CoChat
Sign Up
Cited by 55Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchCholinesterase and Neurodegenerative Diseases

Dietary choline intake is necessary to prevent systems‐wide organ pathology and reduce Alzheimer's disease hallmarks

Open access
Dave, Nikhil, Judd, Jessica M., Decker, Annika, Winslow, Wendy, Sarette, Patrick, Villarreal Espinosa, Oscar, Tallino, Savannah, Bartholomew, Samantha K. +8 more·2023·Aging Cell
DOI 10.1111/acel.13775PMC PMC9924938

Published version of a preprint

Open this paper in CoChat — free accountOpen PDF

Abstract

There is an urgent need to identify modifiable environmental risk factors that reduce the incidence of Alzheimer's disease (AD). The B‐like vitamin choline plays key roles in body‐ and brain‐related functions. Choline produced endogenously by the phosphatidylethanolamine N‐methyltransferase protein in the liver is not sufficient for adequate physiological functions, necessitating daily dietary intake. ~90% of Americans do not reach the recommended daily intake of dietary choline. Thus, it's imperative to determine whether dietary choline deficiency increases disease outcomes. Here, we placed 3xTg‐AD, a model of AD, and non‐transgenic (NonTg) control mice on either a standard laboratory diet with sufficient choline (ChN; 2.0 g/kg choline bitartrate) or a choline‐deficient diet (Ch‐; 0.0 g/kg choline bitartrate) from 3 to 12 (early to late adulthood) months of age. A Ch‐ diet reduced blood plasma choline levels, increased weight, and impaired both motor function and glucose metabolism in NonTg mice, with 3xTg‐AD mice showing greater deficits. Tissue analyses showed cardiac and liver pathology, elevated soluble and insoluble Amyloid‐β and Thioflavin S structures, and tau hyperphosphorylation at various pathological epitopes in the hippocampus and cortex of 3xTg‐AD Ch‐ mice. To gain mechanistic insight, we performed unbiased proteomics of hippocampal and blood plasma samples. Dietary choline deficiency altered hippocampal networks associated with microtubule function and postsynaptic membrane regulation. In plasma, dietary choline deficiency altered protein networks associated with insulin metabolism, mitochondrial function, inflammation, and fructose metabolic processing. Our data highlight that dietary choline intake is necessary to prevent systems‐wide organ pathology and reduce hallmark AD pathologies.

AI snapshot

Written from the paper’s full text.

TL;DR

Dietary choline deficiency from 3 to 12 months in female NonTg and 3xTg‐AD mice reduced plasma and brain choline, increased weight and glucose intolerance, caused cardiac and liver pathology, and exacerbated Aβ and tau pathology in 3xTg‐AD mice. Proteomics linked choline deficiency to hippocampal microtubule/postsynaptic networks and plasma insulin, mitochondrial, inflammatory, and fructose metabolic pathways.

Key findings

  • Ch‐ reduced plasma choline (p < 0.0001) and hippocampal/cortical choline (both p < 0.0001), increased percent weight change (NonTg Ch‐ vs. ChN, p = 0.026; 3xTg‐AD Ch‐ vs. ChN, p < 0.0001), and impaired glucose tolerance AUC (NonTg Ch‐ vs. ChN, p = 0.0042; 3xTg‐AD Ch‐ vs. ChN, p < 0.0001).
  • Ch‐ impaired motor function on rotarod (Day 1 p = 0.0002, Day 2 p = 0.0002, Day 3 p < 0.0001), but no diet effects were detected in Morris water maze spatial learning/memory; 3xTg‐AD mice showed genotype deficits.
  • Ch‐ induced cardiac and liver pathology: 3xTg‐AD Ch‐ mice had highest heart weight (p = 0.0018), Col1a1/Myh7/Nppa were elevated in all groups except NonTg ChN (p < 0.05), all NonTg Ch‐ mice exhibited NAFLD, and three 3xTg‐AD Ch‐ mice showed NASH; liver PEMT did not differ across groups.
  • In 3xTg‐AD mice, Ch‐ increased soluble Aβ42 (Hp p = 0.014; Ctx p < 0.0001), Aβ oligomers (Hp p = 0.0054; Ctx p = 0.021), insoluble Aβ42 (Hp p = 0.035; Ctx p < 0.0001), Thioflavin S structures (p = 0.039), soluble pTau Ser181 (Hp p < 0.0001; Ctx p = 0.0009), soluble pTau Ser396 (Hp/Ctx p < 0.0001), and AT8‐positive CA1 cells (p = 0.049). Proteomics identified 86 and 249 differentially abundant hippocampal proteins in NonTg and 3xTg‐AD Ch‐ comparisons, and 80 and 70 in plasma, respectively.

Methods

  • Female NonTg and 3xTg‐AD mice were placed at 3 months on either ChN (2.0 g/kg choline bitartrate) or Ch‐ (0.0 g/kg) AIN76A diet and aged to ~12 months; group sizes were NonTg ChN n = 20, 3xTg‐AD ChN n = 15, NonTg Ch‐ n = 18, 3xTg‐AD Ch‐ n = 16.
  • At 10 months, mice underwent rotarod and Morris water maze testing; body weight, food consumption, glucose tolerance test, plasma choline, brain choline, ELISAs for Aβ/pTau, histology (H&E, Thioflavin S, AT8), qRT‐PCR, and PEMT western blot were performed.
  • Unbiased LC–MS/MS with label‐free quantification was performed on hippocampal and plasma samples (n = 4/group), with gene ontology analysis via STRINGv11.5; statistics used two‐way ANOVA, repeated measures ANOVA, Bonferroni post hoc tests, and unpaired t‐tests.

