the brain regions assessed up to 12 months of age, suggesting additional pathways/processes need to be perturbed likely in combination with extended aging to further align these models to human LOAD.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Mice require mutations or engineering of the human sequence to drive plaque deposition, and neither is present in these mice.

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

    Interpretationreasoning

    We cannot rule out that the interaction between HFD and Plcg2M28L observed in the brain is due to increased susceptibility to Type 2 diabetes in LOAD1.Plcg2M28L compared to the other strains tested.

    “Therefore, although we suggest not likely, we cannot rule out the interaction between HFD and Plcg2M28L observed in the brain is due to increased susceptibility to Type 2 diabetes in LOAD1.Plcg2M28L compared to the other strains tested.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    This is the first study to show that specific LOAD risk variants interact with HFD to exacerbate LOAD phenotypes whereas others do not.

    “To our knowledge, this is the first study to show that specific LOAD risk variants interact with HFD to exacerbate LOAD phenotypes whereas others do not.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    MODEL-AD has created a new Trem2R47H allele (Trem2*R47H HSS) that incorporates a human splice site and restores Trem2 expression to normal levels, at least in young wild type B6 mice.

    “MODEL-AD has created a new Trem2R47H allele (Trem2*R47H HSS) that incorporates a human splice site (HSS) and restores Trem2 expression to normal levels, at least in young wild type B6 mice (JAX#33781).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites JAX#33781

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

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

    Premisecitation

    Reduced expression levels of Trem2 in Trem2R47H mice are caused by a cryptic splice site that results in an aberrant splice form.

    “This may be due in part to the reduced expression levels of Trem2 in Trem2R47H mice caused by a cryptic splice site that results in an aberrant splice form (JAX#27918).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites JAX#27918

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

  • May combine two claims.

    Study design and conductown data

    Despite all mice carrying the APOE4 and Trem2R47H variants, linear modeling identified the specific effects of the Plcg2M28L and Mthfr677C>T variants and the Plcg2M28L:HFD and Mthfr677C>T:HFD interactions.

    “Despite the fact that all mice carried the APOE4 and Trem2R47H variants, linear modeling identified the specific effects of the Plcg2M28L and Mthfr677C > T variants and the Plcg2M28L:HFD and Mthfr677C > T:HFD interactions.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Combining genetic and environmental risk factors (e.g., HFD) leads to better translational and preclinical models of LOAD.

    “In summary, combining genetic and environmental risk factors (e.g., HFD) leads to better translational and preclinical models of LOAD.”
    Quote in the paperNot a substantial claim
48 of 48

  • The paper relies on this without support.

    The majority of studies to date have focused on the use of early-onset AD models.

    “The majority of studies, to date, have focused on the use of early-onset AD models.”

  • The paper relies on this without support.

    No single LOAD-associated variant is sufficient to cause AD.

    “Importantly, unlike relatively rare cases of familial AD (fAD), which are predominantly caused by mutations in APP or one APP processing gene, no single LOAD-associated variant is sufficient to cause AD.”

  • The paper relies on this without support.

    Combinations of genetic risk factors are required to develop LOAD.

    “It is anticipated that combinations of genetic risk factors are required to develop LOAD.”

  • The paper relies on this without support.

    LOAD1, LOAD1.Plcg2M28L, and LOAD1.Mthfr677C>T did not natively recapitulate all phenotypes relevant to LOAD.

    “Despite carrying multiple genetic risk variants for LOAD, LOAD1, LOAD1.Plcg2M28L, and LOAD1.Mthfr677C > T did not natively recapitulate all phenotypes relevant to LOAD, making these strains ideal to test the effects of environmental risk factors, such as diet.”

  • The paper relies on this without support.

    The effects of a western-like diet in the context of multiple genetic risk factors for LOAD have not been studied.

    “However, the effects of a western-like diet in the context of multiple genetic risk factors for LOAD have not been studied.”

  • The paper relies on this without support.

    APOE4 is the greatest genetic risk factor for LOAD.

    “The E4 allele of apolipoprotein E (APOE4) is the greatest genetic risk factor but with variations in many other genes, including triggering receptor expressed on myeloid cells 2 (TREM2), also contribute to risk.”

  • The paper relies on this without support.

    Variations in many other genes, including TREM2, also contribute to LOAD risk.

    “The E4 allele of apolipoprotein E (APOE4) is the greatest genetic risk factor but with variations in many other genes, including triggering receptor expressed on myeloid cells 2 (TREM2), also contribute to risk.”

  • The paper relies on this without support.

    A hallmark of LOAD and other dementias is the loss of neurons, particularly in the cortex and hippocampus.

    “A hallmark of LOAD and other dementias is the loss of neurons, particularly in the cortex and hippocampus.”

  • The paper relies on this without support.

    The cortical and hippocampal neuronal cell loss is largely absent in the most widely used mouse models of fAD and LOAD.

    “However, the cortical and hippocampal neuronal cell loss is largely absent in the most widely used mouse models of fAD and LOAD.”

  • The paper relies on this without support.

    The second hallmark of LOAD is neuroinflammation, particularly microglia activation.

