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Cited by 179Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsAdvanced Neuroimaging Techniques and Applications

White matter diffusion alterations precede symptom onset in autosomal dominant Alzheimer’s disease

Open access
Araque Caballero, Miguel Ángel, Suárez-Calvet, Marc, Duering, Marco, Franzmeier, Nicolai, Benzinger, Tammie, Fagan, Anne M, Bateman, Randall J, Jack, Clifford R +18 more·2018·Brain
DOI 10.1093/brain/awy229PMC PMC6158739
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Abstract

White matter alterations are present in the majority of patients with Alzheimer's disease type dementia. However, the spatiotemporal pattern of white matter changes preceding dementia symptoms in Alzheimer's disease remains unclear, largely due to the inherent diagnostic uncertainty in the preclinical phase and increased risk of confounding age-related vascular disease and stroke in late-onset Alzheimer's disease. In early-onset autosomal-dominantly inherited Alzheimer's disease, participants are destined to develop dementia, which provides the opportunity to assess brain changes years before the onset of symptoms, and in the absence of ageing-related vascular disease. Here, we assessed mean diffusivity alterations in the white matter in 64 mutation carriers compared to 45 non-carrier family non-carriers. Using tract-based spatial statistics, we mapped the interaction of mutation status by estimated years from symptom onset on mean diffusivity. For major atlas-derived fibre tracts, we determined the earliest time point at which abnormal mean diffusivity changes in the mutation carriers were detectable. Lastly, we assessed the association between mean diffusivity and cerebrospinal fluid biomarkers of amyloid, tau, phosphorylated-tau, and soluble TREM2, i.e. a marker of microglia activity. Results showed a significant interaction of mutations status by estimated years from symptom onset, i.e. a stronger increase of mean diffusivity, within the posterior parietal and medial frontal white matter in mutation carriers compared with non-carriers. The earliest increase of mean diffusivity was observed in the forceps major, forceps minor and long projecting fibres-many connecting default mode network regions-between 5 to 10 years before estimated symptom onset. Higher mean diffusivity in fibre tracts was associated with lower grey matter volume in the tracts' projection zones. Global mean diffusivity was correlated with lower cerebrospinal fluid levels of amyloid-β1-42 but higher levels of tau, phosphorylated-tau and soluble TREM2. Together, these results suggest that regionally selective white matter degeneration occurs years before the estimated symptom onset. Such white matter alterations are associated with primary Alzheimer's disease pathology and microglia activity in the brain.

AI snapshot

Written from the paper’s full text.

TL;DR

In autosomal dominant Alzheimer’s disease, white matter mean diffusivity increases begin about 10 years before estimated symptom onset, first in anterior and posterior callosal fibres. These diffusion changes track amyloid/tau pathology and microglial activation and precede hippocampal grey matter atrophy.

Key findings

  • Voxel-wise EYO × mutation status interactions on mean diffusivity were significant predominantly in posterior parietal and medial frontal white matter; global PSMD interaction was B(SE) = 1.7(0.6) × 10⁻⁶, P < 0.001.
  • Mean diffusivity increases became significant first at EYO = (−10, −5) for forceps major and forceps minor; PSMD also became abnormal at EYO = (−10, −5), after CSF amyloid-β₁₋₄₂ [EYO = (−15, −10)], PIB-PET [EYO = (−20, −15)], and CSF total tau [EYO = (−20, −15)], concurrent with CSF soluble TREM2 [EYO = (−10, −5)], and before hippocampal volume [EYO = (−5, 0)].
  • Higher PSMD was associated with lower CSF amyloid-β₁₋₄₂ [B(SE) = −0.47(0.12), P < 0.001], higher precuneus PIB-PET [B(SE) = 0.68(0.15), P < 0.001], higher CSF total tau [B(SE) = 0.38(0.12), P = 0.003], higher P-tau [B(SE) = 0.41(0.12), P < 0.001], and higher CSF soluble TREM2 [B(SE) = 0.29(0.14), P = 0.042].
  • Higher tract-specific mean diffusivity was associated with lower grey matter volume in the projection zones of all tracts except the hippocampal cingulum bundle (FDR-corrected P < 0.01).

Methods

  • Participants were from the Dominantly Inherited Alzheimer Network (DIAN, data freeze 9); after exclusions, the final sample was n = 109 (64 mutation carriers, 45 non-carriers), with mutations in PSEN1 (n = 47), PSEN2 (n = 8), and APP (n = 9).
  • DTI was acquired with 64 diffusion directions and analyzed using Tract-Based Spatial Statistics (TBSS); mean diffusivity was the primary measure, with fractional anisotropy, radial diffusivity, and axial diffusivity as exploratory measures, plus the global PSMD marker.
  • Analyses tested EYO × mutation status interactions, tract-level trajectories across EYO, and relationships of mean diffusivity/PSMD with CSF amyloid-β₁₋₄₂, total tau, P-tau181, soluble TREM2, PIB-PET, and grey matter volume in tract projection zones.

Limitations

  • The paper states that findings from autosomal dominant Alzheimer’s disease may not generalize to sporadic late-onset Alzheimer’s disease, and that age-related vascular pathology may contribute more strongly in late-onset disease.
  • The paper states that it cannot preclude Wallerian degeneration secondary to grey matter atrophy, that mean diffusivity is only one DTI index, and that TBSS has limitations including misregistration, crossing fibres, and inaccurate voxel assignment between neighbouring tracts.
  • The paper notes that the asymptomatic-carrier interaction analysis was not significant, probably due to limited power; the text also makes evident that EYO-based timing is estimated rather than directly observed longitudinally, and some biomarker/PET analyses had smaller subsets.

