Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer’s disease
Open accessAbstract
Neurofilament light chain (NfL) is a promising fluid biomarker of disease progression for various cerebral proteopathies. Here we leverage the unique characteristics of the Dominantly Inherited Alzheimer Network and ultrasensitive immunoassay technology to demonstrate that NfL levels in the cerebrospinal fluid (n = 187) and serum (n = 405) are correlated with one another and are elevated at the presymptomatic stages of familial Alzheimer's disease. Longitudinal, within-person analysis of serum NfL dynamics (n = 196) confirmed this elevation and further revealed that the rate of change of serum NfL could discriminate mutation carriers from non-mutation carriers almost a decade earlier than cross-sectional absolute NfL levels (that is, 16.2 versus 6.8 years before the estimated symptom onset). Serum NfL rate of change peaked in participants converting from the presymptomatic to the symptomatic stage and was associated with cortical thinning assessed by magnetic resonance imaging, but less so with amyloid-β deposition or glucose metabolism (assessed by positron emission tomography). Serum NfL was predictive for both the rate of cortical thinning and cognitive changes assessed by the Mini-Mental State Examination and Logical Memory test. Thus, NfL dynamics in serum predict disease progression and brain neurodegeneration at the early presymptomatic stages of familial Alzheimer's disease, which supports its potential utility as a clinically useful biomarker.
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- Findingown data
In the DIAN cohort, cerebrospinal fluid NfL and serum NfL concentrations are correlated with each other.
“NfL levels in the cerebrospinal fluid (n = 187) and serum (n = 405) are correlated with one another”
- Also stated in: § Abstract · boosted
“CSF and serum NfL levels were tightly associated”
Quote in the paperSubstantial claim - Also stated in: § Abstract · boosted
- Findingown data
In DIAN participants, serum NfL is significantly higher in mutation carriers than in non-carriers at about 6.8 years before estimated symptom onset.
“serum NfL was also increased at −6.8 EYO”
Quote in the paperSubstantial claim - Findingown data
In a prospective analysis of 39 mutation carriers, serum NfL rate of change predicts further cortical thinning and changes in MMSE and Logical Memory.
“significant (predictive) associations were found between serum NfL rate of change and cortical thinning as well as MMSE and Logical Memory test”
Quote in the paperSubstantial claim - Findingown data
Baseline serum NfL predicts decreases in MMSE and Logical Memory scores.
“was also predicative for a decrease in MMSE and Logical Memory scores”
Quote in the paperSubstantial claim - Findingown data
Baseline serum NfL predicts future annualized cortical thinning in both presymptomatic and symptomatic mutation carriers.
“baseline NfL was highly predictive of future annualized cortical thinning, for both presymptomatic and symptomatic mutation carriers, at subsequent visits”
Quote in the paperSubstantial claim
- Findingown data
In DIAN participants, CSF and serum NfL levels do not differ among the three familial Alzheimer's disease mutations (APP, PSEN1, PSEN2).
“No differences in CSF or serum NfL levels between the three familial Alzheimer’s disease mutations were found”
Quote in the paperNot a substantial claim - Findingown data
Serum NfL rate of change has a positive but non-significant association with precuneus amyloid-β deposition rate.
“Although there was a positive relationship between NfL rate of change and the rate of change in precuneus amyloid-β deposition (amyloid-β-PET), the association did not reach significance”
Quote in the paperNot a substantial claim - Findingown data
Serum NfL rate of change does not differ among APP, PSEN1, and PSEN2 mutation carriers.
“No differences in NfL rate of change were found between mutations in APP, PSEN1, and PSEN2”
Quote in the paperNot a substantial claim - Findingown data
The earliest estimated years to symptom onset at which serum NfL rate of change significantly separates mutation carriers from non-carriers is −16.2 years.
“the first EYO point where this increase became significant was at − 16.2 years”
- Also stated in: § Abstract · plain
“the NfL annual rate of change can distinguish non-carriers and mutation carriers as early as 16 years before the estimated symptom onset”
Quote in the paperSubstantial claim - Also stated in: § Abstract · plain
- Findingown data
In longitudinal DIAN data, the rate of change of serum NfL is significantly higher in mutation carriers than in non-carriers.
“the NfL rates of change were significantly elevated in mutation carriers relative to non-carriers”
Quote in the paperSubstantial claim - Findingown data
Serum NfL rate of change distinguishes presymptomatic mutation carriers from non-carriers more accurately than baseline serum NfL in ROC analysis.
“the rate of change could distinguish presymptomatic mutation carriers from non-carriers more accurately compared to base-line serum NfL using receiver operating characteristics analysis”
Quote in the paperSubstantial claim - Findingown data
In DIAN participants, CSF NfL is significantly higher in mutation carriers than in non-carriers at about 6.8 years before estimated symptom onset.
“NfL in the CSF was significantly increased between mutation carriers and non-carriers at −6.8 EYO”
Quote in the paperSubstantial claim - Findingown data
Serum neurofilament light rate of change per year distinguishes presymptomatic and symptomatic mutation carriers from non-carriers better than a single cross-sectional serum neurofilament light measurement.
“Rate of change per year of serum NfL is a better parameter to distinguish presymptomatic and symptomatic mutation carriers from non-carriers compared to single cross-sectional serum NfL.”