Limitations

  • The paper states that brain choline levels rise post‐mortem, so comparisons between live plasma choline and post‐mortem brain choline should be made with caution; it also hypothesizes that lack of further MWM impairment in 3xTg‐AD Ch‐ mice may reflect ceiling effects in 3xTg‐AD ChN performance, and notes that heavier Ch‐ mice may be more likely to fall faster on rotarod.
  • The paper states that future work is needed to test whether liver disease contributes to reduced peripheral Aβ clearance and increased brain Aβ burden.
  • Evident from the text: only female 3xTg‐AD mice were used because males do not display consistent neuropathology, and findings are from a mouse model with no human validation; proteomics and some histology used small group sizes (e.g., n = 4/group).

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

Integrity signals

Registry

Crossref · 10.1111/acel.13775

Cites

46 of 46 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

0 of 65 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    3xTg-AD choline-deficient mice had higher soluble pTau Ser396 in the hippocampus and cortex than 3xTg-AD choline-sufficient mice.

    “For soluble pTau Ser396, we found significantly higher levels in the Hp (t(13) = 9.045, p < 0.0001) and Ctx (t(13) = 7.691, p < 0.0001) in 3xTg‐AD Ch‐ mice (Figure 4k).”
    Quote in the paperSubstantial claim
  • Findingown data

    3xTg-AD choline-deficient mice had higher insoluble amyloid-beta 42 in the hippocampus and cortex than 3xTg-AD choline-sufficient mice.

    “For insoluble Aβ42 fractions, 3xTg‐AD Ch‐ mice had significantly higher levels in the Hp (t(13) = 2.357, p = 0.035) and Ctx (t(13) = 13.90, p < 0.0001; Figure 4g).”
    Quote in the paperSubstantial claim
  • Findingown data

    In the rotarod task, 3xTg-AD mice had shorter latency to fall than NonTg mice on Days 1, 2, and 3.

    “significant main effects of genotype, where the 3xTg‐AD mice fell off the spinning rod significantly faster than NonTg mice on Day 1 (p = 0.001), Day 2 (p = 0.016) and the Day 3 probe trial (p < 0.0001).”
    Quote in the paperNot a substantial claim
  • Findingown data

    Choline-deficient mice had higher percent weight change from baseline than choline-sufficient mice.

    “Ch‐ mice had a higher percent weight change than their ChN counterparts.”
    Quote in the paperNot a substantial claim
  • Findingown data

    NonTg choline-sufficient mice had healthy livers.

    “Staining for the ChN mice showed that NonTg mice had healthy livers”
    Quote in the paperSubstantial claim
  • The quote only partly states this claim. 11
  • May combine two claims. 48
  • Classified as probably not a substantial claim. 30

  • The quote only partly states this claim.

    Findingown data

    A choline-deficient diet increased tau hyperphosphorylation at various pathological epitopes in the hippocampus and cortex of 3xTg-AD mice.

    “tau hyperphosphorylation at various pathological epitopes”
    • Also stated in: § Ch‐ reduces hippocampal (Hp) and cortical (Ctx) choline levels and exacerbates soluble and insoluble amyloid‐ß (Aß) pathology and tau hyperphosphorylation · plain
      “Collectively, these data illustrate that Ch‐ exacerbates tau pathology in 3xTg‐AD mice.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    A choline-deficient diet elevated soluble and insoluble amyloid-beta in the hippocampus and cortex of 3xTg-AD mice.

    “elevated soluble and insoluble Amyloid‐β”
    • Also stated in: § Ch‐ reduces hippocampal (Hp) and cortical (Ctx) choline levels and exacerbates soluble and insoluble amyloid‐ß (Aß) pathology and tau hyperphosphorylation · boosted
      “collectively showing that Ch‐ increases levels of toxic Aβ pathology in 3xTg‐AD mice.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    A choline-deficient diet impaired glucose metabolism in NonTg and 3xTg-AD mice.

    “impaired both motor function and glucose metabolism in NonTg mice”
    • Also stated in: § Ch‐ increases body weight, impairs glucose metabolism, and reduces plasma choline levels · plain
      “Ch‐ mice had higher glucose levels than ChN mice (Figure 2e).”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    A choline-deficient diet impaired motor function in NonTg and 3xTg-AD mice.

    “impaired both motor function and glucose metabolism in NonTg mice”
    • Also stated in: § Ch‐ throughout adulthood impairs motor function · plain
      “Ch‐ mice fell sooner than the ChN mice”
    Quote in the paperSubstantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    3xTg-AD choline-deficient mice had higher insoluble amyloid-beta 40 in the cortex than 3xTg-AD choline-sufficient mice, with a non-significant trend in the hippocampus.

    “In the Ctx (t(13) = 2.398, p = 0.032), 3xTg‐AD Ch‐ mice exhibited significantly higher levels of insoluble Aβ40 (Figure 4f).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the hippocampus, 3xTg-AD choline-sufficient versus NonTg choline-sufficient mice showed upregulation of App, Mapt just under threshold (Log2 FC = 0.97), and downregulation of Apoa1 and Nptn.

    “including upregulation of the amyloid precursor protein (App; Log2 FC = 1.58) and microtubule‐associated protein tau (Mapt), although Log2 FC was just under 1 (Log2 FC = 0.97), as well as downregulation of Apolipoprotein A1 (Apoa1; Log2 FC = −1.27), and Neuroplastin (Nptn; Log2 FC = −1.55).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    3xTg-AD mice consumed more food than NonTg mice, but there was no significant diet effect on food consumption.