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

Integrity signals

Registry

Crossref · 10.1093/brain/awy229

Cites

111 of 111 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

45 of 75 cited sources checked · 14 supported · 2 flagged · accuracy not yet measured

  • Premisereasoning

    Previous DTI studies in autosomal-dominant Alzheimer's disease lacked sufficient statistical power, considering relatively low sample sizes (n = 8 to 18 asymptomatic carriers), to detect the subtle pre-symptomatic phase.

    “However, these studies either lacked sufficient statistical power considering the relatively low sample sizes (n = 8 to 18 of asymptomatic carriers) to detect subtle pre-symptomatic phase”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Ringman et al., 2007 source
    • cites Ryan et al., 2013 source

      The Subjects section reports 10 presymptomatic carriers, and the Discussion says this study’s small sample limited statistical power. The paper does not establish the claimed 8–18-carrier range for previous DTI studies or say that those studies could not detect presymptomatic changes; its Discussion describes presymptomatic DTI changes in both this study and another study. (LLM, conf=0.86)

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

      The Discussion (page unavailable) says previous DT-MRI studies consistently reported white-matter differences in presymptomatic familial Alzheimer’s disease—the opposite of the claim that they lacked power to detect them. It raises genetic heterogeneity and age as possible reasons its own study did not replicate those findings. Its limited-power caveat concerns associations in its own asymptomatic-carrier sample, not the previous studies. (LLM, conf=0.85)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Premisecitation

    For all analyses, mean diffusivity was used as the primary DTI measure in autosomal-dominant Alzheimer's disease because previous studies found mean diffusivity to be the most sensitive DTI marker to detect fibre tract alterations.

    “For all analyses, we used mean diffusivity as our primary DTI measure in autosomal-dominant Alzheimer’s disease, since previous studies found mean diffusivity to be the most sensitive DTI marker to detect fibre tract alterations (Clerx et al., 2012; Nowrangi et al., 2013).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Clerx et al., 2012 source
    • cites Nowrangi et al., 2013 source

      The Discussion (page not provided) says MD may be more sensitive to change over 12 months than FA, supporting the rationale for choosing MD. But the study examined normal controls, MCI, and AD—not autosomal-dominant AD—and its tentative longitudinal finding does not establish MD as the most sensitive DTI marker for detecting fibre-tract alterations generally. The citing authors’ choice to use MD for all analyses is their own method, not a finding attributed to this source. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Premisecitation

    Neuroimaging and biomarker studies show consistencies in the sequential onset of amyloid deposition, tau, FDG-PET hypometabolism, grey matter atrophy, and clinical presentation between late-onset and autosomal-dominant Alzheimer's disease.

    “Nevertheless, neuroimaging and biomarker studies show consistencies in the sequential onset of amyloid deposition, tau, FDG-PET hypometabolism, grey matter atrophy, and clinical presentation between late-onset and autosomal-dominant Alzheimer’s disease (Bateman et al., 2012; Benzinger et al., 2013; Young et al., 2014; Gordon et al., 2018; Oxtoby et al., 2018), suggesting substantial commonalities”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Bateman et al., 2012 source

      The Results (Combined Model) describe the sequence of amyloid deposition, CSF tau increase, brain atrophy, cerebral hypometabolism, and clinical impairment in autosomal-dominant Alzheimer’s disease. The Discussion says these results suggest only the possibility of common pathophysiology with sporadic late-onset disease; this paper does not establish that the full sequence is consistent between the two forms. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites Benzinger et al., 2013 source
    • cites Young et al., 2014 source

      The Results (Event sequences; page unavailable) report an ordering of CSF biomarkers, atrophy measures and cognitive changes in the sporadic-disease cohort. The Introduction describes FDG-PET hypometabolism as part of a hypothetical sequence, not a sequence established by this study. It also says whether findings from familial Alzheimer’s disease apply to sporadic disease “remains to be determined,” so the claimed consistency between the two is not established by this paper. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Premisecitation

    The integration of white matter changes within standard biomarker models of the pathological cascade in Alzheimer's disease remains missing.

    “However, the integration of white matter changes within standard biomarker models of the pathological cascade in Alzheimer’s disease remains missing (Jack et al., 2013).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Jack et al., 2013 source

      In “Our Original Model – Lancet Neurology 2010” (page unavailable), the paper lists the biomarkers in its original and updated models without identifying white matter changes as a separate component. That supports the omission in this model, but the paper does not establish that white matter changes remain absent from standard biomarker models generally. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
  • Premisecitation

    White matter changes in the preclinical phase before the occurrence of cognitive impairment have been examined only in a few studies.

    “Despite these previous findings in symptomatic Alzheimer’s disease participants, white matter changes in the preclinical phase before the occurrence of cognitive impairment have been examined only in a few studies (Gold et al., 2012).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Gold et al., 2012 source
  • May combine two claims. 32
  • Classified as probably not a substantial claim. 25

  • May combine two claims.

    Premisereasoning

    Previous DTI studies in autosomal-dominant Alzheimer's disease did not estimate years from symptom onset (EYO), which reduced the sensitivity to detect DTI changes that occur in close proximity to the onset of dementia symptoms.