Quote in the paperSubstantial claim - Findingown data
Serum neurofilament light rate of change differs between mutation carriers and non-carriers beginning 16.2 years before expected years of onset, based on 99% credible intervals of the posterior difference distribution that exclude zero.
“EYO was considered statistically significant if the 99% equal-tailed credible intervals of the posterior distribution did not overlap 0 (16.2 years before EYO).”
- Also stated in: § Extended Data · plain
“Difference of posterior distribution for serum NfL rate of change between mutation carriers and non-carriers, as a function of EYO (n = 196).”
Quote in the paperSubstantial claim - Also stated in: § Extended Data · plain
- Findingown data
No differences in the rate of change of log serum neurofilament light were found among APP, PSEN1, and PSEN2 mutation carriers.
“no differences in the rate of change of log(serum NfL) (year−1) levels among APP (n = 24), PSEN1 (n = 104), and PSEN2 (n = 5) mutation carriers (F(2, 130) = 0.4678, P = 0.6274) was found.”
- Also stated in: § Extended Data · plain
“Similarly, no differences were found when age and disease status (presymptomatic, symptomatic) were treated as covariates in a two-tailed pairwise Student’s t-test.”
Quote in the paperNot a substantial claim - Also stated in: § Extended Data · plain
- Findingown data
In mutation carriers, baseline serum neurofilament light levels differ from those in non-carriers beginning 6.8 years before expected years of onset, as indicated by 99% credible intervals of the posterior difference distribution that exclude zero.
“EYO was considered statistically significant if the 99% equal-tailed credible intervals of the posterior distribution did not overlap 0 (6.8 years before EYO for both baseline CSF and serum NfL).”
Quote in the paperSubstantial claim - Findingown data
In mutation carriers, baseline CSF neurofilament light levels differ from those in non-carriers beginning 6.8 years before expected years of onset, as indicated by 99% credible intervals of the posterior difference distribution that exclude zero.
“EYO was considered statistically significant if the 99% equal-tailed credible intervals of the posterior distribution did not overlap 0 (6.8 years before EYO for both baseline CSF and serum NfL).”
Quote in the paperSubstantial claim - Findingown data
No differences in baseline log serum neurofilament light were found among APP, PSEN1, and PSEN2 mutation carriers.
“No differences in log(CSF NfL) or log(serum NfL) were found between the groups (F(2, 104)= 1.8108, P = 0.1686 and F(2, 240)= 1.9205, P = 0.1488, respectively).”
- Also stated in: § Extended Data · plain
“Similarly, no differences were found by two-tailed pairwise Student’s t-test when age and disease status (presymptomatic, symptomatic) were treated as covariates.”
Quote in the paperNot a substantial claim - Also stated in: § Extended Data · plain
- Findingown data
An individual's deviation from the expected years of onset-adjusted median rate of change in neurofilament light is not associated with their expected age of symptom onset.
“No difference between an individual’s deviation from the EYO-adjusted median rate of change in NfL and their expected age of symptom onset using LMEMs.”
- Also stated in: § Extended Data · plain
“group comparisons, P > 0.146.”
Quote in the paperNot a substantial claim - Also stated in: § Extended Data · plain
- Findingown data
No differences in baseline log CSF neurofilament light were found among APP, PSEN1, and PSEN2 mutation carriers.
“No differences in log(CSF NfL) or log(serum NfL) were found between the groups (F(2, 104)= 1.8108, P = 0.1686 and F(2, 240)= 1.9205, P = 0.1488, respectively).”
- Also stated in: § Extended Data · plain
“Similarly, no differences were found by two-tailed pairwise Student’s t-test when age and disease status (presymptomatic, symptomatic) were treated as covariates.”
Quote in the paperNot a substantial claim - Also stated in: § Extended Data · plain
- Interpretationown data
In familial Alzheimer's disease, changes in serum NfL over time forecast later neurodegeneration and clinical worsening during the presymptomatic period.
“Thus, NfL dynamics in serum predict disease progression and brain neurodegeneration at the early presymptomatic stages of familial Alzheimer’s disease”
Quote in the paperSubstantial claim - Interpretationown data
Serum NfL has potential utility as a clinically useful biomarker.
“which supports its potential utility as a clinically useful biomarker”
Quote in the paperSubstantial claim- Rests on an assumption: Collecting CSF requires an invasive procedure, and imaging is costly, so neither fits easily into routine care.
- Premisecitation
Data from DIAN and other large cohorts indicate that Alzheimer's pathology starts over twenty years before symptoms appear.
“Cross-sectional and longitudinal data analyses of DIAN and other large Alzheimer’s disease cohorts have demonstrated that the pathological processes in Alzheimer’s disease begin more than two decades before the onset of clinical symptoms.”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [1] Bateman, R. J. et al. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N. Engl. J. Med. 367, 795–804 (2012). source
Not checked in the free run.
- cites [2] Gordon, B. A. et al. Spatial patterns of neuroimaging biomarker change in individuals from families with autosomal dominant Alzheimer’s disease: a longitudinal study. Lancet Neurol. 17, 241–250 (2018). source
Not checked in the free run.
- cites [22] McDade, E. et al. Longitudinal cognitive and biomarker changes in dominantly inherited Alzheimer disease. Neurology 91, e1295–e1306 (2018). source
Not checked in the free run.
