Decreased cerebrospinal fluid Aβ 42 correlates with brain atrophy in cognitively normal elderly
Open accessAbstract
Objective: For therapies for Alzheimer's disease (AD) to have the greatest impact, it will likely be necessary to treat individuals in the “preclinical” (presymptomatic) stage. Fluid and neuroimaging measures are being explored as possible biomarkers of AD pathology that could aid in identifying individuals in this stage to target them for clinical trials and to direct and monitor therapy. The objective of this study was to determine whether cerebrospinal fluid (CSF) biomarkers for AD suggest the presence of brain damage in the preclinical stage of AD. Methods: We investigated the relation between structural neuroimaging measures (whole‐brain volume) and levels of CSF amyloid‐β (Aβ) 40 , Aβ 42 , tau, and phosphorylated tau 181 (ptau 181 ), and plasma Aβ 40 and Aβ 42 in well‐characterized research subjects with very mild and mild dementia of the Alzheimer type (n = 29) and age‐matched, cognitively normal control subjects (n = 69). Results: Levels of CSF tau and ptau 181 , but not Aβ 42 , correlated inversely with whole‐brain volume in very mild and mild dementia of the Alzheimer type, whereas levels of CSF Aβ 42 , but not tau or ptau 181 , were positively correlated with whole‐brain volume in nondemented control subjects. Interpretation: Reduction in CSF Aβ 42 , likely reflecting Aβ aggregation in the brain, is associated with brain atrophy in the preclinical phase of AD. This suggests that there is toxicity associated with Aβ aggregation before the onset of clinically detectable disease. Increases in CSF tau (and ptau 181 ) are later events that correlate with further structural damage and occur with clinical onset and progression. Ann Neurol 2009;65:176–183
AI snapshot
Written from the paper’s full text.
TL;DR
In cognitively normal elderly, lower CSF Aβ42 was associated with smaller whole-brain volume, suggesting Aβ-related brain atrophy in the preclinical stage of Alzheimer’s disease. In very mild/mild dementia of the Alzheimer type, CSF tau and ptau181—but not Aβ42—correlated inversely with whole-brain volume.
Key findings
- Among non-demented controls (CDR 0, n=69), CSF Aβ42 was positively correlated with whole-brain volume, whereas CSF Aβ40, tau, ptau181, and plasma Aβ40/Aβ42 were not.
- Non-demented individuals with CSF Aβ42 <500 pg/mL had significantly smaller whole-brain volumes than those with CSF Aβ42 ≥500 pg/mL (p=0.0005); hippocampal volume was also smaller (mean=6793.59, SD=786.46, n=26 vs mean=7338.48, SD=720.09, n=32; p=0.008).
- In the PET PIB subset (n=37), all PIB-positive individuals had CSF Aβ42 <500 pg/mL (13/13, 100% sensitivity), and most PIB-negative individuals had CSF Aβ42 ≥500 pg/mL (20/24, 83% specificity).
- In very mild/mild DAT (CDR>0, n=29), whole-brain volume was inversely correlated with CSF tau and ptau181, but not with CSF Aβ42, CSF Aβ40, or plasma Aβ40/Aβ42.
Methods
- Community-dwelling volunteers (n=98; ages 60–91) from the Washington University ADRC: CDR 0 n=69, CDR 0.5 n=21, CDR 1 n=8; CDR 0.5 and CDR 1 were combined as CDR>0 (n=29).
- CSF and plasma Aβ40, Aβ42, tau, and ptau181 were measured by ELISA; MRI-derived normalized whole-brain volume and hippocampal volume were obtained, with PET PIB amyloid imaging in 37 participants.
- Analyses used t-tests/chi-square for group comparisons and bivariate or age-adjusted partial Pearson correlations between imaging and fluid measures, with p=0.05 and no correction for multiple comparisons.
Limitations
- Stated: no correction for multiple comparisons was applied, so some significant differences may be due to chance; the CDR 1 group was too small (n=8) for meaningful separate analysis.
- Stated: hippocampal volumes were unavailable for 12 of 98 subjects due to Freesurfer processing errors.
- Evident: the design is cross-sectional, with LP/blood and MRI performed within 2 years of each other, so temporal or causal direction cannot be established from these correlations.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
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Cites
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Claims the paper makes
0 of 26 cited sources checked · 0 supported · 0 flagged
- Findingown data
In non-demented controls, CSF Aβ42 is positively correlated with whole brain volume after adjustment for age.
“levels of CSF Aβ42, but not tau or ptau181, was positively correlated with whole brain volume in non-demented controls.”
- Also stated in: § Results · plain
“nWBV was significantly correlated with CSF Aβ42 (Fig. 1B); non-demented individuals with low CSF Aβ42 had smaller brain volumes than those with higher CSF Aβ42.”
Quote in the paperSubstantial claim - Also stated in: § Results · plain
- Findingown data
In non-demented controls, whole brain volume is not associated with CSF Aβ40 levels.
“brain volume was not associated with levels of CSF Aβ40 (Fig. 1A)”
Quote in the paperNot a substantial claim - Findingown data
In non-demented controls, mean hippocampal volume is smaller in those with CSF Aβ42 <500 pg/mL than in those with CSF Aβ42 ≥500 pg/mL.
“The mean hippocampal volume was also smaller in CDR 0 subjects with CSF Aβ42 <500 pg/mL (mean=6793.59, SD=786.46, n=26) compared to those with CSF Aβ42 values ≥500 pg/mL (mean=7338.48, SD=720.09, n=32) (p=0.008).”
Quote in the paperSubstantial claim - Findingown data
In non-demented controls, whole brain volume is not associated with plasma Aβ40 levels.
“nor with plasma Aβ40 (r=−0.0390, p=0.776)”
Quote in the paperNot a substantial claim - Findingown data
In non-demented controls, whole brain volume is not associated with CSF ptau181 levels.
“ptau181 (r=−0.0020, p=0.987)”
Quote in the paperNot a substantial claim
- Findingown data
In non-demented controls, individuals with CSF Aβ42 <500 pg/mL have significantly smaller whole brain volumes on average than those with CSF Aβ42 ≥500 pg/mL.
“Non-demented individuals with CSF Aβ42 <500 pg/mL (likely indicative of brain amyloid) exhibited significantly smaller brain volumes (p=0.0005) on average than those with CSF Aβ42 ≥500 pg/mL (Fig. 1F).”
Quote in the paperSubstantial claim - Findingown data
In non-demented controls, whole brain volume is not associated with CSF tau levels.
“tau (Fig. 1C)”
Quote in the paperNot a substantial claim - Findingown data
In very mild/mild DAT, whole brain volume is inversely correlated with CSF tau levels.
“Levels of CSF tau and ptau181, but not Aβ42, correlated inversely with whole brain volume in very mild/mild DAT”
- Also stated in: § Results · plain
“whole brain volume was inversely correlated with levels of CSF tau (Fig. 2C)”
Quote in the paperNot a substantial claim - Also stated in: § Results · plain
- Findingown data
In very mild/mild DAT, none of the fluid measures correlate with hippocampal volume.
“None of the fluid measures correlated with hippocampal volume in the very mildly/mildly demented cohort (Table 2).”
Quote in the paperNot a substantial claim - Findingown data
In very mild/mild DAT, mean CSF tau, ptau181, and tau(s)/Aβ42 ratios are significantly higher than in non-demented controls.
“Subjects with very mild/mild DAT also exhibited the typical AD fluid biomarker phenotype characterized by significantly lower mean levels of CSF Aβ42, higher CSF tau, ptau181 and the tau(s)/Aβ42 ratios, 8-11, 13, 14 with no change in mean levels of CSF Aβ40 or plasma Aβ40 or Aβ42.”
Quote in the paperNot a substantial claim - Findingown data
In the subset with PET PIB (n=37), all PIB-positive individuals had CSF Aβ42 values below 500 pg/mL (13/13, 100% sensitivity).
“all PIB-positive individuals had CSF Aβ42 values below the cut-off of 500 pg/mL (13/13, 100% sensitivity)”
Quote in the paperSubstantial claim - Findingown data
In very mild/mild DAT, mean CSF Aβ42 levels are significantly lower than in non-demented controls.
“Subjects with very mild/mild DAT also exhibited the typical AD fluid biomarker phenotype characterized by significantly lower mean levels of CSF Aβ42, higher CSF tau, ptau181 and the tau(s)/Aβ42 ratios, 8-11, 13, 14 with no change in mean levels of CSF Aβ40 or plasma Aβ40 or Aβ42.”
Quote in the paperNot a substantial claim - Findingown data
In very mild DAT (CDR 0.5) only, whole brain volume is correlated with CSF ptau181 (r=−0.4340, p=0.0560, approaching statistical significance).
“and ptau181 (r=−0.4340, p=0.0560, approaching statistical significance)”
Quote in the paperNot a substantial claim - Findingown data
In very mild/mild DAT, whole brain volume is not associated with CSF Aβ42 levels.