    “or did not estimate years from symptom onset (EYO) (Ringman et al., 2007; Ryan et al., 2013; Parra et al., 2015), which reduced the sensitivity to detect DTI changes that occur in close proximity to the onset of dementia symptoms.”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Ringman et al., 2007 source
    • cites Ryan et al., 2013 source

      The Materials and methods (Subjects; page unavailable) explicitly says Ryan et al. calculated estimated time to symptom onset for presymptomatic mutation carriers using each participant’s age and their parent’s age at symptom onset. Table 1 also reports years from estimated age at onset. This contradicts the claim that the study did not estimate EYO; the paper does not establish the claimed loss of sensitivity from failing to do so. (LLM, conf=0.92)

      Checked by a reasoning model — may be wrong.

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

      The Participants and Statistical analyses sections describe grouping carriers by clinical status and analyzing DT-MRI measures by group; they do not describe estimating years from symptom onset. The Discussion treats age as relevant to time to clinical expression, but does not say that omitting EYO reduced sensitivity to detect DTI changes near symptom onset. Page numbers are not available in our copy. (LLM, conf=0.78)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Major fibre tracts such as the forceps major and forceps minor, inferior fronto-occipital fasciculus as well as the posterior cingulum show white matter alterations in Alzheimer's disease dementia.

    “In particular, major fibre tracts such as the forceps major and forceps minor, inferior fronto-occipital fasciculus as well as the posterior cingulum show white matter alterations in Alzheimer’s disease dementia (Taylor et al., 2001; Teipel et al., 2002; Douaud et al., 2011; Mito et al., 2018).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites Taylor et al., 2001 source
    • cites Teipel et al., 2002 source
    • cites Douaud et al., 2011 source

      The Results (page unavailable) report white matter diffusion abnormalities in the corpus callosum and the dorsal and posterior cingulum in patients with Alzheimer’s disease. They do not identify the forceps major or forceps minor separately, or report alterations in the inferior fronto-occipital fasciculus; those tract-specific parts of the claim are not supported by this paper. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    White matter alterations can be detected in vivo by diffusion tensor imaging (DTI).

    “White matter alterations can be detected in vivo by diffusion tensor imaging (DTI) (Alexander et al., 2007).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Alexander et al., 2007 source

  • Classified as probably not a substantial claim.

    Premisecitation

    A few DTI studies on white matter alterations in autosomal-dominant Alzheimer's disease have been previously conducted.

    “A few DTI studies on white matter alterations in autosomal-dominant Alzheimer’s disease have been previously conducted (Ringman et al., 2007; Ryan et al., 2013; Parra et al., 2015; Sanchez-Valle et al., 2016).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Ringman et al., 2007 source
    • cites Ryan et al., 2013 source
    • cites Parra et al., 2015 source

  • May combine two claims.

    Premisecitation

    In autosomal-dominant Alzheimer's disease, mutation carriers will all develop dementia and the future onset of dementia symptoms can be more precisely estimated.

    “In contrast, in autosomal-dominant Alzheimer’s disease mutation carriers will all develop dementia and the future onset of dementia symptoms can be more precisely estimated (Ryman et al., 2014).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Ryman et al., 2014 source

      The Discussion says family history and mutation type help estimate when symptoms will begin, supporting the estimation part of the claim. But it also says many carriers of later-onset mutations may die from unrelated causes before symptoms begin, so it does not support the assertion that all carriers will develop dementia. The Methods define onset as progressive cognitive symptoms, not a dementia diagnosis; page numbers are unavailable in our copy. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Age-related vascular changes may influence disease progression in late-onset Alzheimer's disease, including the development of white matter alterations, which is less likely to be captured in autosomal dominant Alzheimer's disease where dementia symptoms typically emerge between 30 and 50 years of age.

    “Age-related vascular changes may influence disease progression in late-onset Alzheimer’s disease, including the development of white matter alterations (Iturria-Medina et al., 2016), which is less likely to be captured in autosomal dominant Alzheimer’s disease where dementia symptoms typically emerge between 30 and 50 years of age.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Iturria-Medina et al., 2016 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

  • Classified as probably not a substantial claim.

    Premisecitation

    Biomarker studies demonstrate successive development of primary pathologies including amyloid-β and tau followed by alterations of medial temporal and parietal grey matter in both sporadic late-onset Alzheimer's disease and genetically-caused Alzheimer's disease.

    “So far, biomarker studies demonstrated the successive development of primary pathologies including amyloid-β and tau (as measured by biofluid and molecular PET markers) followed by alterations of medial temporal and parietal grey matter (as measured by volumetric MRI and FDG-PET) in both sporadic late-onset Alzheimer’s disease (Jack et al., 2012) and genetically-caused Alzheimer’s disease (Bateman”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites Jack et al., 2012 source

      The Background (page unavailable) identifies CSF and PET measures of amyloid, CSF tau, FDG-PET, and structural MRI, and describes an ordered sequence of biomarker changes. But it explicitly calls that sequence a hypothetical model awaiting validation; the Results do not demonstrate the claimed succession of amyloid and tau pathology followed by regional grey-matter changes. Jack et al. is cited for the sporadic Alzheimer’s disease portion of the sentence, not the genetically caused disease portion, which has a separate citation. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites Bateman et al., 2012 source

      The Results sections on brain atrophy and cerebral glucose metabolism report hippocampal atrophy on MRI and reduced precuneus metabolism on FDG-PET in mutation carriers. The Combined Model reports an earlier CSF amyloid-β change, but CSF tau elevation and brain atrophy were both detected approximately 15 years before expected symptom onset; it does not establish that tau changes preceded atrophy. Bateman et al. is cited for the genetically caused disease portion, not the separately cited sporadic disease portion. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    Results from DTI show that fibre tract alterations are widespread in the brain at the stage of mild cognitive impairment and Alzheimer's disease dementia.