- cites [25] Burnham, S. C. et al. Clinical and cognitive trajectories in cognitively healthy elderly individuals with suspected non-Alzheimer’s disease pathophysiology (SNAP) or Alzheimer’s disease pathology: a longitudinal study. Lancet Neurol. 15, 1044–1053 (2016). source
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- Premisecitation
The DIAN cohort consists of people from families with highly penetrant autosomal-dominant mutations in APP, PSEN1, or PSEN2.
“DIAN participants are members of families carrying highly penetrant autosomal-dominant mutations in the genes encoding the amyloid beta precursor protein (APP) or presenilin 1 (PSEN1) or 2 (PSEN2)19.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [19] Moulder, K. L. et al. Dominantly Inherited Alzheimer Network: facilitating research and clinical trials. Alzheimers Res. Ther. 5, 48 (2013). source
Not checked in the free run.
- Premisecitation
Thinning in the precuneus has been observed about 16 years before symptoms begin.
“In fact, precuneus thinning was also detected around 16 years before symptom onset2”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [2] Gordon, B. A. et al. Spatial patterns of neuroimaging biomarker change in individuals from families with autosomal dominant Alzheimer’s disease: a longitudinal study. Lancet Neurol. 17, 241–250 (2018). source
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- Interpretationown data
During the presymptomatic phase, a faster rise in serum NfL means a person is nearer to developing symptoms.
“In presymptomatic Alzheimer’s disease, the greater the NfL rate of change, the closer an individual is to converting to symptomatic Alzheimer’s disease”
Quote in the paperSubstantial claim - Premisecitation
Earlier work found little or only marginal elevation of absolute blood NfL in people with presymptomatic or mild Alzheimer's disease.
“Consistently, previous studies reported only non-significant or barely significant increases in absolute NfL in the blood in presymptomatic or even mildly cognitive impaired Alzheimer’s disease patients6,9,13.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [6] Mattsson, N., Andreasson, U., Zetterberg, H. & Blennow, K. Association of plasma neurofilament light with neurodegeneration in patients with Alzheimer disease. JAMA Neurol. 74, 557–566 (2017). source
Not checked in the free run.
- cites [9] Weston, P. S. J. et al. Serum neurofilament light in familial Alzheimer disease: a marker of early neurodegeneration. Neurology 89, 2167–2175 (2017). source
Not checked in the free run.
- cites [13] Bacioglu, M. et al. Neurofilament light chain in blood and CSF as marker of disease progression in mouse models and in neurodegenerative diseases. Neuron 91, 56–66 (2016). source
Not checked in the free run.
- Premisecitation
Atrophy of individual cortical regions occurs earlier than overall brain atrophy.
“However, atrophy of individual cortical regions occurs earlier1,2,22,25.”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [1] Bateman, R. J. et al. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N. Engl. J. Med. 367, 795–804 (2012). source
Not checked in the free run.
- cites [2] Gordon, B. A. et al. Spatial patterns of neuroimaging biomarker change in individuals from families with autosomal dominant Alzheimer’s disease: a longitudinal study. Lancet Neurol. 17, 241–250 (2018). source
Not checked in the free run.
- cites [22] McDade, E. et al. Longitudinal cognitive and biomarker changes in dominantly inherited Alzheimer disease. Neurology 91, e1295–e1306 (2018). source
Not checked in the free run.
- cites [25] Burnham, S. C. et al. Clinical and cognitive trajectories in cognitively healthy elderly individuals with suspected non-Alzheimer’s disease pathophysiology (SNAP) or Alzheimer’s disease pathology: a longitudinal study. Lancet Neurol. 15, 1044–1053 (2016). source
Not checked in the free run.
- Study design and conductown data
The prospective prediction analysis was not adequately powered to show that NfL rate of change is a better predictor of disease progression than absolute NfL values.
“Although our prospective predication analysis was not adequately powered to demonstrate that NfL rate of change is indeed a better predictor of disease progression (neurodegeneration and cognitive decline) than absolute NfL values”
Quote in the paperSubstantial claim - Study design and conductown data
Because assessments were separated by 2-3 years, the study could not establish how the interval used to compute NfL change relates to its ability to predict clinical outcomes.
“The current study design with the 2–3 years interval between participant assessments did not allow us to determine the relationship between the time over which the NfL rate of change was calculated and its clinical predictability.”
Quote in the paperNot a substantial claim - Premisecitation
The assay likely detects a short, stable ~10 kD fragment from the core domain of NfL.
“The antigen detected with the (ultrasensitive) immunoassay used in this study is presumably a short and stable fragment (~10 kD) of the core domain of NfL15,29.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [15] Brureau, A. et al. NF-L in cerebrospinal fluid and serum is a biomarker of neuronal damage in an inducible mouse model of neurodegeneration. Neurobiol. Dis. 104, 73–84 (2017). source
Not checked in the free run.
- cites [29] Norgren, N., Karlsson, J. E., Rosengren, L. & Stigbrand, T. Monoclonal antibodies selective for low molecular weight neurofilaments. Hybrid. Hybridomics 21, 53–59 (2002). source
Not checked in the free run.
- May combine two claims. 22
- Classified as probably not a substantial claim. 18
May combine two claims.
Findingown dataSerum NfL rate of change is significantly associated with precuneus cortical thinning rate in symptomatic mutation carriers, with a trend in presymptomatic mutation carriers.