“nWBV in subjects with very mild/mild DAT was not associated with levels of CSF Aβ42 (Fig. 2A)”
Quote in the paperNot a substantial claim - Findingown data
In the subset with PET PIB (n=37), most PIB-negative individuals had CSF Aβ42 values ≥500 pg/mL (20/24, 83% specificity).
“most PIB-negative individuals had CSF Aβ42 values ≥500 (20/24; 83% specificity) (Fig. 1E).”
Quote in the paperSubstantial claim - Findingown data
In very mild/mild DAT, whole brain volume is not associated with plasma Aβ42 levels.
“or Aβ42 (Fig. 2B)”
Quote in the paperNot a substantial claim - Findingown data
In very mild/mild DAT, whole brain volume is inversely correlated with CSF ptau181 levels.
“Levels of CSF tau and ptau181, but not Aβ42, correlated inversely with whole brain volume in very mild/mild DAT”
- Also stated in: § Results · plain
“and ptau181 (Fig. 2D)”
Quote in the paperNot a substantial claim - Also stated in: § Results · plain
- Findingown data
In very mild DAT (CDR 0.5) only, whole brain volume is correlated with CSF tau (r=−0.4810, p=0.0320).
“subjects with very mild DAT showed correlations between nWBV and CSF tau (r=−0.4810, p=0.0320)”
Quote in the paperNot a substantial claim - Findingown data
In very mild DAT (CDR 0.5) only, whole brain volume is correlated with CSF Aβ42 (r=0.4930, p=0.0270).
“Interestingly, nWBV was now also correlated with CSF Aβ42 (r=0.4930, p=0.0270) in the CDR 0.5 group, similar to what we observed in the CDR 0 group.”
Quote in the paperNot a substantial claim - Findingown data
In non-demented controls, whole brain volume is not associated with plasma Aβ42 levels.
“or Aβ42 (Fig. 1D)”
Quote in the paperNot a substantial claim - Findingown data
The very mild/mild DAT group has significantly reduced whole brain and hippocampal volumes compared with non-demented controls.
“The very mild/mild DAT group also exhibited significantly reduced whole brain (nWBV) and hippocampal (HC) volumes, as has been reported previously.6, 27”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [6] Kantarci K Jack CR Jr Quantitative magnetic resonance techniques as surrogate markers of Alzheimer's disease NeuroRx 2004 1 196 205 15717020 PMC534925 source
Not checked in the free run.
- cites [27] Fotenos AF Snyder AZ Girton LE Normative estimates of cross-sectional and longitudinal brain volume decline in aging and AD Neurology 2005 64 1032 1039 15781822 source
Not checked in the free run.
- Findingown data
In very mild/mild DAT, whole brain volume is not associated with CSF Aβ40 levels.
“nor with levels of CSF Aβ40 (r=0.0830, p=0.6820)”
Quote in the paperNot a substantial claim - Findingown data
In non-demented controls, none of the fluid measures correlate with hippocampal volume.
“None of the fluid measures correlated with hippocampal volume in the non-demented cohort (Table 2).”
Quote in the paperNot a substantial claim - Findingown data
In very mild/mild DAT, whole brain volume is not associated with plasma Aβ40 levels.
“or plasma Aβ40 (r=0.1240, p=0.5470)”
Quote in the paperNot a substantial claim - Interpretationreasoning
There is toxicity associated with Aβ aggregation prior to the onset of clinically detectable disease.
“This suggests that there is toxicity associated with Aβ aggregation prior to the onset of clinically detectable disease.”
Quote in the paperSubstantial claim - Interpretationreasoning
The association between low CSF Aβ42 and small brain volume in the non-demented cohort may reflect underlying Aβ aggregation and deposition and consequent and/or concomitant axonal and synaptic degeneration leading to measurable atrophy in the preclinical phase.
“the association between low CSF Aβ42 and small brain volume in this non-demented cohort may reflect underlying Aβ aggregation and deposition and consequent and/or concomitant axonal and synaptic degeneration leading to measurable atrophy in the preclinical phase.”
Quote in the paperSubstantial claim- The authors state this as an assumption: Whole brain atrophy is the consequence of years of axonal and neuronal degeneration.
- Interpretationown data
Reduction in CSF Aβ42, likely reflecting Aβ aggregation in the brain, is associated with brain atrophy in the preclinical phase of AD.
“Reduction in CSF Aβ42, likely reflecting Aβ aggregation in the brain, is associated with brain atrophy in the preclinical phase of AD.”
- Also stated in: § Discussion · hedged
“Results of the present study suggest that alterations in Aβ42 metabolism, likely reflecting Aβ aggregation in the brain, are associated with brain atrophy in the “preclinical” phase of AD (as well as the very early CDR 0.5 stage)”
Quote in the paperSubstantial claim- The authors state this as an assumption: Whole brain atrophy is the consequence of years of axonal and neuronal degeneration.
- Also stated in: § Discussion · hedged
- May combine two claims. 12
- Classified as probably not a substantial claim. 11
May combine two claims.
Findingown dataIn very mild/mild DAT, mean CSF Aβ40 and plasma Aβ40 and Aβ42 levels do not differ from non-demented controls.
“with no change in mean levels of CSF Aβ40 or plasma Aβ40 or Aβ42.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationAD pathology begins a decade or longer before the appearance of any cognitive symptoms and signs of dementia (preclinical AD), with impairments becoming clinically detectable only after substantial neuronal cell death.
“AD pathology is estimated to begin a decade or longer prior to the appearance of any cognitive symptoms and signs of dementia (a stage termed “preclinical AD”), with impairments becoming clinically detectable only after substantial neuronal cell death has taken place.1-5”
Quote in the paperSubstantial claim0 of 5 sources checked- cites [1] Price J Ko A Wade M Neuron number in the entorhinal cortex and CA1 in preclinical Alzheimer's disease Arch Neurol 2001 58 1395 1402 11559310 source
Not checked in the free run.
- cites [2] Gomez-Isla T Price JL McKeel DW Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer's disease J Neurosci 1996 16 4491 4500 8699259 PMC6578866 source
Not checked in the free run.
- cites [3] Morris J Price J Pathologic correlates of nondemented aging, mild cognitive impairment, and early stage Alzheimer's disease J Mol Neurosci 2001 17 101 118 11816784
Not checked in the free run.
- cites [4] Hulette CM Welsh-Bohmer KA Murray MG Neuropathological and neuropsychological changes in “normal” aging: Evidence for preclinical Alzheimer disease in cognitively normal individuals J Neuropathol Exp Neurol 1998 57 1168 1174 9862640 source
Not checked in the free run.
- cites [5] Markesbery W Schmitt F Kryscio R Neuropathologic substrate of Mild Cognitive Impairment Arch Neurol 2006 63 38 46 16401735 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationWhole brain atrophy is a fundamental but not specific feature of AD and has been quantified antemortem by MRI in cross-sectional and longitudinal studies.
“Whole brain atrophy, the presumed consequence of years of axonal and neuronal degeneration, is a fundamental but not specific feature of AD and has been quantified antemortem by magnetic resonance imaging (MRI) in both cross-sectional and longitudinal studies. 6, 7”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [6] Kantarci K Jack CR Jr Quantitative magnetic resonance techniques as surrogate markers of Alzheimer's disease NeuroRx 2004 1 196 205 15717020 PMC534925
Not checked in the free run.
- cites [7] Scahill RI Fox NC Longitudinal imaging in dementia Br J Radiol 2007 80 Spec No 2 S92 98 18445749
Not checked in the free run.
- The authors state this as an assumption: Whole brain atrophy is the consequence of years of axonal and neuronal degeneration.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationCSF Aβ42 levels are typically reduced in dementia of the Alzheimer type (DAT), reflecting its aggregation and deposition as amyloid in the brain.
“Levels of CSF Aβ42 are typically reduced in dementia of the Alzheimer type (DAT),8-11 reflecting its aggregation and deposition as amyloid in the brain,12”
Quote in the paperNot a substantial claim0 of 5 sources checked- cites [8] Sunderland T Linker G Mirza N Decreased β-amyloid1-42 and increased tau levels in cerebrospinal fluid of patients with Alzheimer's disease JAMA 2003 289 2094 2103 12709467 source
Not checked in the free run.
- cites [9] Galasko D Chang L Motter R High cerebrospinal fluid tau and low amyloid β42 levels in the clinical diagnosis of Alzheimer's disease and relation to apolipoprotein E genotype Arch. Neurol 1998 55 937 945 9678311 source
Not checked in the free run.
- cites [10] Kanai M Matsubara E Isoe K Longitudinal study of cerebrospinal fluid levels of tau, Aβ1-40, and Aβ1-42(43) in Alzheimer's disease: A study in Japan Ann. Neurol 1998 44 17 26 9667589 source
Not checked in the free run.