    “We found a significant main effect of genotype (F (1, 14) = 11.69, p = 0.0042; Figure 2c), where the 3xTg‐AD mice consumed significantly more than NonTg mice, but no significant diet effects”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In the Morris water maze Day 6 probe trial, 3xTg-AD mice crossed the platform location fewer times and had higher latency to first cross than NonTg mice.

    “3xTg‐AD mice crossed the platform location significantly fewer times than NonTg mice (F (1, 64) = 12.276, p = 0.0008; Figure 1g) and had a higher latency to first cross the platform location (F (1, 64) = 6.948, p = 0.0105; Figure 1h)”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    3xTg-AD choline-deficient mice had higher AT8-positive cell numbers in the CA1 region of the hippocampus than 3xTg-AD choline-sufficient mice.

    “we stained against AT8, which is associated with intraneuronal tau filaments (Dave et al., 2021), and found significantly higher stained cells in 3xTg‐AD Ch‐ mice (t(6) = 2.462, p = 0.049; Figure 4n–p).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Dave et al., 2021

      Not checked in the free run.

  • The quote only partly states this claim.

    Findingown data

    A choline-deficient diet increased body weight in NonTg and 3xTg-AD mice.

    “increased weight”
    • Also stated in: § Ch‐ increases body weight, impairs glucose metabolism, and reduces plasma choline levels · plain
      “Ch‐ mice had a higher percent weight change than their ChN counterparts.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    3xTg-AD mice showed greater deficits than NonTg mice in weight, motor function, and glucose metabolism under a choline-deficient diet.

    “with 3xTg‐AD mice showing greater deficits.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    3xTg-AD mice had higher heart weight normalized by tibia length than NonTg mice.

    “where 3xTg‐AD mice had a higher heart weight than NonTg mice (Figure 3a).”
    Quote in the paperNot a substantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    Of the 26 common plasma proteins, 6 were upregulated, 4 downregulated, and 16 expressed in opposing directions.

    “Of the 26 proteins whose levels were altered due to Ch‐ in both NonTg Ch‐ versus NonTg ChN and 3xTg‐AD Ch‐ versus 3xTg‐AD ChN comparisons (Figure 6f; Figure S2), 6 were upregulated, 4 were downregulated, and 16 were expressed in opposing directions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Choline deficiency significantly lowered choline in plasma and brain tissue, and liver PEMT showed no compensation.

    “We confirmed significantly lower levels of choline in plasma and brain tissue with Ch‐ and found no compensation of liver PEMT for dietary choline deficiency.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    3xTg‐AD Ch‐ mice showed the most severe weight gain and glucose metabolism impairments and the highest pathological burden.

    “3xTg‐AD Ch‐ mice not only showed the most severe weight gain and glucose metabolism impairments but also had the highest pathological burden”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the hippocampus, NonTg choline-deficient versus NonTg choline-sufficient mice had 86 differentially abundant proteins; 3xTg-AD choline-deficient versus 3xTg-AD choline-sufficient mice had 249; 34 were common.

    “In the NonTg Ch‐ vs. NonTg ChN comparison, 86 differentially abundant proteins were identified, and in the 3xTg‐AD Ch‐ vs. 3xTg‐AD ChN comparison, 249 differentially abundant proteins were identified (Figure 5a,b). Thirty‐four proteins were commonly identified as differentially abundant due to Ch‐ in both NonTg and 3xTg‐AD mice”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In plasma, NonTg choline-deficient versus NonTg choline-sufficient mice had 80 differentially abundant proteins; 3xTg-AD choline-deficient versus 3xTg-AD choline-sufficient mice had 70; 26 were common.

    “In the NonTg Ch‐ vs. NonTg ChN comparison, 80 differentially abundant proteins were identified. In the 3xTg‐AD Ch‐ vs. 3xTg‐AD ChN comparison, 70 differentially abundant proteins were identified (Figure 6a,b). Twenty‐six proteins were commonly identified as differentially abundant due to Ch‐ in both NonTg and 3xTg‐AD plasma”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Ch‐ mice weighed significantly more than ChN animals and had higher body weights despite similar food consumption.

    “It is important to note that Ch‐ mice did weigh significantly more than ChN animals”
    • Also stated in: § DISCUSSION · plain
      “Ch‐ mice had higher body weights than their ChN counterparts despite similar food consumption.”
    Quote in the paperNot a substantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    Of the 34 common hippocampal proteins, 6 were upregulated, 16 downregulated, and 12 expressed in opposing directions.

    “Of the 34 proteins that were differentially abundant due to Ch‐ in both NonTg Ch‐ vs. NonTg ChN and 3xTg‐AD Ch‐ vs. 3xTg‐AD ChN comparisons (Figure 5f; Figure S2), 6 were upregulated, 16 were downregulated, and 12 were expressed in opposing directions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The 3xTg‐AD phenotype and the Ch‐ diet led to cardiac hypertrophy, with 3xTg‐AD Ch‐ mice showing the most severe cardiac hypertrophy.

    “In the present study, we found that the 3xTg‐AD phenotype and the Ch‐ diet led to cardiac hypertrophy, with 3xTg‐AD Ch‐ mice showing the most severe cardiac hypertrophy.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    In plasma, 3xTg-AD choline-sufficient versus NonTg choline-sufficient mice had 126 differentially abundant proteins, 49 upregulated and 76 downregulated.