“NfL rates of change in serum and rates of precuneus cortical thinning were significantly associated in symptomatic mutation carriers with a trend toward significance in presymptomatic mutation carriers”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataSerum NfL rate of change is highest in mutation carriers converting from presymptomatic to symptomatic status and does not increase further in symptomatic carriers.
“the rate of change in serum NfL peaked in the converter group with no further increase in the symptomatic carriers”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataSerum NfL rate of change is significantly associated with precuneus glucose metabolism rate in symptomatic mutation carriers but not in presymptomatic mutation carriers.
“The rate of change in serum NfL and the rate of change in precuneus glucose metabolism (18F-fluorodeoxyglucose (18F-FDG) PET) were significantly associated in symptomatic mutation carriers but not in presymptomatic mutation carriers”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn a regression model with two slope breaks, the first bifurcation point in serum neurofilament light rate of change between mutation carriers and non-carriers was at −18.6 years before expected years of onset, and the second was at −5.8 years before expected years of onset.
“With this model the first bifurcation point was found at −18.6 years before EYO, the second at −5.8 years before EYO.”
- Also stated in: § Extended Data · plain
“A regression analysis was performed with two breaks of slope (see Methods for calculation).”
Quote in the paperSubstantial claim- Also stated in: § Extended Data · plain
May combine two claims.
Interpretationown dataThe results suggest that serum NfL tracks cortical thinning more closely than other imaging changes and that it mainly indicates neurodegeneration.
“These results indicate that NfL changes in the blood most closely reflect cortical thinning and support the view that serum NfL is primarily a marker of neurodegeneration.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Premisenone givenImproved NfL assays have shown that CSF and blood NfL are closely correlated.
“Advancements in NfL measurements have revealed tight correlations between NfL in the CSF and blood”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationThe authors chose the precuneus in advance because prior work identified it as the region most affected in autosomal-dominant Alzheimer's disease.
“Since the precuneus region has been shown to be most sensitive to Alzheimer’s disease pathophysiology in autosomal-dominant Alzheimer’s disease2,24, we focused our analyses on this region a priori.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [2] Gordon, B. A. et al. Spatial patterns of neuroimaging biomarker change in individuals from families with autosomal dominant Alzheimer’s disease: a longitudinal study. Lancet Neurol. 17, 241–250 (2018). source
Not checked in the free run.
- cites [24] Benzinger, T. L. S. et al. Regional variability of imaging biomarkers in autosomal dominant Alzheimer’s disease. Proc. Natl Acad. Sci. USA 110, E4502–E4509 (2013). source
Not checked in the free run.
May combine two claims.
InterpretationreasoningRepeated serum NfL measurements provide a dependable, inexpensive, and quick indicator of brain degeneration, similar in diagnostic usefulness to imaging but lacking regional detail.
“This suggests that longitudinal measures of NfL in the serum are a reliable, relatively cheap, and fast readout of neurodegeneration in the brain with comparable diagnostic value to neuroimaging but without the regional resolution.”
Quote in the paperSubstantial claim- Rests on an assumption: Collecting CSF requires an invasive procedure, and imaging is costly, so neither fits easily into routine care.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataThe clinicians who assessed participants did not know their mutation status.
“Clinical evaluators were blinded to each participant’s mutation status.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim. May combine two claims.
PremisecitationFew longitudinal NfL studies exist, and it is still uncertain how useful NfL is as a biomarker before neurodegenerative symptoms begin.
“However, longitudinal analyses are largely missing and the importance of NfL as a molecular biomarker for the presymptomatic phase of neurodegenerative diseases remains unclear6,9,17.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [6] Mattsson, N., Andreasson, U., Zetterberg, H. & Blennow, K. Association of plasma neurofilament light with neurodegeneration in patients with Alzheimer disease. JAMA Neurol. 74, 557–566 (2017). source
Not checked in the free run.
- cites [9] Weston, P. S. J. et al. Serum neurofilament light in familial Alzheimer disease: a marker of early neurodegeneration. Neurology 89, 2167–2175 (2017). source
Not checked in the free run.
- cites [17] Zhou, W. et al. Plasma neurofilament light chain levels in Alzheimer’s disease. Neurosci. Lett. 650, 60–64 (2017). 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 conductown dataThe NfL assay had mean intra-assay coefficients of variation of 4.2% for serum and 3.7% for CSF.
“For serum, the mean intra-assay coefficient of variation of duplicate determinations for concentration was 4.2%. In the CSF, the mean intra-assay coefficient of variation was 3.7%.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim. May combine two claims.
Premisenone givenBefore symptoms appear in Alzheimer's disease, the brain shows cortical thinning and deposits containing amyloid-β and tau.
“In Alzheimer’s disease, presymptomatic changes in the brain include cortical thinning and neuropathological depositions containing amyloid-β and tau.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
PremisecitationFew blood markers exist for the presymptomatic stage of Alzheimer's disease, though some progress has been reported for blood amyloid-β, tau, and NfL.
“Blood biomarkers for the presymptomatic phase of Alzheimer’s disease are largely lacking, although recent progress in the analysis of amyloid-β, tau, and neurofilament light chain (NfL) in the blood have been reported5–10.”
Quote in the paperSubstantial claim0 of 6 sources checked- cites [5] Fandos, N. et al. Plasma amyloid β 42/40 ratios as biomarkers for amyloid β cerebral deposition in cognitively normal individuals. Alzheimers Dement. (Amst) 8, 179–187 (2017). source
Not checked in the free run.