    “Results from DTI showed that fibre tract alterations are widespread in the brain at the stage of mild cognitive impairment and Alzheimer’s disease dementia (Bozzali et al., 2002; Medina et al., 2006; Acosta-Cabronero et al., 2010, 2012; Sexton et al., 2011; Bosch et al., 2012; for reviews see Acosta-Cabronero and Nestor, 2014; Teipel et al., 2015).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Bozzali et al., 2002 source

      The Abstract and Results report DTI abnormalities across several white-matter regions in patients with Alzheimer’s disease, supporting the claim’s breadth for that group, although other regions were spared. The study examined patients with Alzheimer’s disease and healthy controls; it does not establish that these alterations are widespread at the mild cognitive impairment stage. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites Medina et al., 2006 source
    • cites Acosta-Cabronero et al., 2010, 2012

      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). May combine two claims.

    Interpretationcitation

    Those fibre tracts connect regions of the default mode network (DMN) and their degeneration may contribute to the impairment of the DMN and other functional networks in Alzheimer's disease.

    “Those fibre tracts connect regions of the default mode network (DMN) and their degeneration may thus contribute to the impairment of the DMN and other functional networks in Alzheimer’s disease (Taylor et al., 2017).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Taylor et al., 2017 source

      The Methods identify fiber tracts connecting DMN regions, and the Discussion links tract-specific white matter hyperintensities to reduced DMN functional connectivity. The extension to other functional networks is not supported: the Results report no association between tract hyperintensities and connectivity in the two other networks tested. The paper also cautions that its atlas-based approach cannot assure the tracts always connected the DMN regions. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Vascular alterations such as cerebrovascular resistance and hypoperfusion may precede amyloid deposition and are predictive of future disease progression.

    “In support of this hypothesis, recent evidence from neuroimaging studies suggests that vascular alterations such as cerebrovascular resistance and hypoperfusion may precede amyloid deposition and are predictive of future disease progression (Iturria-Medina et al., 2016; Yew et al., 2017).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites Iturria-Medina et al., 2016 source

      The Discussion (page unavailable) says the modeled vascular abnormalities appear earlier than amyloid-β deposition, and the Methods describe cerebral blood-flow imaging. But the paper does not establish cerebrovascular resistance as an early marker or show that these alterations predict an individual’s future disease progression; its Discussion describes prediction as a potential use of the model. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites Yew et al., 2017 source

  • May combine two claims.

    Premisecitation

    The current results are consistent with previous studies reporting that decreased fibre tract integrity in posterior parietal and medial temporal white matter is associated with imminent conversion from asymptomatic cognitive status to mild cognitive impairment within 2 years or with abnormal CSF amyloid and neuroinjury markers.

    “The current results are consistent with previous studies on presumed preclinical Alzheimer’s disease, reporting decreased fibre tract integrity within the posterior parietal white matter and medial temporal white matter to be associated with imminent conversion from asymptomatic cognitive status to mild cognitive impairment within 2 years (Zhuang et al., 2012) or with the presence of both abnormal”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites Zhuang et al., 2012 source
    • cites Bendlin et al., 2012 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
    • cites Kantarci et al., 2014 source

      The Results (Voxel-based Analysis; page unavailable) report decreased white-matter integrity in temporal regions and the precuneus among participants positive for both amyloid and neurodegeneration biomarkers. But the Methods (Classification of subjects into biomarker groups; page unavailable) specify PET and MRI biomarkers, not CSF markers. The two-year conversion claim is attached to Zhuang et al., not this source. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

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

    Premisecitation

    A combined ante-mortem DTI and post-mortem histochemical analysis in cognitively normal participants found amyloid and tau pathology to be associated with ante-mortem DTI alterations selectively in the medial temporal and parietal white matter.

    “In a similar vein, a combined ante-mortem DTI and post-mortem histochemical analysis in brains from cognitively normal participants found amyloid and tau pathology to be associated with ante-mortem DTI alterations selectively in the medial temporal and parietal white matter (Kantarci et al., 2017).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Kantarci et al., 2017 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). May combine two claims.

    Interpretationcitation

    It is possible that age-related cerebrovascular pathology may precede primary Alzheimer's disease pathology and contribute to white matter changes to a stronger degree in subjects with sporadic Alzheimer's disease compared to the relatively young subjects with autosomal-dominant Alzheimer's disease.

    “It should be noted that although white matter changes were detected subsequent to amyloid and tau pathology in the current study, it is still possible that age-related cerebrovascular pathology may precede primary Alzheimer’s disease pathology (Iturria-Medina et al., 2016) and contribute to white matter changes to a stronger degree in subjects with sporadic Alzheimer’s disease compared to the”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Iturria-Medina et al., 2016 source

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

    Premisecitation

    Amyloid-induced vascular constriction, increased vascular resistance, and degeneration of pericytes may further contribute to hypoperfusion.