    “found 126 differentially abundant proteins, 49 of which were upregulated and 76 downregulated.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    3xTg‐AD Ch‐ mice progressed to NASH, with evidence of inflammation and scarring alongside hepatic steatosis.

    “while 3xTg‐AD mice progressed to NASH, with evidence of inflammation and scarring alongside hepatic steatosis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Ch‐ in 3xTg‐AD mice downregulates Vdac1 (Log2 FC = −6.64) and Vdac2 (Log2 FC = −2.84).

    “Ch‐ in 3xTg‐AD mice downregulates Vdac1 (Log2 FC = −6.64) and Vdac2 (Log2 FC = −2.84)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Ide (Log2 FC = 2.57) and Hspd1 (Log2 FC = 6.64) were upregulated in 3xTg‐AD ChN mice compared to NonTg ChN.

    “Notably, both ide (Log2 FC = 2.57) and Hspd1 (Log2 FC = 6.64) were upregulated in 3xTg‐AD ChN mice compared to NonTg ChN.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Other pathologies in Alzheimer's disease include neuroinflammation, cardiac pathology, and insulin dysregulation.

    “Other pathologies in AD include neuroinflammation (Husna Ibrahim et al., 2020; Kandimalla et al., 2017), cardiac pathology (Yang, Li, et al., 2020), and insulin dysregulation (Kandimalla et al., 2017).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Husna Ibrahim et al., 2020

      Not checked in the free run.

    • cites Kandimalla et al., 2017

      Not checked in the free run.

    • cites Yang, Li, et al., 2020

      Not checked in the free run.

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

    Premisecitation

    Tau phosphorylated at serine 181, serine 396, and AT8 (Ser202/Threonine 205) are sites associated with tau pathogenesis in Alzheimer's disease.

    “Tau phosphorylated at serine 181 (pTau Ser181), pTau Ser396, and AT8 (Ser202/Threonine (Thr)205) are sites associated with tau pathogenesis in AD (Dave et al., 2021; Karikari et al., 2020; Mondragón‐Rodríguez et al., 2014).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Dave et al., 2021

      Not checked in the free run.

    • cites Karikari et al., 2020

      Not checked in the free run.

    • cites Mondragón‐Rodríguez et al., 2014

      Not checked in the free run.

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

    Premisecitation

    Alzheimer's disease is characterized by extracellular amyloid-beta plaques and intracellular neurofibrillary tangles, resulting in progressive loss of cognitive abilities and memory.

    “AD is characterized by two hallmark neuropathologies: extracellular amyloid‐beta (Aβ) plaques and intracellular neurofibrillary tangles (NFT), resulting in a progressive loss of cognitive abilities and memory (Deture & Dickson, 2019).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Deture & Dickson, 2019

      Not checked in the free run.

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

    Premisecitation

    Environmental factors may play a role in sporadic Alzheimer's disease, which accounts for more than 95% of total cases.

    “An abundance of work has highlighted that environmental factors may play a role in sporadic AD, which accounts for >95% of total cases (Kandimalla et al., 2017; Velazquez et al., 2019, 2020; Yang, Li, et al., 2020; Yang, Jiang, et al., 2020).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Kandimalla et al., 2017

      Not checked in the free run.

    • cites Velazquez et al., 2019, 2020

      Not checked in the free run.

    • cites Yang, Li, et al., 2020

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    A choline-deficient diet does not exacerbate spatial memory impairments in 3xTg-AD mice nor impair performance in NonTg mice.

    “These data indicate that Ch‐ does not exacerbate spatial memory impairments in 3xTg‐AD mice nor impair performance in NonTg mice.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Dietary choline intake is necessary to prevent systems-wide organ pathology and reduce hallmark Alzheimer's disease pathologies.

    “Our data highlight that dietary choline intake is necessary to prevent systems‐wide organ pathology and reduce hallmark AD pathologies.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Adulthood choline supplementation in a mouse model of Alzheimer's disease reduces amyloid-beta plaque density, learning and memory deficits, and brain inflammation.

    “Additionally, adulthood choline supplementation in a mouse model of AD significantly reduces Aβ plaque density, learning and memory deficits, and brain inflammation (Velazquez et al., 2019).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Velazquez et al., 2019

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Cardiac dysfunction can be caused by both Alzheimer's disease mutations and choline deficiency.

    “These data demonstrate that cardiac dysfunction can be caused by both AD mutations and Ch‐.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    The Institute of Medicine established an adequate daily intake for choline to prevent fatty liver disease: 550 mg/day for adult men and 425 mg/day for adult women.

    “In 1998, the Institute of Medicine (IOM) established an adequate daily intake (ADI) threshold for choline consumption to prevent fatty liver disease; 550 and 425 mg/day for adult men and women, respectively (Institute of Medicine, 1998).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Institute of Medicine, 1998

      Not checked in the free run.

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

    Premisecitation

    Choline is an essential nutrient and a key precursor in the synthesis of choline phospholipids, betaine, and acetylcholine, a neurotransmitter involved in neurogenesis, synapse formation, learning, and memory.

    “Choline, an essential nutrient found in a variety of foods, is a key precursor in the synthesis of choline phospholipids, betaine, and acetylcholine, a neurotransmitter involved in neurogenesis, synapse formation, learning, and memory (Blusztajn, 1998).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Blusztajn, 1998

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    A choline-deficient diet increases weight and impairs glucose metabolism in both control and Alzheimer's disease mice, with 3xTg-AD mice showing greater deficits.