- cites [6] Mattsson, N., Andreasson, U., Zetterberg, H. & Blennow, K. Association of plasma neurofilament light with neurodegeneration in patients with Alzheimer disease. JAMA Neurol. 74, 557–566 (2017). source
Not checked in the free run.
- cites [7] Nakamura, A. et al. High performance plasma amyloid-β biomarkers for Alzheimer’s disease. Nature 554, 249–254 (2018). source
Not checked in the free run.
- cites [8] Ovod, V. et al. Amyloid β concentrations and stable isotope labeling kinetics of human plasma specific to central nervous system amyloidosis. Alzheimers Dement. 13, 841–849 (2017). source
Not checked in the free run.
- cites [9] Weston, P. S. J. et al. Serum neurofilament light in familial Alzheimer disease: a marker of early neurodegeneration. Neurology 89, 2167–2175 (2017). source
Not checked in the free run.
- cites [10] Mielke, M. M. et al. Plasma phospho-tau181 increases with Alzheimer’s disease clinical severity and is associated with tau- and amyloid-positron emission tomography. Alzheimers Dement. 14, 989–997 (2018). source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationIn mice and in several neurological conditions, including proteopathic neurodegenerative diseases, fluid NfL changes have been associated with brain damage and atrophy.
“Changes of NfL in bodily fluids have been linked to brain damage and brain atrophy in mouse models and multiple neurological disorders including proteopathic neurodegenerative diseases11,13–16.”
Quote in the paperSubstantial claim0 of 5 sources checked- cites [11] Petzold, A. Neurofilament phosphoforms: surrogate markers for axonal injury, degeneration and loss. J. Neurol. Sci. 233, 183–198 (2005). source
Not checked in the free run.
- cites [13] Bacioglu, M. et al. Neurofilament light chain in blood and CSF as marker of disease progression in mouse models and in neurodegenerative diseases. Neuron 91, 56–66 (2016). source
Not checked in the free run.
- cites [14] Barro, C. et al. Serum neurofilament as a predictor of disease worsening and brain and spinal cord atrophy in multiple sclerosis. Brain 141, 2382–2391 (2018). source
Not checked in the free run.
- cites [15] Brureau, A. et al. NF-L in cerebrospinal fluid and serum is a biomarker of neuronal damage in an inducible mouse model of neurodegeneration. Neurobiol. Dis. 104, 73–84 (2017). source
Not checked in the free run.
- cites [16] Kuhle, J. et al. Serum neurofilament light chain in early relapsing remitting MS is increased and correlates with CSF levels and with MRI measures of disease severity. Mult. Scler. 22, 1550–1559 (2016). source
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
PremisecitationBrain amyloid-β buildup is thought to begin 15-20 years before symptoms, with cortical metabolism decline at 10-15 years and atrophy at 5-10 years.
“The accumulation of amyloid-β in the brain (estimated 15–20 years before clinical onset) is followed by declines in cortical metabolism (estimated 10–15 years before clinical onset) and brain atrophy (5–10 years before clinical onset)1,2,22,25.”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [1] Bateman, R. J. et al. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N. Engl. J. Med. 367, 795–804 (2012). source
Not checked in the free run.
- cites [2] Gordon, B. A. et al. Spatial patterns of neuroimaging biomarker change in individuals from families with autosomal dominant Alzheimer’s disease: a longitudinal study. Lancet Neurol. 17, 241–250 (2018). source
Not checked in the free run.
- cites [22] McDade, E. et al. Longitudinal cognitive and biomarker changes in dominantly inherited Alzheimer disease. Neurology 91, e1295–e1306 (2018). source
Not checked in the free run.
- cites [25] Burnham, S. C. et al. Clinical and cognitive trajectories in cognitively healthy elderly individuals with suspected non-Alzheimer’s disease pathophysiology (SNAP) or Alzheimer’s disease pathology: a longitudinal study. Lancet Neurol. 15, 1044–1053 (2016). source
Not checked in the free run.
May combine two claims.
Interpretationown dataThe authors interpret their data as indicating that the rate of NfL change predicts better before symptoms, while absolute NfL predicts better after symptoms appear.
“our observations suggest that this is the case in presymptomatic Alzheimer’s disease, while absolute NfL levels are better predictors in the symptomatic phase.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
PremisecitationStudies indicate that familial and sporadic Alzheimer's disease have very similar pathogenesis, pathophysiology, and progression.
“Studies have indicated that the pathogenesis of familial and sporadic Alzheimer’s disease are very similar and share similar pathophysiology and progression36–39.”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [36] Bateman, R. J. et al. Autosomal-dominant Alzheimera’s disease: a review and proposal for the prevention of Alzheimera’s disease. Alzheimers Res. Ther. 3, 1 (2011). source
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- cites [37] Cairns, N. J. et al. Neuropathologic assessment of participants in two multi-center longitudinal observational studies: the Alzheimer Disease Neuroimaging Initiative (ADNI) and the Dominantly Inherited Alzheimer Network (DIAN). Neuropathology 35, 390–400 (2015). source
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- cites [38] Tang, M. et al. Neurological manifestations of autosomal dominant familial Alzheimer’s disease: a comparison of the published literature with the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS). Lancet Neurol. 15, 1317–1325 (2016). source
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- cites [39] Thomas, J. B. et al. Functional connectivity in autosomal dominant and late-onset Alzheimer disease. JAMA Neurol. 71, 1111–1122 (2014). source
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Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationHigher absolute blood NfL after symptoms appear matches findings in progressive supranuclear palsy, Huntington's disease, and multiple sclerosis.