- cites [11] Motter R Vigo-Pelfrey C Kholodenko D Reduction of β-amyloid peptide42 in the cerebrospinal fluid of patients with Alzheimer's disease Ann. Neurol 1995 38 643 648 7574461 source
Not checked in the free run.
- cites [12] Fagan A Mintun M Mach R Inverse relation between in vivo amyloid imaging load and CSF Aβ42 in humans Ann Neurol 2006 59 512 519 16372280 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationCSF tau and phosphorylated tau species are elevated in DAT and are hypothesized to reflect the presence of neurofibrillary tangles and/or neurodegeneration, although not all studies support this conclusion.
“levels of CSF tau and phosphorylated tau (ptau) species are elevated in DAT8, 13, 14 and are hypothesized to reflect the presence of neurofibrillary tangles and/or neurodegeneration,15, 16 although not all studies support this conclusion.17”
Quote in the paperNot a substantial claim0 of 6 sources checked- cites [8] Sunderland T Linker G Mirza N Decreased β-amyloid1-42 and increased tau levels in cerebrospinal fluid of patients with Alzheimer's disease JAMA 2003 289 2094 2103 12709467
Not checked in the free run.
- cites [13] Andreasen N Vanmechelen E Van de Voorde A Cerebrospinal fluid tau protein as a biochemical marker for Alzheimer's disease: A community based follow up study J. Neurol. Neurosurg. Psych 1998 64 298 305 PMC2170016 9527138
Not checked in the free run.
- cites [14] Arai H Terajima M Miura M Tau in cerebrospinal fluid: A potential diagnostic marker in Alzheimer's disease Ann. Neurol 1995 38 649 652 7574462
Not checked in the free run.
- cites [15] Tapiola T Overmyer M Lehtovirta M The level of cerebrospinal fluid tau correlates with neurofibrillary tangles in Alzheimer's disease Neuroreport 1997 8 3961 3963 9462474
Not checked in the free run.
- cites [16] Buerger K Ewers M Pirttila T CSF phosphorylated tau protein correlates with neocortical neurofibrillary pathology in Alzheimer's disease Brain 2006 129 3035 3041 17012293 source
Not checked in the free run.
- cites [17] Engelborghs S Sleegers K Cras P No association of CSF biomarkers with APOEepsilon4, plaque and tangle burden in definite Alzheimer's disease Brain 2007 130 2320 2326 17586559
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductcitationThe rate of postmortem confirmation of AD clinical diagnosis at the authors' Center is 92%, including the very mild CDR 0.5 stage.
“The rate of postmortem confirmation of AD clinical diagnosis in our Center is 92% 22, including the very mild CDR 0.5 stage.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [22] Storandt M Grant E Miller J Morris J Longitudinal course and neuropathologic outcomes in original vs revised MCI and in pre-MCI Neurology 2006 67 467 473 16894109
Not checked in the free run.
Classified as probably not a substantial claim.
Study design and conductreasoningCorrelations between imaging and CSF biomarker measures were adjusted for age in all analyses.
“As chronological age was associated with fluid and imaging measures, correlations were adjusted for age in all analyses.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
Study design and conductreasoningThe analyses did not correct for multiple comparisons, so some statistically significant differences reported may be due to chance.
“without correction for multiple comparisons. Since the Type I error rate rises with increasing numbers of statistical tests, some statistically significant differences reported may be due to chance.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationThe CSF tau/Aβ42 ratio predicts future cognitive decline in cognitively normal elders and individuals with MCI.
“the CSF tau/Aβ42 ratio predicts future cognitive decline in cognitively normal elders 34, 50 and individuals with MCI,51”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [34] Fagan A Roe C Xiong C Cerebrospinal fluid tau/Aβ42 ratio as a prediction of cognitive decline in nondemented older adults Arch. Neurol 2007 64 343 349 17210801 source
Not checked in the free run.
- cites [50] Li G Sokal I Quinn J CSF tau/Aβ42 ratio for increased risk of mild cognitive impairment: A follow-up study Neurology 2007 69 631 639 17698783
Not checked in the free run.
- cites [51] Hansson O Zetterberg H Buchhave P Association between CSF biomarkers and incipient Alzheimer's disease in patients with mild cognitive impairment: A follow-up study Lancet Neurol 2006 5 228 234 16488378
Not checked in the free run.
May combine two claims.
Study design and conductown dataThe non-demented and very mild/mild DAT groups differed significantly in age, education, and MMSE scores.
“The groups differed significantly with regard to age (slightly older in the CDR>0 group), education (less in the CDR>0 group), and MMSE scores (lower in the CDR>0 group).”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningReductions in CSF Aβ42 reflect the presence of amyloid plaques but perhaps also diffuse (non-fibrillar) plaques and/or concomitant Aβ oligomer formation, which could contribute to neurotoxicity and volume loss without being visualized by PET PIB.
“Reductions in CSF Aβ42 reflect the presence of amyloid plaques but perhaps also diffuse (non-fibrillar) plaques and/or concomitant Aβ oligomer formation, both of which could contribute to neurotoxicity (neuritic and/or cellular) and consequent volume loss, but would not be visualized with PET PIB.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductcitationThe automated hippocampal volume technique has been reported to generate volumes with high correspondence to manually generated volumes.
“has been reported to generate volumes with a high correspondence to manually generated volumes. 31”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [31] Fischl B Salat D Busa E Whole brain segmentation: Automated labeling of neuroanatomical structures in the human brain Neuron 2002 33 341 355 11832223 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductcitationMultivariate outliers were defined using Mahalanobis Distance and Cook's Distance, and partial correlations controlling for age were repeated after omitting outliers.
“Mahalanobis Distance and Cook's Distance methods 33 were used to define multivariate outliers, and partial correlations (controlling for age) were again performed on the new data set in which outliers were omitted.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [33] Cohen J Cohen P West S Aiken L Applied Multiple Regression/Correlations Analysis for the Behavioral Sciences 2003 Lawrence Erlbaum Associates Mahwah, New Jersey Third Edition
Not checked in the free run.
May combine two claims.
InterpretationreasoningIncreases in CSF tau and ptau181 are later events that correlate with further structural damage and occur with clinical onset and progression.
“Increases in CSF tau (and ptau181) are later events that correlate with further structural damage and occur with clinical onset and progression.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenLP/blood collection and MRI were performed within 2 years of each other.
“LP/blood collection and MRI were performed within 2 years of each other.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductnone givenCSF samples were free from any blood contamination.
“CSF samples were free from any blood contamination.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown dataHippocampal volumes were obtained from all but 12 of the 98 subjects, with omissions due to Freesurfer processing errors.
“Hippocampal volumes were obtained from all but 12 of the 98 subjects (omissions due to Freesurfer processing errors).”
Quote in the paperNot a substantial claim
The authors state this as an assumption.
Whole brain atrophy is the consequence of years of axonal and neuronal degeneration.
“Whole brain atrophy, the presumed consequence of years of axonal and neuronal degeneration, is a fundamental but not specific feature of AD”
The paper relies on this without support.
The relationship between fluid measures and brain volumetric measures is unclear, especially in non-demented elderly individuals and those with early stage DAT.
“The extent to which these fluid measures relate to brain volumetric measures remains unclear, especially in non-demented elderly individuals and those with early stage DAT.”
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?
Low concentrations of Aβ42 in the CSF reflect the presence of cerebral Aβ deposition, likely as a result of Aβ42 being sequestered into amyloid plaques, changing the equilibrium between the brain and CSF pools of Aβ.
“low concentrations of Aβ42 in the cerebrospinal fluid (CSF) reflect the presence of cerebral Aβ deposition, likely as a result of Aβ42 being sequestered into amyloid plaques, changing the equilibrium between the brain and CSF pools of Aβ (20-22).”
From Human ApoE isoforms differentially regulate brain amyloid-β peptide clearance (2011) · cites this paper as [22]
The Introduction and Discussion (page numbers not provided) say that low CSF Aβ42 reflects cerebral amyloid aggregation and deposition, including plaques. Our copy does not describe sequestration into plaques as changing the equilibrium between brain and CSF Aβ pools, so that specific mechanism is unsupported. (LLM, conf=0.85)
Experimental — accuracy not yet measuredA CSF Aβ42 concentration lower than 500 pg/mL has been utilized as a reliable threshold for the presence of cerebral Aβ deposition in humans.
“Given that a CSF Aβ42 concentration lower than 500 pg/mL has been utilized as a reliable threshold for the presence of cerebral Aβ deposition in humans (7, 19, 22, 26)”
From Human ApoE isoforms differentially regulate brain amyloid-β peptide clearance (2011) · cites this paper as [22]
The best predictor for conversion to MCI and then AD is a decrease in extracellular Aβ42.
“That the best predictor for conversion to MCI and then AD is a decrease in the levels of extracellular Aβ42 might have seemed surprising to proponents of the prevalent extracellular Aβ cascade hypothesis.”
From Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease (2010) · cites this paper as [48]
The earliest diagnostic change indicating that an individual without known cognitive deficits will decline cognitively and develop AD is a drop in CSF Aβ42.
“Recently it is becoming apparent that the earliest diagnostic change indicating that an individual without known cognitive deficits will go on to decline cognitively and develop AD is a drop in levels of Aβ42 in the CSF [15, 48].”
From Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease (2010) · cites this paper as [48]
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Self-citationFagan, A. M., Mintun, M. A., Mach, R. H., Lee, S., Dence, C. S., Shah, A. R., LaRossa, G. N., Spinner, M. L., Klunk, W. E., Mathis, C. A., et al. (2006) · Annals of Neurology · doi:10.1002/ana.20730 · Cited by 1,246 · see citing works
Self-citationDickerson, B. C., Bakkour, A., Salat, D. H., Feczko, E., Pacheco, J., Greve, D. N., Grodstein, F., Wright, C. I., Blacker, D., Rosas, H. D., et al. (2009) · Cerebral Cortex · doi:10.1093/cercor/bhn113 · Cited by 1,153 · cited 1× · see citing works
“During this period, lasting possibly a decade or more, amyloid is depositing in several brain regions, including cortical regions that have recently been shown to exhibit thinning during this presymptomatic stage.(48) The hippocampus proper is not a region with prominent early amyloid deposition, so hippocampal volume…”
BackgroundSelf-citationFagan, A. M., Roe, C. M., Xiong, C., Mintun, M. A., Morris, J. C., & Holtzman, D. M. (2007) · Archives of Neurology · doi:10.1001/archneur.64.3.noc60123 · Cited by 897 · see citing works
Self-citationMotter, R., Vigo‐Pelfrey, C., Kholodenko, D., Barbour, R., Johnson‐Wood, K., Galasko, D., Chang, L., Miller, B., Clark, C., Green, R., et al. (1995) · Annals of Neurology · doi:10.1002/ana.410380413 · Cited by 701 · see citing works
Early Aβ accumulation and progressive synaptic loss, gliosis, and tangle formation in AD brain
Ingelsson, M., Fukumoto, H., Newell, K. L., Growdon, J. H., Hedley–Whyte, E. T., Frosch, M. P., Albert, M. S., Hyman, B. T., & Irizarry, M. C. (2004) · Neurology · doi:10.1212/01.wnl.0000115115.98960.37 · Cited by 666 · cited 1× · see citing works
“In addition, studies suggest that by the time individuals become cognitively impaired because of AD, cortical amyloid deposition is close to reaching its maximal extent.(39,40) A recent antemortem study reported a positive correlation between whole-brain atrophy and cortical amyloid as detected by PET PIB in a small n…”
BackgroundBerg, L., McKeel, D. W., Miller, J. P., Storandt, M., Rubin, E. H., Morris, J. C., Baty, J., Coats, M., Norton, J., Goate, A. M., et al. (1998) · Archives of Neurology · doi:10.1001/archneur.55.3.326 · Cited by 657 · cited 1× · see citing works
“Cognitive status was determined annually in accordance with standard protocols and criteria.(18,19) A Clinical Dementia Rating (CDR)(20) of 0 (n 69) indicated no dementia, whereas CDRs of 0.”
MethodSelf-citationSunderland, T., Linker, G., Mirza, N., Putnam, K. T., Friedman, D. L., Kimmel, L. H., Bergeson, J., Manetti, G. J., Zimmermann, M., Tang, B., et al. (2003) · JAMA · doi:10.1001/jama.289.16.2094 · Cited by 656 · see citing works
Antemortem MRI findings correlate with hippocampal neuropathology in typical aging and dementia
Jack, C. R., Dickson, D. W., Parisi, J. E., Xu, Y. C., Cha, R. H., O’Brien, P. C., Edland, S. D., Smith, G. E., Boeve, B. F., Tangalos, E. G., et al. (2002) · Neurology · doi:10.1212/wnl.58.5.750 · Cited by 610 · see citing works
Neuron Number in the Entorhinal Cortex and CA1 in Preclinical Alzheimer Disease
Price, J. L., Ko, A. I., Wade, M. J., Tsou, S. K., McKeel, D. W., & Morris, J. C. (2001) · Archives of Neurology · doi:10.1001/archneur.58.9.1395 · Cited by 596 · see citing works
Self-citationBuerger, K., Ewers, M., Pirttila, T., Zinkowski, R., Alafuzoff, I., Teipel, S. J., DeBernardis, J., Kerkman, D., McCulloch, C., Soininen, H., et al. (2006) · Brain · doi:10.1093/brain/awl269 · Cited by 586 · see citing works
Normative estimates of cross-sectional and longitudinal brain volume decline in aging and AD
Fotenos, A. F., Snyder, A. Z., Girton, L. E., Morris, J. C., & Buckner, R. L. (2005) · Neurology · doi:10.1212/01.wnl.0000154530.72969.11 · Cited by 579 · cited 1× · see citing works
“brain (nWBV) and hippocampal volumes, as has been reported previously.(6,27) To better understand the relation between the structural and fluid biomarker measures in cognitively normal elderly, we next compared the CSF and plasma measures with nWBV in nondemented individuals (Fig 1).”
MethodSelf-citationMorris, J. C., & Price, J. L. (2001) · Journal of Molecular Neuroscience · doi:10.1385/jmn:17:2:101 · Cited by 513 · see citing works
Self-citationNeuropathologic Substrate of Mild Cognitive Impairment
Markesbery, W. R., Schmitt, F. A., Kryscio, R. J., Davis, D. G., Smith, C. D., & Wekstein, D. R. (2006) · Archives of Neurology · doi:10.1001/archneur.63.1.38 · Cited by 460 · see citing works
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Cirrito, J. R., May, P. C., O'Dell, M. A., Taylor, J. W., Parsadanian, M., Cramer, J. W., Audia, J. E., Nissen, J. S., Bales, K. R., Paul, S. M., et al. (2003) · The Journal of Neuroscience · doi:10.1523/jneurosci.23-26-08844.2003 · Cited by 394 · cited 1× · see citing works
“CSF A 40 and plasma A 40 and A 42 were assayed by enzyme-linked immunosorbant assay, as described elsewhere.(23) For all biomarker measures, samples were continuously kept on ice, and assays were performed on sample aliquots after a single thaw after initial freezing.”
MethodSelf-citationValidation of clinical diagnostic criteria for Alzheimer's disease
Morris, J. C., McKeel, D. W., Fulling, K., Torack, R. M., & Berg, L. (1988) · Annals of Neurology · doi:10.1002/ana.410240105 · Cited by 362 · cited 1× · see citing works
“Cognitive status was determined annually in accordance with standard protocols and criteria.(18,19) A Clinical Dementia Rating (CDR)(20) of 0 (n 69) indicated no dementia, whereas CDRs of 0.”
MethodSelf-citationKanai, M., Matsubara, E., Isoe, K., Urakami, K., Nakashima, K., Arai, H., Sasaki, H., Abe, K., Iwatsubo, T., Kosaka, T., et al. (1998) · Annals of Neurology · doi:10.1002/ana.410440108 · Cited by 340 · see citing works
Hippocampal neurons in pre-clinical Alzheimer's disease.