    “Collectively, these results show that Ch‐ increases weight and impairs glucose metabolism in both the control and AD mice, with 3xTg‐AD mice showing greater deficits.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Choline deficiency plays a role in cardiovascular disease, liver toxicity, and hypertension.

    “choline deficiency plays a role in cardiovascular disease, liver toxicity, and hypertension (Institute of Medicine, 1998; Millard et al., 2018)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Institute of Medicine, 1998

      Not checked in the free run.

    • cites Millard et al., 2018

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Choline supplementation is associated with attenuated microglial activation and reduced insulin resistance in the brain and periphery.

    “For example, choline supplementation is associated with attenuated microglial activation and reduced insulin resistance in the brain and periphery (Gao et al., 2017; Velazquez et al., 2019; Zeisel, 2017)”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Gao et al., 2017

      Not checked in the free run.

    • cites Velazquez et al., 2019

      Not checked in the free run.

    • cites Zeisel, 2017

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Dietary choline deficiency throughout adulthood led to motor impairments, weight gain, impaired glucose metabolism, cardiac pathology, and liver disease in both NonTg and 3xTg-AD mice, and elevations of Alzheimer's disease pathology in the 3xTg-AD mouse.

    “We find that dietary choline deficiency (Ch‐) throughout adulthood led to motor impairments, weight gain, impaired glucose metabolism, cardiac pathology, and liver disease, in both NonTg and 3xTg‐AD mice, and elevations of AD pathology in the 3xTg‐AD mouse.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    A healthy liver is critical for the clearance of circulating Aβ in the periphery and hepatic disease reduces the clearance of peripherally‐circulating Aβ.

    “A healthy liver is critical for the clearance of circulating Aβ in the periphery and hepatic disease reduces the clearance of peripherally‐circulating Aβ (Estrada et al., 2019).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Estrada et al., 2019

      Not checked in the free run.

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

    Premisecitation

    Ch‐ has been linked to clinical markers of cardiovascular disease.

    “Ch‐ has been linked to clinical markers of cardiovascular disease (Millard et al., 2018)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Millard et al., 2018

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Ch‐ was sufficient to induce cardiac hypertrophy in NonTg mice and further exacerbate cardiac hypertrophy in 3xTg‐AD mice.

    “illustrating that Ch‐ was sufficient to induce cardiac hypertrophy in NonTg mice, and further exacerbate cardiac hypertrophy in 3xTg‐AD mice”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Healthy tau plays important roles in microtubule stabilization, protein transport, synaptic plasticity, and learning and memory.

    “This is notable given the important role of healthy tau in microtubule stabilization, protein transport, synaptic plasticity, and learning and memory (Velazquez et al., 2018).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Velazquez et al., 2018

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Choline deficiency may alter microtubule function in 3xTg-AD hippocampus and exacerbate microtubule dysfunction caused by tau pathogenesis.

    “This data suggests that Ch‐ may alter microtubule function in 3xTg‐AD Hp and exacerbate microtubule dysfunction caused by tau pathogenesis.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Previous work has shown that choline modulates the expression of alpha7 nicotinic acetylcholine and Sigma‐1 receptors.

    “Previous work has shown that choline modulates the expression of alpha7 nicotinic acetylcholine and Sigma‐1 receptors (Velazquez et al., 2019).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Velazquez et al., 2019

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Choline plays an important role in energy metabolism.

    “Choline plays an important role in energy metabolism (Zeisel, 2017)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Zeisel, 2017

      Not checked in the free run.

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

    Interpretationcitation

    These findings corroborate previous work showing that adulthood dietary choline supplementation modulates the abundance of critical neuroreceptors in the 3xTg-AD hippocampus.

    “These findings corroborate previous work showing that adulthood dietary choline supplementation modulates the abundance of critical neuroreceptors in the 3xTg‐AD Hp (Velazquez et al., 2019).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Velazquez et al., 2019

      Not checked in the free run.

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

    Premisecitation

    Obesity, diabetes, and insulin resistance can induce NAFLD.

    “work has shown that obesity, diabetes, and insulin resistance can also induce this phenotype”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kneeman et al., 2012

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    3xTg‐AD mice ubiquitously express the PS1 M146V knockin mutation, while APPswe and MAPT P301L are predominantly expressed in the CNS.

    “Notably, 3xTg‐AD mice ubiquitously express the PS1 M146V knockin mutation, while APPswe and MAPT P301L are predominantly expressed in the CNS (Velazquez et al., 2017).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Velazquez et al., 2017

      Not checked in the free run.

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

    Premisecitation

    There is an established link between cardiovascular disease and the development of dementias, including AD.

    “and there is an established link between cardiovascular disease and the development of dementias, including AD (Yang, Li, et al., 2020; Yang, Jiang, et al., 2020).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Yang, Li, et al., 2020

      Not checked in the free run.

    • cites Yang, Jiang, et al., 2020

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Postmenopausal females and males do not respond to low choline supply due to a lack of PEMT induction, while premenopausal females are protected from low choline.

    “Notably, postmenopausal females and males do not respond to low choline supply due to a lack of PEMT induction, however, premenopausal females have been shown to be protected from low choline (Fischer et al., 2007).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Fischer et al., 2007

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hyperinflammation, mitochondrial dysfunction, and glucose metabolism impairments are observed in AD.

    “Hyperinflammation, mitochondrial dysfunction, and glucose metabolism impairments are observed in AD (Kandimalla et al., 2017; Velazquez et al., 2017).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Kandimalla et al., 2017

      Not checked in the free run.