“Increased absolute NfL levels in the blood in the symptomatic disease phase is consistent with similar observations in progressive supranuclear palsy28, Huntington’s disease30, and multiple sclerosis14.”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [28] Rojas, J. C. et al. Plasma neurofilament light chain predicts progression in progressive supranuclear palsy. Ann. Clin. Transl. Neurol. 3, 216–225 (2016). source
Not checked in the free run.
- cites [30] Byrne, L. M. et al. Neurofilament light protein in blood as a potential biomarker of neurodegeneration in Huntington’s disease: a retrospective cohort analysis. Lancet Neurol. 16, 601–609 (2017). source
Not checked in the free run.
- cites [14] Barro, C. et al. Serum neurofilament as a predictor of disease worsening and brain and spinal cord atrophy in multiple sclerosis. Brain 141, 2382–2391 (2018). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAll NfL samples were measured blinded.
“All samples were measured blinded.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningBecause CSF and blood NfL are tightly linked, the authors infer that blood NfL mirrors brain changes.
“The strong association between NfL levels in the CSF and blood indicates that NfL changes in the blood reflect changes in the brain”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown dataThe ADNI Imaging Core confirmed that PET scans followed the protocol and had no major artifacts.
“The ADNI Imaging Core verified that the PET images were acquired using the established protocol and free of substantial artifacts.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationNfL forms part of the axonal cytoskeleton and is found mainly in large myelinated axons.
“NfL is a component of the axonal cytoskeleton and is primarily expressed in large-caliber myelinated axons11,12.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [11] Petzold, A. Neurofilament phosphoforms: surrogate markers for axonal injury, degeneration and loss. J. Neurol. Sci. 233, 183–198 (2005). source
Not checked in the free run.
- cites [12] Schlaepfer, W. W. & Lynch, R. G. Immunofluorescence studies of neurofilaments in the rat and human peripheral and central nervous system. J. Cell Biol. 74, 241–250 (1977). source
Not checked in the free run.
May combine two claims.
InterpretationcitationThat NfL tracks cortical thinning but not amyloid-β deposition fits the idea that amyloid-β aggregation triggers later neurodegeneration, after which the two processes diverge.
“The association between NfL and cortical thinning, rather than amyloid-β deposition, is in line with cerebral amyloid-β aggregation being a trigger of subsequent neurodegeneration that, however, become independent of each other at later disease stages31.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [31] Karran, E., Mercken, M. & De Strooper, B. The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics. Nat. Rev. Drug Discov. 10, 698–712 (2011). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenMRI scans were checked by the ADNI Imaging Core for artifacts and adherence to protocol.
“The ADNI Imaging Core screened images for artifacts and protocol compliance.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationIn DIAN, CSF tau rises about 15 years before expected symptoms, earlier than baseline CSF NfL rises.
“In the DIAN cohort, the increase of tau in the CSF (absolute levels, cross-sectional) occurs as early as 15 years before the estimated age of symptom onset32, which is much earlier than the increase of base-line NfL in the CSF.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [32] Fagan, A. M. et al. Longitudinal change in CSF biomarkers in autosomal-dominant Alzheimer’s disease. Sci. Transl. Med. 6, 226ra230 (2014). 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 conductcitationAlthough CSF samples were thawed once more in Munich, earlier evidence found that as many as four freeze-thaw cycles do not substantially alter CSF NfL.
“Thus, CSF samples had one additional freeze–thaw cycle in Munich; however, prior work has indicated no significant effect of up to four freeze–thaw cycles on NfL in CSF43.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [43] Kuhle, J. et al. A comparative study of CSF neurofilament light and heavy chain protein in MS. Mult. Scler. 19, 1597–1603 (2013). source
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
PremisecitationMRI, PET, and CSF assays for amyloid-β and tau can detect these presymptomatic changes.
“These pathological changes can be assessed by magnetic resonance imaging (MRI), positron-emission tomography (PET), and measurement of amyloid-β and tau protein levels in the cerebrospinal fluid (CSF)1–4.”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [1] Bateman, R. J. et al. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N. Engl. J. Med. 367, 795–804 (2012). source
Not checked in the free run.
- cites [2] Gordon, B. A. et al. Spatial patterns of neuroimaging biomarker change in individuals from families with autosomal dominant Alzheimer’s disease: a longitudinal study. Lancet Neurol. 17, 241–250 (2018). source
Not checked in the free run.
- cites [3] Jack, C. R. Jr. et al. NIA-AA Research Framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 14, 535–562 (2018). source
Not checked in the free run.
- cites [4] Sperling, R. A., Karlawish, J. & Johnson, K. A. Preclinical Alzheimer disease: the challenges ahead. Nat. Rev. Neurol. 9, 54–58 (2013). source
Not checked in the free run.
May combine two claims.
Interpretationown dataIn symptomatic Alzheimer's disease, serum NfL rate of change reaches a plateau while absolute NfL levels continue to rise.