West, M. J., Kawas, C. H., Stewart, W. F., Rudow, G. L., & Troncoso, J. C. (2004) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2003.12.005 · Cited by 317 · see citing works
Tau in cerebrospinal fluid: A potential diagnostic marker in Alzheimer's disease
Arai, H., Terajima, M., Miura, M., Higuchi, S., Muramatsu, T., Machida, N., Seiki, H., Takase, S., Clark, C., Lee, V. M., et al. (1995) · Annals of Neurology · doi:10.1002/ana.410380414 · Cited by 314 · see citing works
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Longitudinal course and neuropathologic outcomes in original vs revised MCI and in pre-MCI
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Self-citationChanges in premorbid brain volume predict Alzheimer’s disease pathology
Silbert, L. C., Quinn, J. F., Moore, M. M., Corbridge, E., Ball, M. J., MURDOCH, G. H., Sexton, G. J., & Kaye, J. A. (2003) · Neurology · doi:10.1212/01.wnl.0000079053.77227.14 · Cited by 280 · cited 1× · see citing works
“The correlations we observed between levels of CSF tau (and ptau181), but not A 42, and whole-brain volume in DAT are consistent with histopathological findings of associations between atrophy measures and neurofibrillary tangle burden or Braak neurofibrillary tangle stage, but not A plaque load.(37,38) In addition, s…”
ResultCSF tau/Aβ 42 ratio for increased risk of mild cognitive impairment
Li, G., Sokal, I., Quinn, J. F., Leverenz, J. B., Brodey, M., Schellenberg, G. D., Kaye, J. A., Raskind, M. A., Zhang, J., Peskind, E. R., et al. (2007) · Neurology · doi:10.1212/01.wnl.0000267428.62582.aa · Cited by 274 · see citing works
Longitudinal CSF and MRI biomarkers improve the diagnosis of mild cognitive impairment
de Leon, M. J., DeSanti, S., Zinkowski, R. P., Mehta, P. D., Praticò, D., Segal, S., Rusinek, H., Li, J., Tsui, W., Louis, L. A. S., et al. (2005) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2005.07.003 · Cited by 253 · see citing works
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β‐amyloid burden is not associated with rates of brain atrophy
Josephs, K. A., Whitwell, J. L., Ahmed, Z., Shiung, M. M., Weigand, S. D., Knopman, D. S., Boeve, B. F., Parisi, J. E., Petersen, R. C., Dickson, D. W., et al. (2007) · Annals of Neurology · doi:10.1002/ana.21223 · Cited by 224 · see citing works
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Rapid three‐dimensional T1‐weighted MR imaging with the MP‐RAGE sequence
Mugler, J. P., & Brookeman, J. R. (1991) · Journal of Magnetic Resonance Imaging · doi:10.1002/jmri.1880010509 · Cited by 174 · see citing works
Frontal-Hippocampal Double Dissociation Between Normal Aging and Alzheimer's Disease
Head, D. M., Snyder, A. Z., Girton, L. E., Morris, J. C., & Buckner, R. L. (2004) · Cerebral Cortex · doi:10.1093/cercor/bhh174 · Cited by 158 · see citing works
Self-citationThe level of cerebrospinal fluid tau correlates with neurofibrillary tangles in Alzheimerʼs disease
Tapiola, T., Overmyer, M., Lehtovirta, M., Helisalmi, S., Ramberg, J., Alafuzoff, I. I., Riekkinen, P. J., & Soininen, H. S. (1997) · Neuroreport · doi:10.1097/00001756-199712220-00022 · Cited by 139 · see citing works
Cerebrospinal fluid biomarkers for disease stage and intensity in cognitively impaired patients
Wahlund, L.-O., & Blennow, K. (2003) · Neuroscience Letters · doi:10.1016/s0304-3940(02)01483-0 · Cited by 114 · see citing works
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CSF and MRI markers independently contribute to the diagnosis of Alzheimer's disease
Schoonenboom, N. S. M., van der Flier, W. M., Blankenstein, M. A., Bouwman, F. H., van Kamp, G. J., Barkhof, F., & Scheltens, P. (2007) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2006.11.018 · Cited by 106 · see citing works
Nagy, Z., Jobst, K. A., Esiri, M. M., Morris, J. H., King, E. M.-F., MacDonald, B., Litchfield, S., Barnetson, L. P. D., & Smith, A. D. (1996) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000106857 · Cited by 93 · see citing works
Self-citationQuantitative magnetic resonance techniques as surrogate markers of Alzheimer’s disease
Kantarci, K., & Jack, C. R. (2004) · NeuroRX · doi:10.1602/neurorx.1.2.196 · Cited by 80 · cited 2× · see citing works
“Whole-brain atrophy, the presumed consequence of years of axonal and neuronal degeneration, is a fundamental but not specific feature of AD and has been quantified antemortem by magnetic resonance imaging (MRI) in both cross-sectional and longitudinal studies.(6,7) The best studied fluid analytes in AD have been cereb…”
BackgroundMethodSchönknecht, P., Pantel, J., Hartmann, T., Werle, E., Volkmann, M., Essig, M., Amann, M., Zanabili, N., Bardenheuer, H. J., Hunt, A., et al. (2003) · Psychiatry Research · doi:10.1016/s0165-1781(03)00197-5 · Cited by 55 · see citing works
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Longitudinal imaging in dementia
Scahill, R. I., & Fox, N. C. (2007) · British Journal of Radiology · doi:10.1259/bjr/78981552 · Cited by 24 · cited 1× · see citing works
“Whole-brain atrophy, the presumed consequence of years of axonal and neuronal degeneration, is a fundamental but not specific feature of AD and has been quantified antemortem by magnetic resonance imaging (MRI) in both cross-sectional and longitudinal studies.(6,7) The best studied fluid analytes in AD have been cereb…”
BackgroundPrice (1999) · doi:10.1002/1531-8249(199903)45:3
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McKhann, G. M., Knopman, D. S., Chertkow, H., Hyman, B. T., Jack, C. R., Kawas, C. H., Klunk, W. E., Koroshetz, W. J., Manly, J. J., Mayeux, R., et al. (2011) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2011.03.005 · Cited by 18,657 · see citing works
“A sequence of events has been described with Aβ pathophysiological processes becoming abnormal first and downstream neuronal injury biomarkers becoming abnormal later [6,7], This might imply a hierarchical ranking of Aβ biomarkers over downstream neuronal injury McKhann et al.”
BackgroundSelf-citationHypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade
Jack, C. R., Knopman, D. S., Jagust, W. J., Shaw, L. M., Aisen, P. S., Weiner, M. W., Petersen, R. C., & Trojanowski, J. Q. (2010) · The Lancet Neurology · doi:10.1016/s1474-4422(09)70299-6 · Cited by 4,806 · see citing works
Jack, C. R., Knopman, D. S., Jagust, W. J., Petersen, R. C., Weiner, M. W., Aisen, P. S., Shaw, L. M., Vemuri, P., Wiste, H. J., Weigand, S. D., et al. (2013) · The Lancet Neurology · doi:10.1016/s1474-4422(12)70291-0 · Cited by 4,396 · see citing works
Alzheimer’s Disease Neuroimaging Initiative
Mueller, S. G., Weiner, M. W., Thal, L. J., Petersen, R. C., Jack, C. R., Jagust, W. J., Trojanowski, J. Q., Toga, A. W., & Beckett, L. A. (2007) · Springer eBooks · doi:10.1007/978-0-387-72076-0_18 · Cited by 1,493 · see citing works
Human ApoE isoforms differentially regulate brain amyloid-β peptide clearance
Castellano, J. M., Kim, J., Stewart, F. R., Jiang, H., DeMattos, R. B., Patterson, B. W., Fagan, A. M., Morris, J. C., Mawuenyega, K. G., Cruchaga, C., et al. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3002156 · Cited by 1,227 · see citing works
“Given that a CSF Ab42 concentration lower than 500 pg/ml has been used as a reliable threshold for the presence of cerebral Ab deposition in humans (7, 19, 22, 26), we determined the proTable 1.”
Self-citationCSF Biomarkers and Incipient Alzheimer Disease in Patients With Mild Cognitive Impairment
Mattsson, N. (2009) · JAMA · doi:10.1001/jama.2009.1064 · Cited by 1,176 · see citing works
Biomarker Modeling of Alzheimer’s Disease
Jack, C. R., & Holtzman, D. M. (2013) · Neuron · doi:10.1016/j.neuron.2013.12.003 · Cited by 1,002 · see citing works
Self-citation<i>APOE</i> predicts amyloid‐beta but not tau Alzheimer pathology in cognitively normal aging
Morris, J. C., Roe, C. M., Xiong, C., Fagan, A. M., Goate, A. M., Holtzman, D. M., & Mintun, M. A. (2010) · Annals of Neurology · doi:10.1002/ana.21843 · Cited by 830 · see citing works
“Data from many of the 241 participants have appeared in previous reports from our ADRC.(20,61,67)”
ResultInfluentialSelf-citationMultimodal techniques for diagnosis and prognosis of Alzheimer's disease
Perrin, R. J., Fagan, A. M., & Holtzman, D. M. (2009) · Nature · doi:10.1038/nature08538 · Cited by 702 · see citing works
Self-citationJack, C. R., Knopman, D. S., Weigand, S. D., Wiste, H. J., Vemuri, P., Lowe, V., Kantarci, K., Gunter, J. L., Senjem, M. L., Ivnik, R. J., et al. (2012) · Annals of Neurology · doi:10.1002/ana.22628 · Cited by 602 · see citing works
“[%] 94 [49] 35 [50] 19 [34] 6 [46] 41 [40] 10 [67]”
Johnson, K. A., Minoshima, S., Bohnen, N. I., Donohoe, K. J., Foster, N. L., Herscovitch, P., Karlawish, J. H., Rowe, C. C., Carrillo, M. C., Hartley, D. M., et al. (2013) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2013.01.002 · Cited by 603 · see citing works
Functional Alterations in Memory Networks in Early Alzheimer’s Disease
Sperling, R. A., Dickerson, B. C., Pihlajamaki, M. M., Vannini, P., LaViolette, P. S., Vitolo, O. V., Hedden, T., Becker, J. A., Rentz, D. M., Selkoe, D. J., et al. (2010) · NeuroMolecular Medicine · doi:10.1007/s12017-009-8109-7 · Cited by 587 · see citing works
“…studies have provided support for the hypothesis that amyloid is an early upstream pathological event, which is related to subsequent neurodegeneration and atrophy in the MTL and surrounding cortices at later stages of prodromal AD (Mormino et al. 2008; Fagan et al. 2009; Jack et al. 2009).”