    • cites Velazquez et al., 2017

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Vdac2 decreases with age and with increased pathology in 3xTg‐AD.

    “Vdac2 has been shown to decrease with age and with increased pathology in 3xTg‐AD”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Singulani et al., 2020

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Saa1 primes microglia for ATP‐dependent interleukin‐1B release, which is associated with AD onset.

    “Saa1 has been shown to prime microglia for ATP‐dependent interleukin‐1B release, which is associated with AD onset (Jang et al., 2019).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Jang et al., 2019

      Not checked in the free run.

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

    Study design and conductnone given

    Gunderson's score remained ≤0.08.

    “Gunderson's score remained ≤0.08.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    All animal procedures were approved in advance by the Institutional Animal Care and Use Committee of Arizona State University.

    “All animal procedures were approved in advance by the Institutional Animal Care and Use Committee of Arizona State University.”
    Quote in the paperNot a substantial claim

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

    Study design and conductcitation

    Only female 3xTg‐AD mice were used because males do not display consistent neuropathology.

    “Only female 3xTg‐AD mice were used because males do not display consistent neuropathology (Velazquez et al., 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Velazquez et al., 2017

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Diet start age was selected due to choline's important role in the developing brain.

    “Diet start age was selected due to choline's important role in the developing brain (Blusztajn, 1998).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Blusztajn, 1998

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based). May combine two claims.

    Interpretationreasoning

    If generalized to humans, these findings may help mitigate the estimated increase in the prevalence of AD and illustrate the importance of adequate dietary choline intake throughout adulthood to offset disease occurrence for the general population.

    “If generalized to humans, these findings may help mitigate the estimated increase in the prevalence of AD and illustrate the importance of adequate dietary choline intake throughout adulthood to offset disease occurrence for the general population.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Vdac1 mediates Aβ toxicity in the brain, and its overexpression triggers cell death.

    “Vdac1 has been shown to mediate Aβ toxicity in the brain, and its overexpression triggers cell death (Shoshan‐Barmatz et al., 2018).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Shoshan-Barmatz et al., 2018

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Glial cell populations are responsive to Saa1 secretion in the blood and Saa1 overexpression increases amyloid aggregation and glial activation in an AD mouse model.

    “Previous literature also indicates that glial cell populations are responsive to Saa1 secretion in the blood and that Saa1 overexpression increases amyloid aggregation and glial activation in an AD mouse model (Jang et al., 2019).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Jang et al., 2019

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Obesity and liver pathology have been linked to fructose metabolic processing and an upregulation of Aldob.

    “Obesity and liver pathology have been linked to fructose metabolic processing and an upregulation of Aldob (Stocks et al., 2022)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Stocks et al., 2022

      Not checked in the free run.

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

    Study design and conductown data

    Levene's test for homogeneity of variance revealed no significant effects.

    “Levene's test for homogeneity of variance revealed no significant effects.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Ide degrades insulin, is directly related to insulin resistance, and also degrades Aβ.

    “Ide degrades insulin, is directly related to insulin resistance, and also degrades Aβ (Kandimalla et al., 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kandimalla et al., 2017

      Not checked in the free run.

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

    Premisecitation

    Ide and its impact on insulin resistance have been linked to cognitive impairment.

    “Ide and its impact on insulin resistance have been linked to cognitive impairment (Yang, Li, et al., 2020; Yang, Jiang, et al., 2020).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Yang, Li, et al., 2020

      Not checked in the free run.

    • cites Yang, Jiang, et al., 2020

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Ch‐ exacerbates AD pathology and synaptic dysfunction.

    “Altogether, these results provide significant evidence that Ch‐ exacerbates AD pathology and synaptic dysfunction.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    A concatenated target/decoy strategy and a false‐discovery rate set to 1.0% were calculated using Percolator.

    “A concatenated target/decoy strategy and a false‐discovery rate (FDR) set to 1.0% were calculated using Percolator.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Vdac1 interacts with several AD‐relevant proteins, including pTau, Aβ, and gamma‐secretase.

    “Additionally, Vdac1 interacts with several AD‐relevant proteins, including pTau, Aβ, and gamma‐secretase (Shoshan‐Barmatz et al., 2018).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Shoshan-Barmatz et al., 2018

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Ch‐ may induce obesity and liver pathology phenotypes, leading to the upregulation of Aldob and Sord.

    “suggesting that Ch‐ may induce obesity and liver pathology phenotypes, leading to the upregulation of these proteins.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Mitochondrial dysfunction has emerged as another driver of AD pathology.

    “Finally, mitochondrial dysfunction has emerged as another driver of AD pathology (Kandimalla et al., 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kandimalla et al., 2017

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Ch‐ modulates Saa1/2 secretion in the plasma, causing glial hyperactivation, increased neuroinflammation, and potentially increased Aβ aggregation.

    “This suggests that Ch‐ modulates Saa1/2 secretion in the plasma, causing glial hyperactivation, increased neuroinflammation, and potentially increased Aβ aggregation.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    T2D has negative effects on brain insulin resistance, oxidative stress, and cognitive decline.

    “large body of literature that demonstrates the negative effects of T2D on brain insulin resistance, oxidative stress, and cognitive decline (Kandimalla et al., 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kandimalla et al., 2017

      Not checked in the free run.

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

    Premisecitation

    Hspd1 modulates diabetes‐induced inflammation and protects against Aβ oligomer‐induced synaptic toxicity.

    “there is growing evidence that Hspd1 modulates diabetes‐induced inflammation and protects against Aβ oligomer‐induced synaptic toxicity (Liyanagamage & Martinus, 2020; Marino et al., 2019).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Liyanagamage & Martinus, 2020

      Not checked in the free run.