    “The second hallmark of LOAD is neuroinflammation, particularly microglia activation.”

  • The paper relies on this without support.

    In our previous study, LOAD1 mice did not show microglia activation.

    “In our previous study, LOAD1 mice did not show microglia activation.”

  • The paper relies on this without support.

    Late-onset AD is a complex disorder that is caused by a combination of genetic and environmental risk factors.

    “Late-onset AD is a complex disorder that is caused by a combination of genetic and environmental risk factors.”

  • The paper relies on this without support.

    The specific combinations of genetic and environmental factors that increase the risk for LOAD are not well understood.

    “However, the specific combinations of genetic and environmental factors that increase the risk for LOAD are not well understood.”

  • The paper relies on this without support.

    It is likely that these vary between individuals, making predictions of risk for LOAD based on their genetics and exposures imprecise.

    “In fact, it is likely that these vary between individuals, making predictions of risk for LOAD based on their genetics and exposures imprecise.”

  • The paper relies on this without support.

    Many inflammation genes, including Csf1, Tgfbr2, Fcer1g, Trem2, and Tyrobp, are expressed by microglia.

    “Many of these “inflammation” genes are expressed by microglia including Csf1, Tgfbr2, Fcer1g, Trem2, and Tyrobp.”

  • The paper relies on this without support.

    PLCG2 is a critical signaling element for various immune receptors and a key regulatory hub gene for immune signaling.

    “PLCG2 is a critical signaling element for various immune receptors and is a key regulatory hub gene for immune signaling.”

  • The paper relies on this without support.

    The HFD used in this study creates a more inflammatory environment in the brain, causing microglia activation.

    “The HFD used here is reported to create a more inflammatory environment in the brain, causing microglia activation.”

  • The paper relies on this without support.

    MTHFR is a key enzyme in the folate/methionine/homocysteine pathway.

    “MTHFR is a key enzyme in the folate/methionine/homocysteine pathway.”

  • The paper relies on this without support.

    In humans, MTHFR677C>T reduces liver enzyme activity, resulting in decreased enzyme function.

    “In humans, MTHFR677C > T reduces liver enzyme activity resulting in a decrease in enzyme function.”

  • The paper relies on this without support.

    Increases in homocysteine increase the risk for vascular inflammation and dysregulation.

    “Common effects of this include increases in homocysteine which is reported to increase the risk for vascular inflammation and dysregulation.”

  • The paper relies on this without support.

    MTHFR is expressed in multiple cells in the brain, particularly vascular-related cells such as endothelial and vascular smooth muscle cells.

    “The MTHFR is also expressed in multiple cells in the brain, particularly in vascular-related cells, such as endothelial and vascular smooth muscle cells.”

  • The paper relies on this without support.

    A function for MTHFR in microglia has not been reported.

    “However, unlike Plcg2M28L, a function for MTHFR in microglia has not been reported”

  • The paper relies on this without support.

    Mice require mutations or engineering of the human sequence to drive plaque deposition, and neither is present in these mice.

    “This is not surprising as mice require mutations or engineering of the human sequence to drive plaque deposition, neither of which are present in these mice.”
23 of 23

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?

  • PLCG2M28L confers increased risk for AD.

    “Conversely, the partial loss‐of‐function M28L variant (PLCG2M28L) confers increased risk for AD. 19 , 20”

    From Alzheimer's disease–associated PLCG2 variants alter microglial state and function in human induced pluripotent stem cell–derived microglia‐like cells (2025) · cites this paper as [20]

    The Introduction identifies Plcg2M28L as an additional genetic risk factor for late-onset AD, supporting the risk claim. But the citing sentence also calls M28L a partial loss-of-function variant, whereas the Introduction says its precise effects have not yet been elucidated; this copy does not support that characterization. No page numbers are available in the indexed passages. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • PLCG2M28L modulates phagocytic capability and alters inflammatory responses.

    “PLCG2M28L, though less studied, has been shown to modulate phagocytic capability and alter inflammatory responses. 19 , 20”

    From Alzheimer's disease–associated PLCG2 variants alter microglial state and function in human induced pluripotent stem cell–derived microglia‐like cells (2025) · cites this paper as [20]

    The Results section reports altered brain and plasma cytokines in LOAD1.Plcg2M28L mice, supporting the inflammatory-response part of the claim. It also reports enrichment of phagocytosis-related gene pathways, but does not show that the variant changes phagocytic capability itself; the Introduction says the precise effects of M28L had not yet been elucidated. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Expression of PLCγ2 M28L in the mouse brain led to a transcriptomic profile that correlated with human AD modules and led to increased microglia density when fed a high fat diet.

    “Expression of PLCγ2 M28L in the mouse brain led to a transcriptomic profile that correlated with human AD modules and led to increased microglia density when fed with a high fat diet (17).”