“In symptomatic Alzheimer’s disease, our results suggest that the NfL rate of change reaches a plateau, whereas absolute NfL levels continue to increase.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationFor each mutation, symptom onset age is usually similar, so the authors could estimate years to symptom onset from other carriers of the same mutation.
“Since the age of symptom onset tends to be consistent for a given mutation, it is possible to calculate for participants an estimated years to symptom onset (EYO) from the known onset of individuals with the same mutation20.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [20] Ryman, D. C. et al. Symptom onset in autosomal dominant Alzheimer disease: a systematic review and meta-analysis. Neurology 83, 253–260 (2014). source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductreasoningBecause the calibrator is full-length NfL, measured values may be higher than the actual blood concentration of the NfL fragment.
“Note that the concentrations (pg ml−1) are calculated from the full-length NfL calibrator and thus may overestimate the concentration of an NfL fragment in the blood.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
Collecting CSF requires an invasive procedure, and imaging is costly, so neither fits easily into routine care.
“However, CSF collection is invasive and imaging modalities are expensive; therefore, they are not well suited to routine clinical practice.”
The paper relies on this without support.
People with sporadic Alzheimer’s disease tend to be older and have more other illnesses, which could affect their blood NfL.
“However, sporadic Alzheimer’s disease patients are typically older and have more comorbidities, which in turn may influence NfL levels in the blood.”
The paper relies on this without support.
Rising NfL is not a signature of Alzheimer’s disease alone.
“While an increase of NfL levels is not specific for Alzheimer’s disease”
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?
The rates of disease progression, affected brain regions, and molecular cascades can vary significantly among individuals and across disease stages, posing significant challenges to the development of predictive models that accurately capture the dynamic pathology of Alzheimer's disease.
“The rates of disease progression, affected brain regions, and molecular cascades can vary significantly among individuals and across disease stages, posing significant challenges to the development of predictive models that accurately capture the dynamic pathology of AD417.”
From Artificial intelligence-driven multi-omics approaches in Alzheimer's disease: Progress, challenges, and future directions (2025) · cites this paper as [417]
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 measuredThe subject had relatively low plasma neurofilament light chain (20.24 pg/mL) for her older age.
“She also had relatively low plasma neurofilament light chain (NfL) measurements (20.24 pg/mL), a blood marker of axonal injury and neurodegeneration12 related to familial AD, particularly for her older age (her result and the mean and standard deviation of non-mutation carriers in the same age range, data not shown).”
From Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: a case report (2019) · cites this paper as [12]
Experimental — accuracy not yet measuredStrong correlations between CSF and serum levels for NfL have been previously reported.
“We observed strong correlations between CSF and serum levels for NfL, as it has been previously reported [31, 88, 89].”
In ADAD and LOAD, the rate of change in CSF and plasma NfL correlates with cortical thickness on structural MRI and cognitive performance.
“Studies of both ADAD and LOAD have demonstrated that rate of change in CSF and plasma NfL levels correlate with cortical thickness on structural MRI and cognitive performance”
From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Preische et al., 2019
Statistics recomputed
Every reported test result, recomputed from its test statistic and degrees of freedom. A result shows as not adding up only once an independent check has confirmed it.
- ConsistentF(2, 104) = 1.8108reported p = .1686 · recomputed p = .169
“F(2, 104)= 1.8108, p = .1686”
- ConsistentF(2, 240) = 1.9205reported p = .1488 · recomputed p = .149
“F(2, 240)= 1.9205, p = .1488”
- ConsistentF(2, 130) = 0.4678reported p = .6274 · recomputed p = .627
“F(2, 130) = 0.4678, p = .6274”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Self-check results appear here once an independent check has confirmed them.
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Self-citationPlasma neurofilament light chain levels in Alzheimer’s disease
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Self-citation
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Alzheimer Disease: An Update on Pathobiology and Treatment Strategies
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“Studies of both ADAD and LOAD have demonstrated that rate of change in CSF and plasma NfL levels correlate with cortical thickness on structural MRI and cognitive performance (Mattsson et al., 2019; Preische et al., 2019).”
Biomarkers for neurodegenerative diseases
Hansson, O. (2021) · Nature Medicine · doi:10.1038/s41591-021-01382-x · Cited by 1,159 · see citing works
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“84 Criteria on appropriate use of biofluid-based biomarkers for individual patients should be defined in phase 4 (eg, when and how these biomarkers should be used).”
Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) investigators, Thijssen, E. H., La Joie, R., Wolf, A., Strom, A., Wang, P., Iaccarino, L., Bourakova, V., Cobigo, Y., Heuer, H., et al. (2020) · Nature Medicine · doi:10.1038/s41591-020-0762-2 · Cited by 761 · see citing works
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“43,44 In sporadic”
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Self-citationA multicentre validation study of the diagnostic value of plasma neurofilament light.
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“No significant differences were observed in accuracies when using CSF biomarkers instead of plasma biomarkers (Supplementary Table 7 and 11).”