BackgroundPrediction of MCI to AD conversion, via MRI, CSF biomarkers, and pattern classification
Davatzikos, C. A., Bhatt, P., Shaw, L. M. J., Batmanghelich, K. N., & Trojanowski, J. Q. (2010) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2010.05.023 · Cited by 577 · see citing works
“…recent studies have suggested that early changes of the SPARE-AD scores and other morphological measurements, as well as CSF biomarkers, in cognitively normal elderly are good predictors of future progression to MCI (Davatzikos et al., 2008a, 2008b, 2009; Driscoll et al., 2009; Fagan et al., 2009).”
Brier, M. R., Thomas, J. B., Snyder, A. Z., Benzinger, T. L., Zhang, D., Raichle, M. E., Holtzman, D. M., Morris, J. C., & Ances, B. M. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.5698-11.2012 · Cited by 595 · see citing works
Self-citationVerghese, P. B., Castellano, J. M., Garai, K., Wang, Y., Jiang, H., Shah, A., Bu, G., Frieden, C., & Holtzman, D. M. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1220484110 · Cited by 556 · see citing works
“S1), a ratio similar to the Aβ40:42 ratio found in human CSF in normal subjects and in patients with late-onset AD (37, 38).”
BackgroundResultInfluentialSelf-citationMorris, J. C., Roe, C. M., Grant, E. A., Head, D., Storandt, M., Goate, A. M., Fagan, A. M., Holtzman, D. M., & Mintun, M. A. (2009) · Archives of Neurology · doi:10.1001/archneurol.2009.269 · Cited by 476 · see citing works
“Data from many of the 159 participants have appeared in other reports from our Alzheimer’s Disease Research Center.”
ResultSelf-citationJack, C. R., Wiste, H. J., Vemuri, P., Weigand, S. D., Senjem, M. L., Zeng, G., Bernstein, M. A., Gunter, J. L., Pankratz, V. S., Aisen, P. S., et al. (2010) · Brain · doi:10.1093/brain/awq277 · Cited by 531 · see citing works
Blood-Based Protein Biomarkers for Diagnosis of Alzheimer Disease
Doecke, J. D. (2012) · Archives of Neurology · doi:10.1001/archneurol.2012.1282 · Cited by 420 · see citing works
Brain β-amyloid load approaches a plateau
Jack, C. R., Wiste, H. J., Lesnick, T. G., Weigand, S. D., Knopman, D. S., Vemuri, P., Pankratz, V. S., Senjem, M. L., Gunter, J. L., Mielke, M. M., et al. (2013) · Neurology · doi:10.1212/wnl.0b013e3182840bbe · Cited by 406 · see citing works
La Joie, R., Perrotin, A., Barré, L., Hommet, C., Mézenge, F., Ibazizene, M., Camus, V., Abbas, A., Landeau, B., Guilloteau, D., et al. (2012) · The Journal of Neuroscience · doi:10.1523/jneurosci.2170-12.2012 · Cited by 374 · see citing works
Relationship between atrophy and β‐amyloid deposition in Alzheimer disease
Chételat, G., Villemagne, V. L., Bourgeat, P., Pike, K. E., Jones, G., Ames, D., Ellis, K. A., Szoeke, C., Martins, R. N., O'Keefe, G. J., et al. (2010) · Annals of Neurology · doi:10.1002/ana.21955 · Cited by 373 · see citing works
“Our findings are similar to a recent study reporting correlation between cerebrospinal fluid A 42 and whole-brain atrophy in nondemented control subjects but not in AD (where atrophy was related to levels of cerebrospinal fluid tau).(25) Second, atrophy in SCI is related to local -amyloid deposition in areas of highes…”
ResultPreventing Alzheimer’s Disease
Selkoe, D. J. (2012) · Science · doi:10.1126/science.1228541 · Cited by 378 · see citing works
Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease
Gouras, G. K., Tampellini, D., Takahashi, R. H., & Capetillo-Zarate, E. (2010) · Acta Neuropathologica · doi:10.1007/s00401-010-0679-9 · Cited by 372 · see citing works
Fagan, A. M., Mintun, M. A., Shah, A. R., Aldea, P., Roe, C. M., Mach, R. H., Marcus, D., Morris, J. C., & Holtzman, D. M. (2009) · EMBO Molecular Medicine · doi:10.1002/emmm.200900048 · Cited by 353 · see citing works
“Therefore, the mean age of our cohort is younger (64.7 10.4) than what we have reported on previously (71.41 8.62; Fagan et al, 2009).”
BackgroundMethodResultInfluentialSelf-citationThe Dynamics of Cortical and Hippocampal Atrophy in Alzheimer Disease
Sabuncu, M. R. (2011) · Archives of Neurology · doi:10.1001/archneurol.2011.167 · Cited by 360 · see citing works
Can Alzheimer disease be prevented by amyloid-β immunotherapy?
Lemere, C. A., & Masliah, E. (2010) · Nature Reviews Neurology · doi:10.1038/nrneurol.2009.219 · Cited by 351 · see citing works
Exercise and Alzheimer’s disease biomarkers in cognitively normal older adults
Liang, K. Y., Mintun, M. A., Fagan, A. M., Goate, A. M., Bugg, J. M., Holtzman, D. M., Morris, J. C., & Head, D. (2010) · Annals of Neurology · doi:10.1002/ana.22096 · Cited by 340 · see citing works
Self-citationJohnson, K. A., Minoshima, S., Bohnen, N. I., Donohoe, K. J., Foster, N. L., Herscovitch, P., Karlawish, J. H., Rowe, C. C., Carrillo, M. C., Hartley, D. M., et al. (2013) · Journal of Nuclear Medicine · doi:10.2967/jnumed.113.120618 · Cited by 329 · see citing works
Antisense Reduction of Tau in Adult Mice Protects against Seizures
DeVos, S. L., Goncharoff, D. K., Chen, G., Kebodeaux, C. S., Yamada, K., Stewart, F. R., Schuler, D. R., Maloney, S. E., Wozniak, D. F., Rigo, F., et al. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.2107-13.2013 · Cited by 311 · see citing works
Self-citationStorandt, M., Mintun, M. A., Head, D. M., & Morris, J. C. (2009) · Archives of Neurology · doi:10.1001/archneurol.2009.272 · Cited by 304 · see citing works
Self-citationQualification of the analytical and clinical performance of CSF biomarker analyses in ADNI
Initiative, T. A. D. N., Shaw, L. M. J., Vanderstichele, H., Knapik-Czajka, M. E., Figurski, M., Coart, E., Blennow, K., Soares, H. D., Simon, A. J., Lewczuk, P., et al. (2011) · Acta Neuropathologica · doi:10.1007/s00401-011-0808-0 · Cited by 297 · see citing works
“Measurement of the CSF concentrations of Ab1–42, t-tau and p-tau181 [using xMAP (multi-analyte) or ELISA (single analyte)-based methods] has been shown to provide at least 85% sensitivity and 80% specificity for diagnosing AD, predicting conversion from MCI to a diagnosis of probable AD, and identifying elderly clinic…”
MethodHead (2012) · doi:10.1001/archneurol.2011.845 · Cited by 267 · see citing works
Role of structural MRI in Alzheimer's disease
Vemuri, P., & Jack, C. R. (2010) · Alzheimer s Research & Therapy · doi:10.1186/alzrt47 · Cited by 246 · see citing works
“While some studies claim that there is an association between CSF biomarkers (specifi cally t-tau and p-tau) and sMRI [42,46,48-54], others have found no association between the two [45,55-57].”
BackgroundMRI cortical thickness biomarker predicts AD-like CSF and cognitive decline in normal adults
Dickerson, B. C., & Wolk, D. A. (2011) · Neurology · doi:10.1212/wnl.0b013e31823efc6c · Cited by 243 · see citing works
McKhann, G. M., Knopman, D. S., Chertkow, H. M., Hyman, B. T., Kawas, C. H., Klunk, W. E., Koroshetz, W. J., Manly, J. J., Mohs, R. C., Morris, J. C., et al. (2011) · Alzheimer s & Dementia · Cited by 240 · see citing works
Self-citation(ADNI), A. D. N. I., Deming, Y., The Alzheimer Disease Genetic Consortium (ADGC), Li, Z., Kapoor, M., Harari, O., Del-Aguila, J. L., Black, K., Carrell, D., Cai, Y., et al. (2017) · Acta Neuropathologica · doi:10.1007/s00401-017-1685-y · Cited by 231 · see citing works
“Low Aβ42 levels (ADRC < 500 pg/mL and ADNI < 192 pg/ mL) have been associated with amyloid positron emission tomography (PET-PIB) evidence of Aβ deposition [25, 69].”