    • cites Marino et al., 2019

      Not checked in the free run.

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

    Study design and conductnone given

    Seven sections were evaluated per animal.

    “Seven sections were evaluated per animal.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Study design and conductnone given

    The AT8 antibody penetrated the full depth of the section, allowing for an equal probability of counting all objects.

    “The AT8 antibody penetrated the full depth of the section, allowing for an equal probability of counting all objects.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Mice were randomly assigned to one of two diets at 3 months of age.

    “Mice were randomly assigned to one of two diets at 3 months of age”
    Quote in the paperSubstantial claim
75 of 75

  • The paper relies on this without support.

    The only relevant difference between the choline-sufficient and choline-deficient diets is choline content.

    “either a standard laboratory diet with sufficient choline (ChN; 2.0 g/kg choline bitartrate) or a choline‐deficient diet (Ch‐; 0.0 g/kg choline bitartrate)”

  • The paper relies on this without support.

    The female mice were cycling throughout the study.

    “our mice, which were cycling throughout the study”

  • The paper relies on this without support.

    Liver PEMT protein levels reflect PEMT functional activity.

    “We measured protein levels of PEMT from liver tissue to determine if Ch‐ led to compensatory upregulation. We found no significant differences across the four groups”

  • The paper relies on this without support.

    AD‐related hyperinflammation, mitochondrial dysfunction, and glucose metabolism impairments are not unique to the brain and occur across the entire body.

    “These dysfunctions are not unique to the brain and are seen across the entire body.”

  • The paper relies on this without support.

    The 3xTg‐AD mouse model recapitulates key features of human AD relevant to this study.

    “3xTg‐AD homozygous mice were generated as previously described (Velazquez et al., 2017).”

  • The paper relies on this without support.

    The choline‐deficient diet in mice models inadequate dietary choline intake in humans.

    “a standard laboratory AIN76A diet (Envigo Teklab Diets, Madison WI) with normal choline levels (ChN; 2.0 g/kg; #TD.180228), based on the human ADI or an AIN76A choline‐deficient (Ch‐; 0.0 g/kg; #TD.110617) diet.”
6 of 6

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?

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, 65) = 16.72reported p = .001 · recomputed p < .001

    “F (1, 65) = 16.72, p = .001”

    The paper prints p at a floor (such as p < .001)

  • ConsistentF(1, 65) = 15.86reported p = .0002 · recomputed p < .001

    “F (1, 65) = 15.86, p = .0002”

  • ConsistentF(1, 65) = 6.114reported p = .016 · recomputed p = .016

    “F (1, 65) = 6.114, p = .016”

  • ConsistentF(1, 65) = 15.69reported p = .0002 · recomputed p < .001

    “F (1, 65) = 15.69, p = .0002”

  • ConsistentF(1, 65) = 20.99reported p < .0001 · recomputed p < .001

    “F (1, 65) = 20.99, p < .0001”

  • ConsistentF(1, 65) = 20.56reported p < .0001 · recomputed p < .001

    “F (1, 65) = 20.56, p < .0001”

  • ConsistentF(1, 256) = 23.335reported p < .0001 · recomputed p < .001

    “F (1, 256) = 23.335, p < .0001”

  • ConsistentF(1, 64) = 12.276reported p = .0008 · recomputed p < .001

    “F (1, 64) = 12.276, p = .0008”

  • ConsistentF(1, 64) = 6.948reported p = .0105 · recomputed p = .011

    “F (1, 64) = 6.948, p = .0105”

  • ConsistentF(1, 65) = 51.96reported p < .0001 · recomputed p < .001

    “F (1, 65) = 51.96, p < .0001”

  • ConsistentF(1, 65) = 52.86reported p < .0001 · recomputed p < .001

    “F (1,65) = 52.86, p < .0001”

  • ConsistentF(1, 65) = 10.91reported p = .0016 · recomputed p = .002

    “F (1, 65) = 10.91, p = .0016”

  • ConsistentF(1, 14) = 11.69reported p = .0042 · recomputed p = .004

    “F (1, 14) = 11.69, p = .0042”

  • ConsistentF(1, 65) = 26.02reported p < .0001 · recomputed p < .001

    “F (1, 65) = 26.02, p < .0001”

  • ConsistentF(1, 65) = 47.01reported p < .0001 · recomputed p < .001

    “F (1, 65) = 47.01, p < .0001”

  • ConsistentF(7, 455) = 2.674reported p = .0101 · recomputed p = .010

    “F (7,455) = 2.674, p = .0101”

  • ConsistentF(1, 65) = 26.04reported p < .0001 · recomputed p < .001

    “F (1, 65) = 26.04, p < .0001”

  • ConsistentF(1, 65) = 47.25reported p < .0001 · recomputed p < .001

    “F (1, 65) = 47.25, p < .0001”

  • ConsistentF(1, 65) = 4.393reported p = .04 · recomputed p = .040

    “F (1, 65) = 4.393, p = .040”

  • ConsistentF(1, 20) = 96.08reported p < .0001 · recomputed p < .001

    “F (1, 20) = 96.08, p < .0001”

  • ConsistentF(1, 22) = 29.63reported p < .0001 · recomputed p < .001

    “F (1, 22) = 29.63, p < .0001”

  • ConsistentF(1, 22) = 13.78reported p = .001 · recomputed p = .001

    “F (1, 22) = 13.78, p = .001”