    “Amyloid-induced vascular constriction, increased vascular resistance, and degeneration of pericytes may further contribute to hypoperfusion (Kisler et al., 2017; Yew et al., 2017).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites Kisler et al., 2017 source

      The Discussion reports that pericyte degeneration reduces cerebral blood-flow responses and oxygen supply, and may contribute to neurovascular dysfunction in disorders such as Alzheimer’s disease. The cited paper does not establish the sentence’s separate claims about amyloid-induced vascular constriction or increased vascular resistance. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites Yew et al., 2017 source

      The Introduction (page unavailable) says amyloid-induced vasoconstriction can increase cerebrovascular resistance, and the Discussion links vascular resistance changes with reduced cerebral blood flow. The cited paper does not address pericyte degeneration, so it supports only part of the attributed claim. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

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

    Premisecitation

    The default mode network shows reduced connectivity in early-stage Alzheimer's disease.

    “a functional network showing reduced connectivity in early-stage Alzheimer’s disease (Sorg et al., 2007; Chhatwal et al., 2013)”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites Sorg et al., 2007 source

      The Abstract says the default mode network has reduced functional connectivity in AD, and the Results report diminished connectivity in patients with amnestic mild cognitive impairment. The study’s patients were at high risk for AD, however, rather than diagnosed with early-stage AD; its direct finding does not establish the claim for that population. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites Chhatwal et al., 2013 source

  • May combine two claims.

    Premisecitation

    WMHs are an MRI detectable marker of white matter changes due to microvascular pathology and are increased in autosomal-dominant Alzheimer's disease.

    “WMHs are considered an MRI detectable marker of white matter changes due to microvascular pathology, and are increased in autosomal-dominant Alzheimer’s disease (Lee et al., 2016).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Lee et al., 2016 source

  • May combine two claims.

    Premisecitation

    Deposition of amyloid-β within microvessels is highly frequent in patients with Alzheimer's disease dementia and is associated with reduced blood flow in transgenic mouse models and humans.

    “Deposition of amyloid-β within microvessels is highly frequent in patients with Alzheimer’s disease dementia (Kalaria, 2016) and associated with reduced blood flow in transgenic mouse models (Han et al., 2008; Saito et al., 2017) and humans (Chung et al., 2009; Dumas et al., 2012).”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites Kalaria, 2016 source
    • cites Han et al., 2008 source

      Han et al. report in the Results that amyloid deposition in older Tg2576 mice is associated with markedly impaired vessel dilation, and the Introduction describes impaired cerebral blood-flow responses in APP mice. The paper supports cerebrovascular dysfunction in transgenic mice, but its reported measurements are vessel responses rather than a direct reduction in blood flow. The patient-frequency and human blood-flow portions of the sentence are attributed to other citations, not Han et al. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites Saito et al., 2017 source

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

    Premisecitation

    A recent longitudinal study in subjects characterized by amyloid and tau PET suggests that fibre tract alterations may be conducive to tau spreading and thus precede grey matter alterations in the projection zones of a tract.

    “Interestingly, a recent longitudinal study in subjects characterized by amyloid and tau PET suggests that fibre tract alterations may be conducive to tau spreading and thus precede grey matter alterations in the projection zones of a tract (Jacobs et al., 2018).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Jacobs et al., 2018 source

      The Results (page unavailable) report that baseline hippocampal cingulum diffusivity predicted later tau accumulation in the connected posterior cingulate cortex in amyloid-positive individuals. The Discussion interprets tract changes as potentially related to tau spreading. However, the study did not establish that tract alterations precede grey-matter alterations generally; its downstream measure was tau accumulation, not grey-matter structural change. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

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

    Premisecitation

    The behaviour of DTI indices in the human brain, which is characterized by a high density of crossing fibre that influence DTI measures, is only partially understood and remains speculative.

    “We caution that the behaviour of the DTI indices in the human brain, which is characterized by a high density of crossing fibre that influence DTI measures (Jeurissen et al., 2013), is only partially understood and remains speculative (Jones et al., 2013).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Jeurissen et al., 2013 source
    • cites Jones et al., 2013 source

  • May combine two claims.

    Study design and conductcitation

    DTI alterations observed in the corticospinal tract in the current study cannot be unambiguously attributed to that tract and may be due to alterations in crossing fibres such as the superior longitudinal fasciculus or corpus callosum.

    “DTI alterations such as those observed in the corticospinal tract in the current study should be interpreted with caution, as the current TBSS approach cannot be unambiguously attributed to that tract, but potentially are because of alterations in crossing fibres such as the superior longitudinal fasciculus or corpus callosum (Douaud et al., 2011; Teipel et al., 2014; Mito et al., 2018).”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites Douaud et al., 2011 source

      The Results (page unavailable) locate a diffusion change where corticospinal projection fibres cross the superior longitudinal fasciculus; the Discussion says that the change reflected affected SLF fibres alongside relatively spared motor fibres. This supports caution about assigning a DTI change to the corticospinal tract alone. The paper discusses corpus callosum abnormalities separately, but does not identify the corpus callosum as a crossing fibre responsible for the corticospinal-region finding. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites Teipel et al., 2014 source
    • cites Mito et al., 2018 source

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

    Study design and conductcitation

    TBSS has several limitations, such as susceptibility to misregistration artefacts, crossing fibres, and inaccurate voxel-assignment between neighbouring fibre tracts during the skeletonization procedure.