BackgroundResultInfluentialSelf-citationAmyloid imaging and CSF biomarkers in predicting cognitive impairment up to 7.5 years later
Roe, C. M., Fagan, A. M., Grant, E. A., Hassenstab, J., Moulder, K. L., Maue Dreyfus, D., Sutphen, C. L., Benzinger, T. L. S., Mintun, M. A., Holtzman, D. M., et al. (2013) · Neurology · doi:10.1212/wnl.0b013e3182918ca6 · Cited by 222 · see citing works
Self-citationEvidence for Ordering of Alzheimer Disease Biomarkers
Jack, C. R. (2011) · Archives of Neurology · doi:10.1001/archneurol.2011.183 · Cited by 221 · see citing works
“80 81-86 Our results concerning evidence for biomarker ordering led to similar conclusions in the “all-participants” sample and in thesampleofparticipantswithanabnormalCSFA (cid:2) 42level.”
Cerebrospinal fluid APOE levels: an endophenotype for genetic studies for Alzheimer's disease
Cruchaga, C., Kauwe, J. S. K., Nowotny, P., Bales, K., Pickering, E. H., Mayo, K., Bertelsen, S., Hinrichs, A., Fagan, A. M., Holtzman, D. M., et al. (2012) · Human Molecular Genetics · doi:10.1093/hmg/dds296 · Cited by 207 · see citing works
Self-citationHong, S., Ostaszewski, B. L., Yang, T., O’Malley, T. T., Jin, M., Yanagisawa, K., Li, S., Bartels, T., & Selkoe, D. J. (2014) · Neuron · doi:10.1016/j.neuron.2014.02.027 · Cited by 213 · see citing works
“In light of numerous such studies implicating a pathogenic role of soluble Ab oligomers and the evidence that lowered Ab42 monomer levels in cerebrospinal fluid (CSF) represents the earliest biomarker for AD (Bateman et al., 2012; Craig-Schapiro et al., 2009; Fagan et al., 2009; Golde et al., 2011; Morris and Selkoe,…”
Fluid Biomarkers in Alzheimer Disease
Blennow, K., Zetterberg, H., & Fagan, A. M. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006221 · Cited by 208 · see citing works
“Further, although no study has examined the added diagnostic value of PIB-PET and CSF biomarkers, there is a strict negative correlation between the degree of PIB binding as seen in PET images and the CSF level of Ab42 (Fagan et al. 2006, 2009b; Forsberg et al. 2008; Grimmer et al. 2009).”
BackgroundResultInfluentialSelf-citationCairns, N. J., Ikonomović, M. D., Benzinger, T. L. S., Storandt, M., Fagan, A. M., Shah, A. R., Taylor‐Reinwald, L., Carter, D. R., Felton, A., Holtzman, D. M., et al. (2009) · Archives of Neurology · doi:10.1001/archneurol.2009.279 · Cited by 203 · see citing works
Self-citationAgreement of amyloid PET and CSF biomarkers for Alzheimer's disease on Lumipulse
Alcolea, D., Pegueroles, J., Muñoz, L., Camacho, V., López‐Mora, D., Fernández‐León, A., Le Bastard, N., Huyck, E., Nadal, A., Olmedo, V., et al. (2019) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.50873 · Cited by 183 · see citing works
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Longitudinal Change of Biomarkers in Cognitive Decline
Lo, R. Y. (2011) · Archives of Neurology · doi:10.1001/archneurol.2011.123 · Cited by 190 · see citing works
CSF biomarkers of Alzheimer disease in HIV-associated neurologic disease
Clifford, D. B., Fagan, A. M., Holtzman, D. M., Morris, J. C., Teshome, M., Shah, A. R., & Kauwe, J. S. K. (2009) · Neurology · doi:10.1212/wnl.0b013e3181c5b445 · Cited by 186 · see citing works
Self-citationPET amyloid-beta imaging in preclinical Alzheimer's disease
Vlassenko, A. G., Benzinger, T. L. S., & Morris, J. C. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2011.11.005 · Cited by 173 · see citing works
Self-citationPerrin, R. J., Craig‐Schapiro, R., Malone, J. P., Shah, A. R., Erdmann-Gilmore, P., Davis, A., Roe, C. M., Peskind, E. R., Li, G., Galasko, D. R., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0016032 · Cited by 172 · see citing works
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Detection and treatment of Alzheimer’s disease in its preclinical stage
Rafii, M. S., & Aisen, P. S. S. (2023) · Nature Aging · doi:10.1038/s43587-023-00410-4 · Cited by 173 · see citing works
Visinin‐like protein‐1: Diagnostic and prognostic biomarker in Alzheimer disease
Tarawneh, R. M., D’Angelo, G., Macy, E., Xiong, C., Carter, D. R., Cairns, N. J., Fagan, A. M., Head, D. M., Mintun, M. A., Ladenson, J. H., et al. (2011) · Annals of Neurology · doi:10.1002/ana.22448 · Cited by 167 · see citing works
“Blood samples (10–15ml) were obtained from a subset of participants (CNC, n 1⁄4 149 and AD, n 1⁄4 64) and processed to obtain plasma as described.(29)”
MethodSelf-citationIndicators of amyloid burden in a population-based study of cognitively normal elderly
Mielke, M. M., Wiste, H. J., Weigand, S. D., Knopman, D. S., Lowe, V. J., Roberts, R. O., Geda, Y. E., Swenson-Dravis, D. M., Boeve, B. F., Senjem, M. L., et al. (2012) · Neurology · doi:10.1212/wnl.0b013e31826e2696 · Cited by 163 · see citing works
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“T111, T205, S208 and T217 were more hyperphosphorylated than T181, which is the most commonly measured target used as a p-tau biomarker for AD (Fagan et al., 2009).”
BackgroundIncreased brain atrophy rates in cognitively normal older adults with low cerebrospinal fluid Aβ1‐42
Schott, J. M., Bartlett, J. W., Fox, N. C., Barnes, J., & Initiative, A. D. N. (2010) · Annals of Neurology · doi:10.1002/ana.22315 · Cited by 145 · see citing works
Ushering in the study and treatment of preclinical Alzheimer disease
Langbaum, J. B. S., Fleisher, A., Chen, K., Ayutyanont, N., Lopera, F. J., Quiroz, Y. T., Caselli, R. J., Tariot, P. N., & Reiman, E. M. (2013) · Nature Reviews Neurology · doi:10.1038/nrneurol.2013.107 · Cited by 145 · see citing works
Shapes of the Trajectories of 5 Major Biomarkers of Alzheimer Disease
Jack, C. R., Vemuri, P., Wiste, H. J., Weigand, S. D., Lesnick, T. G., Lowe, V., Kantarci, K., Bernstein, M. A., Senjem, M. L., Gunter, J. L., et al. (2012) · Archives of Neurology · doi:10.1001/archneurol.2011.3405 · Cited by 145 · see citing works
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Novel plasma biomarker surrogating cerebral amyloid deposition
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3D PIB and CSF biomarker associations with hippocampal atrophy in ADNI subjects
Apostolova, L. G., Hwang, K., Andrawis, J. P., Green, A. E., Babakchanian, S., Morra, J. H., Cummings, J. L., Toga, A. W., Trojanowski, J. Q., Shaw, L. M. J., et al. (2010) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2010.05.003 · Cited by 137 · see citing works
Canine Cognitive Dysfunction and Alzheimer’s Disease – Two Facets of the Same Disease?
Mihevc, S. P., & Majdič, G. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00604 · Cited by 138 · see citing works
Plasma Amyloid-β as a Biomarker in Alzheimer's Disease: The AIBL Study of Aging
Lui, J., Laws, S., Li, Q.-X., Villemagne, V., Ames, D., Brown, B., Bush, A., Ruyck, K. D., Dromey, J., Ellis, K., et al. (2010) · Journal of Alzheimer's Disease · doi:10.3233/jad-2010-090249 · Cited by 141 · see citing works
“A decline in A β levels in the cerebrospinal fluid (CSF) has been reported to help distinguish between patients with AD and normal elderly individuals [4–8].”
When Does Alzheimer′s Disease Really Start? The Role of Biomarkers
Lloret, A., Esteve, D., Lloret, M.-A., Cervera-Ferri, A., Lopez, B., Nepomuceno, M., & Monllor, P. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20225536 · Cited by 131 · see citing works
“Therefore, PiB-PET is only recommended when other clinical evidences of dementia are present [19,26], even though it is considered a valid marker to help in the diagnosis [51].”
BackgroundLeuzy, A., Chiotis, K., Hasselbalch, S. G., Rinne, J. O., de Mendonça, A., Otto, M., Lleó, A., Castelo-Branco, M. S., Santana, I. J., Johansson, J. J., et al. (2016) · Brain · doi:10.1093/brain/aww160 · Cited by 132 · see citing works
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“This is likely to be true for Alzheimer’s Disease (AD) because up to 30% of individuals in screened elderly non-demented control samples show evidence of AD pathology at autopsy [12], and a similar number have biomarker profiles consistent with preclinical AD [13–15], thus reducing the power of a case-control design.”