  • ConsistentF(1, 18) = 27.85reported p < .0001 · recomputed p < .001

    “F (1, 18) = 27.85, p < .0001”

  • ConsistentF(1, 18) = 9.743reported p = .006 · recomputed p = .006

    “F (1, 18) = 9.743, p = .006”

  • ConsistentF(1, 18) = 19.17reported p = .0004 · recomputed p < .001

    “F (1, 18) = 19.17, p = .0004”

  • ConsistentF(1, 20) = 133.5reported p < .0001 · recomputed p < .001

    “F (1, 20) = 133.50, p < .0001”

  • ConsistentF(1, 20) = 165.3reported p < .0001 · recomputed p < .001

    “F (1, 20) = 165.30, p < .0001”

  • Consistentt(13) = 1.712reported p = .111 · recomputed p = .111

    “t(13) = 1.712, p = .111”

  • Consistentt(13) = 1.685reported p = .116 · recomputed p = .116

    “t(13) = 1.685, p = .116”

  • Consistentt(13) = 2.833reported p = .014 · recomputed p = .014

    “t(13) = 2.833, p = .014”

  • Consistentt(13) = 11.59reported p < .0001 · recomputed p < .001

    “t(13) = 11.59, p < .0001”

  • Consistentt(13) = 3.335reported p = .0054 · recomputed p = .005

    “t(13) = 3.335, p = .0054”

  • Consistentt(13) = 2.648reported p = .021 · recomputed p = .020

    “t(13) = 2.648, p = .021”

    The paper states a false-discovery-rate adjustment

  • Consistentt(13) = 1.919reported p = .077 · recomputed p = .077

    “t(13) = 1.919, p = .077”

  • Consistentt(13) = 2.398reported p = .032 · recomputed p = .032

    “t(13) = 2.398, p = .032”

  • Consistentt(13) = 2.357reported p = .035 · recomputed p = .035

    “t(13) = 2.357, p = .035”

  • Consistentt(13) = 13.9reported p < .0001 · recomputed p < .001

    “t(13) = 13.90, p < .0001”

  • Consistentt(14) = 2.281reported p = .039 · recomputed p = .039

    “t(14) = 2.281, p = .039”

  • Consistentt(13) = 13.92reported p < .0001 · recomputed p < .001

    “t(13) = 13.92, p < .0001”

  • Consistentt(13) = 4.293reported p = .0009 · recomputed p < .001

    “t(13) = 4.293, p = .0009”

  • Consistentt(13) = 9.045reported p < .0001 · recomputed p < .001

    “t(13) = 9.045, p < .0001”

  • Consistentt(13) = 7.691reported p < .0001 · recomputed p < .001

    “t(13) = 7.691, p < .0001”

  • Consistentt(13) = 2.228reported p = .0442 · recomputed p = .044

    “t(13) = 2.228, p = .0442”

  • Consistentt(13) = 3.356reported p = .0052 · recomputed p = .005

    “t(13) = 3.356, p = .0052”

  • Consistentt(13) = 0.622reported p = .545 · recomputed p = .545

    “t(13) = 0.622, p = .545”

  • Consistentt(13) = 1.436reported p = .175 · recomputed p = .175

    “t(13) = 1.436, p = .175”

  • Consistentt(6) = 2.462reported p = .049 · recomputed p = .049

    “t(6) = 2.462, p = .049”

47 of 47

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.

  • Figure 6 caption labels a comparison as ChN versus itself

    Minor

    The caption attributes 70 differentially abundant proteins to a 3xTg‐AD ChN-versus-ChN comparison, while the results identify that comparison as Ch‐ versus ChN.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. 10.3389/FIMMU.2021.796867/BIBTEX · DOI

Cited by

Sorted by citations

Authors
Dave, N., Judd, J. M., Decker, A., Winslow, W., Sarette, P., Villarreal Espinosa, O., Tallino, S., Bartholomew, S. K., Bilal, A., Sandler, J., McDonough, I., Winstone, J. K., Blackwood, E. A., Glembotski, C., Karr, T., & Velazquez, R.
Affiliations
  • Arizona State University (US)
  • Arizona Alzheimer’s Consortium (US)
  • Arizona State University‐Banner Neurodegenerative Disease Research Center at the Biodesign Institute Arizona State University Tempe Arizona USA
  • University of Arizona College of Medicine- Phoenix (US)
ORCID
Venue
Aging Cell
Publisher
Wiley
Published
2023-01-15
Volume
22
Issue
2
Pages
e13775-e13775
ISSN
  • 1474-9718 (ISSN-L)
  • 1474-9726
DOI
10.1111/acel.13775
PMC
PMC9924938
OpenAlex
W4316362869
Cited by
55
References
46
Citations by year
2026: 8 · 2025: 19 · 2024: 18 · 2023: 10
FWCI
9.69
Type
journal article
Language
en
Open access
Licence
Locations
  • Aging Cell (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
National Institute on Aging (R01 AG059627, R01 AG062500)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
Keywords
dietary choline, choline deficiency, Alzheimer's disease, 3xTg-AD mice, amyloid-beta, tau hyperphosphorylation, cardiac pathology, liver pathology, hippocampus, plasma proteomics, insulin metabolism, mitochondrial function, inflammation, fructose metabolism, microtubule function, postsynaptic membrane, glucose metabolism, motor function, modifiable risk factors
MeSH terms
Alzheimer Disease, Animals, Choline, Choline Deficiency, Disease Models, Animal, Eating, Mice, Transgenic, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, tau Proteins, Mice

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 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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