    From Multi-omics analyses reveal novel effects of PLCγ2 deficiency in the mouse brain (2023) · cites this paper as [17]

    The Results section reports that Plcg2M28L and its interaction with a high-fat diet correlated with human AD gene-expression modules. It also reports increased microglial density in high-fat-fed female LOAD1.Plcg2M28L mice, but the claim omits the sex restriction and implies a general increase across the mouse brain. The Results specify the cortex, while the Discussion describes the increase as limited to the hippocampus; our copy does not resolve that discrepancy. No page numbers are provided. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • The loss-of-function PLCG2M28L variant confers resistance to the Bruton Tyrosine Kinase inhibitor ibrutinib, worsens Aβ pathology, and increases risk of AD.

    “Conversely, the loss‐of‐function PLCG2M28L variant confers resistance to the Bruton Tyrosine Kinase inhibitor ibrutinib, worsens Aβ pathology, and increases risk of AD.”

    From PLCG2 modulates TREM2 expression and signaling in response to Alzheimer's disease pathology (2025) · cites this paper as [29]

    The Introduction and Methods describe Plcg2M28L as an AD risk variant, but the Introduction says its precise effects have not been elucidated. The Discussion states that the studied mice lacked amyloid-beta plaques, rather than showing worsened Aβ pathology. No passage found in our copy supports loss of function or resistance to ibrutinib. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • PLCG2 loss-of-function has recently been associated with worsened AD pathology.

    “Likewise, PLCG2 loss‐of‐function has recently been associated with worsened AD pathology. 12 , 27 , 29”

    From PLCG2 modulates TREM2 expression and signaling in response to Alzheimer's disease pathology (2025) · cites this paper as [29]

    The Discussion reports more extreme AD-relevant phenotypes in mice carrying Plcg2M28L on a LOAD1 background when exposed to a high-fat/high-sugar diet. It describes loss of function for this variant as predicted, not established. Thus the paper supports a qualified association in this mouse model, but not the broader claim that PLCG2 loss of function generally worsens AD pathology. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

Self-check

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

Each contradiction between two passages listed here was confirmed by an independent check.

  • JAX glucose result is called significant despite p = 0.165

    Major

    The results say the HFD effect on glucose was significant in females in both studies, but give p = 0.165 for the JAX females. The paper defines significance as p < 0.05.

  • Increased IBA1+ cell count is described as reduced density

    Minor

    The same results passage reports increased IBA1+ cells in the cortex, then describes the data as suggestive of reduced IBA1+ cell density.

  • Bilateral region count yields 28, not 27, regions

    Minor

    The image-analysis methods say 56 bilateral regions were paired to yield 27 unique volumes. Pairing 56 regions yields 28 volumes; the passage also lists 28 named regions.

    Reported 27 · recomputed 28

  • Terminal blood collection is called non-anesthetized and anesthetized

    Minor

    The results describe the mice as non-anesthetized for blood samples at both 8 and 12 months. The methods say mice were anesthetized for the terminal, 12-month blood collection.

  • Regression intercept is assigned to males despite a male indicator

    Minor

    The model says sex (male) is included as a regression term, making the reference category female. It then identifies the intercept as the average expression for reference male mice.

5 of 5

Cites

Flagged first, then by citations

Research works printed but not linked: 3

  1. Franklin, 2013, Paxinos and Franklin’s The Mouse Brain In Stereotaxic Coordinates, 1
  2. Hartwig, 2015, The Whole30
  3. 2022, Adult Obesity Facts.

Cited by

Sorted by citations

Related

Authors
Oblak, A. L., Kotredes, K. P., Pandey, R. S., Reagan, A. M., Ingraham, C., Perkins, B., Lloyd, C., Baker, D., Lin, P. B., Soni, D. M., Tsai, A. P., Persohn, S. A., Bedwell, A. A., Eldridge, K., Speedy, R., Meyer, J. A., Peters, J. S., Figueiredo, L. L., Sasner, M., Territo, P. R., Sukoff Rizzo, S. J., Carter, G. W., Lamb, B. T., & Howell, G. R.
Affiliations
  • Indiana University Indianapolis (US)
  • Jackson Laboratory (US)
  • Indiana University School of Medicine
Corresponding author
  • Oblak, Adrian L.
  • Howell, Gareth R.
ORCID
Venue
Frontiers in Aging Neuroscience
Publisher
Frontiers Media SA
Published
2022-06-24
Volume
14
Pages
886575-886575
ISSN
1663-4365 (ISSN-L)
DOI
10.3389/fnagi.2022.886575
PMC
PMC9263289
OpenAlex
W4283460059
Semantic Scholar
6a5aab1c31a9bb811afe93337b9a73943d5ccf96
Cited by
23
References
75
Citations by year
2026: 8 · 2025: 4 · 2024: 7 · 2023: 3 · 2022: 1
FWCI
1.92
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Aging Neuroscience (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • IUScholarWorks (Indiana University) (submittedVersion, cc-by)
  • PubMed Central (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion, cc-by)
Funders
National Institutes of Health (U54AG054345, K01AG054753)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, late-onset Alzheimer's disease, high-fat high-sugar diet, obesity, APOE ε4, genetic risk factors, brain glucose metabolism, cerebral perfusion, cholesterol, glucose, lifestyle intervention

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-18.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-18.

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 ›

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