BackgroundSelf-citationYang, T., Hong, S. Y., O’Malley, T. T., Sperling, R. A., Walsh, D. M., & Selkoe, D. J. (2013) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2012.11.005 · Cited by 121 · see citing works
Exercise Intervention Associated with Cognitive Improvement in Alzheimer’s Disease
Cui, M. Y., Lin, Y., Sheng, J. Y., Zhang, X., & Cui, R. (2018) · Neural Plasticity · doi:10.1155/2018/9234105 · Cited by 128 · see citing works
“This may be due to the participant of the research whom was in the early stage of cognitive decline while ptau is largely formed in the later course of AD [103].”
BackgroundCSF tau markers are correlated with hippocampal volume in Alzheimer's disease
de Souza, L. C., Marie Chupin, A., Lamari, F., Jardel, C., Leclercq, D., Olivier Colliot, A., Lehéricy, S., Dubois, B., & Sarazin, M. (2011) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2011.02.022 · Cited by 125 · see citing works
Biomarkers in Alzheimer's disease drug development
Cummings, J. L. (2011) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2010.06.004 · Cited by 121 · see citing works
Prevalence of preclinical Alzheimer disease
Kern, S., Zetterberg, H., Kern, J., Zettergren, A., Wærn, M., Höglund, K., Andréasson, U., Wetterberg, H., Börjesson‐Hanson, A., Blennow, K., et al. (2018) · Neurology · doi:10.1212/wnl.0000000000005476 · Cited by 120 · see citing works
Alzheimer's Disease Mechanisms and Emerging Roads to Novel Therapeutics
Sala Frigerio, C., & De Strooper, B. (2016) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-070815-014015 · Cited by 116 · see citing works
“For example, it is well known that elderly nondemented controls may show evidence of biochemical AD pathology postmortem (Price et al. 2009) or CSF alterations of Aβ before AD symptoms become manifest (Fagan et al. 2009).”
Serial MRI and CSF biomarkers in normal aging, MCI, and AD
Vemuri, P., Wiste, H. J., Weigand, S. D., Knopman, D. S., Trojanowski, J. Q., Shaw, L. M., Bernstein, M. A., Aisen, P. S., Weiner, M., Petersen, R. C., et al. (2010) · Neurology · doi:10.1212/wnl.0b013e3181e7ca82 · Cited by 154 · see citing works
Mormino, E. C., & Papp, K. V. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-179928 · Cited by 117 · see citing works
“This observation has consistently been observed in postmortem studies [6, 16], CSF studies [17, 18], and Amyloid PET imaging studies [19].”
Brain Ventricular Volume and Cerebrospinal Fluid Biomarkers of Alzheimer's Disease
Ott, B. R., Initiative, T. A. D. N., Cohen, R. A., Gongvatana, A., Okonkwo, O. C., Johanson, C. E., Stopa, E. G., Donahue, J. E., & Silverberg, G. D. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-1406 · Cited by 113 · see citing works
Hong, S., Quintero-Monzon, O., Ostaszewski, B. L., Podlisny, D. R., Cavanaugh, W. T., Yang, T., Holtzman, D. M., Cirrito, J. R., & Selkoe, D. J. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.3272-11.2011 · Cited by 111 · see citing works
Self-citationMelah, K. E., Lu, S. Y.-F., Hoscheidt, S. M., Alexander, A. L., Adluru, N., Destiche, D. J., Carlsson, C. M., Zetterberg, H., Blennow, K., Okonkwo, O. C., et al. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-150897 · Cited by 109 · see citing works
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Is amyloid-β harmful to the brain? Insights from human imaging studies
Jagust, W. (2016) · Brain · doi:10.1093/brain/awv326 · Cited by 110 · see citing works
“CSF measures of amyloid-b1–42 have also been associated with whole brain atrophy (Fagan et al., 2009).”
BackgroundLongitudinal brain structural changes in preclinical Alzheimer's disease
Pegueroles, J., Vilaplana, E., Montal, V., Sampedro, F., Alcolea, D. A., Carmona‐Iragui, M., Clarimón, J., Blesa, R., Lleó, A., Fortea, J., et al. (2016) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2016.08.010 · Cited by 109 · see citing works
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Fluid and PET biomarkers for amyloid pathology in Alzheimer's disease
Cohen, A. D., Landau, S. M., Snitz, B. E., Klunk, W. E., Blennow, K., & Zetterberg, H. (2018) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2018.12.004 · Cited by 107 · see citing works
“Cerebrospinal fluid beta-amyloid(1-42) in Alzheimer disease: differences between early- and late-onset Alzheimer disease and stability during the course of disease.”
BackgroundMethodCho, H., Hashimoto, T., Wong, E. A., Hori, Y., Wood, L. B., Zhao, L., Haigis, K. M., Hyman, B. T., & Irimia, D. (2013) · Scientific Reports · doi:10.1038/srep01823 · Cited by 104 · see citing works
Brain Atrophy in Healthy Aging Is Related to CSF Levels of Aβ1-42
Fjell, A. M., Walhovd, K. B., Fennema‐Notestine, C., McEvoy, L. K., Hagler, D. J., Holland, D., Blennow, K., Brewer, J. B., Dale, A. M., & Initiative, T. A. D. N. (2010) · Cerebral Cortex · doi:10.1093/cercor/bhp279 · Cited by 105 · see citing works
“Theone large study of the relationship between the CSF biomarkers and brain volume found a relationship between low levels of A b 1-42 and smaller whole-brain volumes (Fagan et al. 2009).”
The Beta Amyloid Dysfunction (BAD) Hypothesis for Alzheimer’s Disease
Hillen, H. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.01154 · Cited by 106 · see citing works
“Early biochemical deviations from Aβ physiology in MCI are indicated by lowered CSF Aβ42 monomer already before substantial loss of neurons occurs in later stages of AD (Fagan et al., 2009).”
BackgroundSilva, A. R. T., Santos, A. C. F., Farfel, J. M., Grinberg, L. T., Ferretti, R. E. L., Campos, A. H. J. F. M., Cunha, I. W., Begnami, M. D., Rocha, R. M., Carraro, D. M., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0099897 · Cited by 99 · see citing works
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“…few MRI studies so far have reported correlations between CSF biomarkers and the pattern of brain atrophy or the rate of atrophy progression (Fagan et al., 2009; Fjell et al., 2010a, 2010b; Hampel et al., 2005; Hen-neman et al., 2009; Herukka et al., 2008; Leow et al., 2009; Schuff et al.,…”
Elevated cerebrospinal fluid sphingomyelin levels in prodromal Alzheimer's disease
Košiček, M., Zetterberg, H., Andreasen, N., Peter‐Katalinić, J., & Hecimovic, S. K. (2012) · Neuroscience Letters · doi:10.1016/j.neulet.2012.04.019 · Cited by 102 · see citing works
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“stage, before PET imaging becomes abnormal [32],”
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Alzheimer’s Disease Biomarkers and Future Decline in Cognitive Normal Older Adults
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Cerebrospinal Fluid Biomarkers of Alzheimer's Disease
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Self-citation11C-PiB Imaging of Human Immunodeficiency Virus–Associated Neurocognitive Disorder
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- Authors
- Fagan, A. M., Head, D., Shah, A. R., Marcus, D., Mintun, M., Morris, J. C., & Holtzman, D. M.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- Fagan, Anne M.
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2009-02
- Volume
- 65
- Issue
- 2
- Pages
- 176-183
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- PMC
- PMC2763631
- OpenAlex
- W2088129757
- Semantic Scholar
- 38dd6ce07732345d02e7f299e98dc24aad1252f6
- Cited by
- 327
- References
- 53
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 5 · 2023: 9 · 2022: 8 · 2021: 17 · 2020: 9 · 2019: 13 · 2018: 15 · 2017: 15 · 2016: 15 · 2015: 21 · 2014: 24 · 2013: 30 · 2012: 38
- FWCI
- 27.33
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (UL1TR000448)
- National Institute on Aging (P 50 AG05681, P50AG005681, P01 AG0 3991, P01AG003991, U19AG032438, P01AG026276)
- National Institute of Neurological Disorders and Stroke (P30NS057105, P30NS048056)
- National Center for Research Resources (UL1RR024992)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Cerebrospinal fluid and hydrocephalus
- Keywords
- Alzheimer's disease, cerebrospinal fluid biomarkers, amyloid-beta 42, Aβ40, tau protein, phosphorylated tau 181, brain atrophy, total brain volume, preclinical Alzheimer's disease, mild cognitive impairment, Alzheimer-type dementia, plasma amyloid-beta, CSF tau
- MeSH terms
- Aged, Aged, 80 and over, Aging, Alzheimer Disease, Aniline Compounds, Female, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Middle Aged, Neuropsychological Tests, Peptide Fragments, Thiazoles, Geriatric Assessment, Chi-Square Distribution, Amyloid beta-Peptides, Pick Disease of the Brain, Positron-Emission Tomography
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 2026-10-10.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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