    “Furthermore, although TBSS is a widely-used approach to analyse DTI, the method has several limitations as previously described, such as susceptibility to misregistration artefacts, crossing fibres, and inaccurate voxel-assignment between neighbouring fibre tracts during the skeletonization procedure (Zalesky, 2011; de Groot et al., 2013; Bach et al., 2014).”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites Zalesky, 2011 source
    • cites de Groot et al., 2013 source

      The Introduction (page not provided) describes residual alignment errors and warns that TBSS skeleton projection can lose anatomical tract topology; the Conclusions report better alignment with an alternative registration approach. These passages support the misregistration limitation, but our copy does not identify crossing fibres or inaccurate assignment of voxels between neighbouring tracts as TBSS limitations. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites Bach et al., 2014 source

  • May combine two claims.

    Findingown data

    We found significant interactions of EYO by mutation status on mean diffusivity predominantly in posterior parietal and medial frontal regions of the white matter, indicating a faster increase of mean diffusivity in carriers compared to non-carriers.

    “We found significant interactions of EYO by mutation status on mean diffusivity predominantly in posterior parietal and medial frontal regions of the white matter (Fig. 1, peak coordinates in Table 2), indicating a faster increase of mean diffusivity in carriers compared to non-carriers.”
    Quote in the paperSubstantial claim

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

    Findingown data

    Carriers were less educated than non-carriers.

    “Carriers were less educated than non-carriers [t(93.8) = −2.03, P = 0.045], but the groups did not differ in terms of age, sex distribution and APOE ɛ4 genotype distribution.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    For global white matter differences in mean diffusivity, assessed by the PSMD biomarker, the interaction effect EYO × mutation status was B(SE) = 1.7(0.6) × 10−6, P < 0.001, indicating a faster progression in PSMD with EYO for carriers.

    “For global white matter differences in mean diffusivity, assessed by the PSMD biomarker, the interaction effect EYO × mutation status was B(standard error, SE) = 1.7(0.6) × 10−6, P < 0.001, indicating a faster progression in PSMD with EYO for carriers.”
    Quote in the paperSubstantial claim

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

    Findingown data

    Cortical siderosis was detected in the subject who had one microbleed.

    “Cortical siderosis was detected in the subject who had one microbleed.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The symptomatic carrier group (clinical dementia rating > 0, n = 31) showed increased mean diffusivity compared to non-carriers (n = 32, after matching the EYO range) primarily in regions of the posterior white matter, similar to the TBSS analysis of the interaction EYO × mutation status.

    “The symptomatic carrier group (clinical dementia rating > 0, n = 31) showed increased mean diffusivity compared to non-carriers (n = 32, after matching the EYO range) primarily in regions of the posterior white matter, similar to the TBSS analysis of the interaction EYO × mutation status (Supplementary Fig. 2A and Supplementary Table 1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    For exploratory reasons, fractional anisotropy, radial diffusivity and axial diffusivity were also analysed, and they showed a substantial spatial overlap particularly in regions including forceps major, forceps minor and posterior parietal part of the cingulum bundle.

    “For exploratory reasons, we also analysed fractional anisotropy, radial diffusivity and axial diffusivity, which showed a substantial spatial overlap particularly in regions including forceps major, forceps minor and posterior parietal part of the cingulum bundle.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisenone given

    A difficulty in the interpretation of previous findings is the uncertain future development of dementia symptoms at the presumed preclinical stage of Alzheimer's disease.

    “A difficulty in the interpretation of these previous findings is the uncertain future development of dementia symptoms at the presumed preclinical stage of Alzheimer’s disease.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    The groups did not differ in terms of age, sex distribution and APOE ɛ4 genotype distribution.

    “Carriers were less educated than non-carriers [t(93.8) = −2.03, P = 0.045], but the groups did not differ in terms of age, sex distribution and APOE ɛ4 genotype distribution.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    White matter alterations may stem from vascular amyloid deposition and microvascular damage.

    “Such white matter alterations cannot be fully accounted for as degenerative processes secondary to grey matter damage (Brun and Englund, 1986; Englund, 1998; Agosta et al., 2011), but may stem from vascular amyloid deposition and microvascular damage (Weller et al., 2009).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Weller et al., 2009 source

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

    Study design and conductown data

    Carriers included in the final sample were slightly younger and had a lower EYO than carriers who were excluded.

    “Compared to the carriers who were excluded, those carriers included were slightly younger [mean (standard deviation, SD) = 38.3 (11.3) versus 41.5 (10.0) years, P = 0.04] and had a lower EYO [mean (SD) = −9.1 (11.2) versus −4.6 (9.9) EYO, P = 0.02].”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    We controlled for the influence of white matter hyperintensities, i.e. macrostructural white matter changes that can significantly alter DTI measures such as mean diffusivity.

    “We controlled for the influence of white matter hyperintensities, i.e. macrostructural white matter changes that can significantly alter DTI measures such as mean diffusivity (Medina et al., 2006).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Medina et al., 2006 source

  • May combine two claims.

    Study design and conductown data

    No differences in gender distribution, APOE genotype or years of education were present between the included and excluded carrier groups, nor between included and excluded non-carriers.

    “No differences in gender distribution, APOE genotype or years of education were present between the carrier groups, nor were any differences in those variables detected between included and excluded non-carriers.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    The proportion of carriers versus non-carriers was similar between the final sample and the excluded participants.

    “The proportion of carriers versus non-carriers was similar between the final sample and the excluded participants (57.2% versus 61.9%, P = 0.6).”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Post-mortem studies show loss of myelin, axonal degeneration and gliosis in the brains of patients with Alzheimer's disease.

    “Post-mortem studies showed loss of myelin, axonal degeneration and gliosis in the brains from patients with Alzheimer’s disease (Brun and Englund, 1986).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Brun and Englund, 1986 source

  • May combine two claims.

    Interpretationreasoning

    PSMD was sensitive to the earliest white matter changes observed in the callosal fibres and may be a candidate marker for early white matter changes such as occurring in Alzheimer's disease.

    “The current findings suggest that PSMD was sensitive to the earliest white matter changes observed in the callosal fibres, and may thus be a candidate marker for early white matter changes such as occurring in Alzheimer’s disease.”
    Quote in the paperSubstantial claim

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

    Interpretationown data

    The non-significant interaction within asymptomatic carriers and all non-carriers was probably due to a lack of power of this smaller sample.

    “The results of the regression analysis of the interaction EYO × mutation status within the asymptomatic carrier group and all non-carriers was not significant, probably due to a lack power of this smaller sample.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Previous neuroimaging and post-mortem brain studies have observed white matter alterations in the presence of minimal or only weak grey matter atrophy, suggesting that in principle white matter alterations in Alzheimer's disease are not dependent on grey matter atrophy.

    “However, previous neuroimaging as well as post-mortem brain studies have observed white matter alterations in the presence of minimal or only weak grey matter atrophy (de la Monte, 1989; Zhuang et al., 2012), suggesting that in principle white matter alterations in Alzheimer’s disease are not dependent on grey matter atrophy.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites de la Monte, 1989 source
    • cites Zhuang et al., 2012 source

  • May combine two claims.

    Interpretationown data

    These fibre tract alterations were not restricted to WMH areas, suggesting that subtle changes in the normal-appearing white matter were already present years before the onset of dementia symptoms.

    “These fibre tract alterations were not restricted to WMH areas, suggesting that subtle changes in the normal-appearing white matter were already present years before the onset of dementia symptoms.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    WMHs manifest as regions of increased diffusivity in DTI and likely reflect the tip of the iceberg of underlying microstructural white matter changes: subtle white matter degeneration, detectable at first only with DTI, may gradually increase before becoming visible as macroscopic WMHs, which in turn give rise to lacunes.

    “WMHs manifest as regions of increased diffusivity in DTI and likely reflect the tip of the iceberg of underlying microstructural white matter changes: subtle white matter degeneration, detectable at first only with DTI, may gradually increase before becoming visible as macroscopic WMHs (Pelletier et al., 2015), which in turn give rise to lacunes (Duering et al., 2013).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Pelletier et al., 2015

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

    • cites Duering et al., 2013 source

  • May combine two claims.

    Interpretationreasoning

    In autosomal-dominant Alzheimer's disease, age-related changes such as vascular pathology that may impact on white matter integrity are unlikely to be detected, but may still exist in late-onset Alzheimer's disease.

    “Since in autosomal-dominant Alzheimer’s disease, the genetically caused increase in amyloid accumulation may begin already in the third or fourth decade of life, any age-related changes such as vascular pathology that may impact on white matter integrity are unlikely to be detected in autosomal-dominant Alzheimer’s disease, but may still exist in late-onset Alzheimer’s disease.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Current DTI findings show where mean diffusivity alterations can be first detected, but not necessarily where they first occur.

    “It is important to note that current findings on DTI assessed white matter differences show where mean diffusivity alterations can be first detected, but not necessarily where they first occur.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Higher mean diffusivity was associated with lower CSF amyloid-β1-42, higher CSF tau and CSF soluble TREM2, suggesting that early white matter alterations were associated with primary Alzheimer's disease pathology and microglia activity.

    “Higher mean diffusivity was associated with lower CSF amyloid-β1-42, higher CSF tau and CSF soluble TREM2, suggesting that early white matter alterations were associated with primary Alzheimer’s disease pathology and microglia activity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The difference of microstructural white matter degeneration inside versus outside of WMHs is likely of quantitative rather than qualitative nature, and the same potentially amyloid related pathomechanisms may underlie these white matter alterations.

    “Thus, the difference of microstructural white matter degeneration inside versus outside of WMHs is likely of quantitative rather than qualitative nature, and the same potentially amyloid related pathomechanisms may underlie these white matter alterations.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    The cingulum bundle is a thin white matter tract, which may render a region of interest approach less sensitive to detect diffusion alterations in that tract.

    “However, the cingulum bundle is only a thin white matter tract, which may render a region of interest approach less sensitive to detect diffusion alterations in that tract.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    White matter alterations start in circumscribed regions predominantly in posterior parietal and medial prefrontal white matter, preceding the onset of dementia symptoms by more than a decade.

    “In conclusion, the current findings suggest that white matter alterations start in circumscribed regions predominantly in posterior parietal and medial prefrontal white matter, preceding the onset of dementia symptoms by more than a decade.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    DTI alterations may stem from a variety of tissue changes including altered crossing fibres, permeability of the axonal membrane, inflammation, or oedema.

    “DTI alterations may stem from a variety of tissue changes including altered crossing fibres, permeability of the axonal membrane, inflammation, or oedema (Jones et al., 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Jones et al., 2013 source

  • May combine two claims.

    Study design and conductreasoning

    In the current study, the first white matter changes were detected in mutation carriers a decade before symptom onset, when no substantial grey matter atrophy is yet present, and at a relatively young age (mean ∼38 years), rendering it unlikely that those DTI alterations were due to gross misregistration artefacts.

    “However, in the current study the first white matter changes were detected in the mutation carriers a decade before symptoms onset, i.e. when no substantial grey matter atrophy is yet present, and at a relatively young age (mean ∼38 years), rendering it unlikely that those DTI alterations were due to gross misregistration artefacts.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    To reduce the likelihood of partial volume effects, a conservative white matter mask was applied, excluding regions most prone to artefacts such as the fornix.

    “Furthermore, to reduce the likelihood of partial volume effects, we applied a conservative white matter mask, excluding regions most prone to artefacts such as the fornix.”
    Quote in the paperSubstantial claim
49 of 49

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.

  • Consistentt(93.8) = -2.03reported p = .045 · recomputed p = .045

    “t(93.8) = −2.03, p = .045”

1 of 1

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.

  • Conclusion claims onset more than a decade early

    Major

    The conclusion says white matter alterations precede symptoms by more than a decade, but the earliest significant tract change reported is at EYO = −10, exactly a decade before estimated onset.

  • Included-carrier characteristics differ from Table 1

    Major

    The text gives included carriers a mean age of 38.3 years and mean EYO of −9.1, whereas Table 1 gives carriers 38.0 years and −8.4 EYO. The accompanying standard deviations also differ.

  • Three CSF biomarkers are described but four are listed

    Minor

    The methods call these "three CSF biomarkers" but name amyloid-β1-42, total tau, P-tau181 and soluble TREM2.

  • Carrier symptom-status percentages do not match the counts

    Minor

    Among the 63 carriers with a recorded symptom status, 32 asymptomatic carriers represent 50.8%, not 52%; the remaining 31 represent 49.2%, not 48%.

    Reported 52 · recomputed 50.793651

  • Final-sample carrier percentage is incorrect

    Minor

    The final sample contains 64 carriers among 109 participants, or 58.7%, not 57.2%.

    Reported 57.2 · recomputed 58.715596

5 of 5

Cites

Flagged first, then by citations

4 of the 115 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

Authors
Araque Caballero, M. Á., Suárez-Calvet, M., Duering, M., Franzmeier, N., Benzinger, T., Fagan, A. M., Bateman, R. J., Jack, C. R., Levin, J., Dichgans, M., Jucker, M., Karch, C., Masters, C. L., Morris, J. C., Weiner, M., Rossor, M., Fox, N. C., Lee, J.-H., Salloway, S., Danek, A., Goate, A., Yakushev, I., Hassenstab, J., Schofield, P. R., Haass, C., & Ewers, M.
Affiliations
  • Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität LMU, Munich, Germany
  • German Center for Neurodegenerative Diseases (DZNE, Munich), Munich, Germany
  • Institut für Schlaganfall- und Demenzforschung (DE)
  • Washington University in St. Louis (US)
  • Mayo Clinic (US)
  • German Center for Neurodegenerative Diseases (DE)
  • The University of Melbourne (AU)
  • University of California, San Francisco (US)
  • University College London (GB)
  • Asan Medical Center (KR)
  • Brown University (US)
  • Icahn School of Medicine at Mount Sinai (US)
  • Technical University of Munich (DE)
  • UNSW Sydney (AU)
Corresponding author
Ewers, Michael
ORCID
Venue
Brain
Publisher
Oxford University Press (OUP)
Published
2018-09-25
Volume
141
Issue
10
Pages
3065-3080
ISSN
  • 0006-8950 (ISSN-L)
  • 1460-2156
DOI
10.1093/brain/awy229
PMC
PMC6158739
OpenAlex
W2891943095
Semantic Scholar
cff25aa951231949504f754bdfc475c64d3b2e09
Cited by
179
References
115
Citations by year
2026: 19 · 2025: 24 · 2024: 19 · 2023: 20 · 2022: 23 · 2021: 31 · 2020: 28 · 2019: 13 · 2018: 1
FWCI
12.68
Type
journal article
Language
en
Open access
Licence
Locations
  • Brain (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • UNSWorks (University of New South Wales, Sydney, Australia) (submittedVersion, cc-by-nc-nd)
  • Minerva Access (University of Melbourne) (submittedVersion, cc-by)
  • Europe PMC (PubMed Central) (submittedVersion, cc-by)
  • PubMed Central (submittedVersion, cc-by)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by)
  • UCL Discovery (University College London) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • mediaTUM (Technical University of Munich) (submittedVersion)
  • DZNE Pub (submittedVersion)
Funders
  • ERC (PCIG12-GA-2012-334259)
  • Alzheimer Forschung Initiative
  • National Institute for Health Research University College London Hospitals Biomedical Research Centre
  • MRC Dementias Platform UK (MR/L023784/1, MR/009076/1)
  • Dominantly Inherited Alzheimer’s Network
  • DIAN
  • National Institute on Aging
  • NIA (U19AG032438)
  • German Center for Neurodegenerative Diseases
  • DZNE
  • Raul Carrea Institute for Neurological Research
  • FLENI
  • Research and Development Grants for Dementia
  • Japan Agency for Medical Research and Development
  • AMED
  • Korea Health Technology R&D Project
  • Korea Health Industry Development Institute
  • KHIDI
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced Neuroimaging Techniques and Applications
Keywords
autosomal dominant Alzheimer's disease, white matter degeneration, mean diffusivity, preclinical Alzheimer's disease, symptom onset, mutation carriers, default mode network, forceps major, forceps minor, gray matter volume, cerebrospinal fluid biomarkers, amyloid-beta 42, tau protein, phosphorylated tau, soluble TREM2
MeSH terms
Adult, Alzheimer Disease, Brain, Female, Humans, Male, Middle Aged, Diffusion Tensor Imaging, White Matter

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 2026-10-11.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-11.

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.

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