Blood biomarkers for Alzheimer’s disease in clinical practice and trials
Hansson, O., Blennow, K., Zetterberg, H., & Dage, J. (2023) · Nature Aging · doi:10.1038/s43587-023-00403-3 · Cited by 522 · see citing works
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Self-citationThe role of TDP-43 mislocalization in amyotrophic lateral sclerosis
Suk, T. R., & Rousseaux, M. W. C. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00397-1 · Cited by 456 · see citing works
Blood plasma phosphorylated-tau isoforms track CNS change in Alzheimer’s disease
Barthélemy, N. R., Horie, K., Sato, C., & Bateman, R. J. (2020) · Journal of Experimental Medicine · doi:10.1084/jem.20200861 · Cited by 437 · see citing works
Self-citationNeurofilaments as biomarkers in neurological disorders — towards clinical application
Khalil, M., Teunissen, C. E., Lehmann, S., Otto, M., Piehl, F., Ziemssen, T., Bittner, S., Sormani, M. P., Gattringer, T., Abu‐Rumeileh, S., et al. (2024) · Nature Reviews Neurology · doi:10.1038/s41582-024-00955-x · Cited by 480 · see citing works
“In autosomal dominant Alzheimer disease, changes in blood levels of NfL seem to precede the first clinical manifestations by more than a decade and also predict clinical progression within the Alzheimer disease continuum 142–144 .”
Self-citationBiomarkers for Alzheimer’s disease—preparing for a new era of disease-modifying therapies
Zetterberg, H., & Bendlin, B. B. (2020) · Molecular Psychiatry · doi:10.1038/s41380-020-0721-9 · Cited by 379 · see citing works
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Blood‐based biomarkers for Alzheimer's disease
Leuzy, A., Mattsson, N., Palmqvist, S., Janelidze, S., Dage, J. L., & Hansson, O. (2021) · EMBO Molecular Medicine · doi:10.15252/emmm.202114408 · Cited by 352 · see citing works
Alzheimer's disease: From immunotherapy to immunoprevention
Jucker, M., & Walker, L. C. (2023) · Cell · doi:10.1016/j.cell.2023.08.021 · Cited by 353 · see citing works
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de Wolf, F., Ghanbari, M., Licher, S., McRae‐McKee, K., Gras, L. A., Weverling, G. J., Wermeling, P. R., Sedaghat, S., Ikram, M. K., Waziry, R., et al. (2020) · Brain · doi:10.1093/brain/awaa054 · Cited by 328 · see citing works
“, 2017, 2019) and in people at genetically determined risk for Alzheimer’s disease compared to control subjects, even before the onset of symptoms (Preische et al., 2019).”
Neurofilaments: neurobiological foundations for biomarker applications
Gafson, A., Barthélemy, N. R., Bomont, P., Carare, R. O., Durham, H. D., Julien, J., Kühle, J., Leppert, D., Nixon, R. A., Weller, R. O., et al. (2020) · Brain · doi:10.1093/brain/awaa098 · Cited by 327 · see citing works
Self-citationDeveloping the ATX(N) classification for use across the Alzheimer disease continuum
Hampel, H. J., Cummings, J. L., Blennow, K., Gao, P., Jack, C. R., & Vergallo, A. (2021) · Nature Reviews Neurology · doi:10.1038/s41582-021-00520-w · Cited by 331 · see citing works
Tauopathies: new perspectives and challenges
Zhang, Y., Wu, K.-M., Yang, L., Dong, Q., & Yu, J.-T. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00533-z · Cited by 323 · see citing works
“The level of NfL in plasma is highly associated with CSF NfL and varies rapidly around the onset of symptoms in AD patients [149].”
BackgroundChatterjee, P., Pedrini, S., Doecke, J. D., Thota, R. N., Villemagne, V. L., Doré, V., Singh, A. K., Wang, P., Rainey‐Smith, S. R., Fowler, C. J., et al. (2022) · Alzheimer s & Dementia · doi:10.1002/alz.12724 · Cited by 317 · see citing works
Self-citationBlood neurofilament light: a critical review of its application to neurologic disease
Barro, C., Chitnis, T., & Weiner, H. L. (2020) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.51234 · Cited by 296 · see citing works
“Of note, the change in blood NfL levels measured longitudinally over time in an individual had a better prognostic value than the absolute blood NfL level at a single time point.(15) Thus, the confounding effect of comorbidities was controlled for using longitudinal measurements.”
BackgroundSelf-citationChallenges and hopes for Alzheimer’s disease
Tatulian, S. A. (2022) · Drug Discovery Today · doi:10.1016/j.drudis.2022.01.016 · Cited by 291 · see citing works
Verberk, I. M. W., Thijssen, E., Koelewijn, J., Mauroo, K., Vanbrabant, J., de Wilde, A., Zwan, M. D., Verfaillie, S. C. J., Ossenkoppele, R., Barkhof, F., et al. (2020) · Alzheimer's Research & Therapy · doi:10.1186/s13195-020-00682-7 · Cited by 258 · see citing works
“Moreover, NfL levels were higher in non-demented individuals with evidence of amyloid pathology compared to those without [21, 24], and NfL levels increase already in the presymptomatic Alzheimer’s disease stages [25], with an accelerated increase at time of symptom onset [26].”
BackgroundCullen, N. C., Leuzy, A., Janelidze, S., Palmqvist, S., Svenningsson, A. L., Stomrud, E., Dage, J. L., Mattsson, N., & Hansson, O. (2021) · Nature Communications · doi:10.1038/s41467-021-23746-0 · Cited by 270 · see citing works
Elahi, F. M., Casaletto, K. B., Joie, R. L., Walters, S. M., Harvey, D. J., Wolf, A. A., Edwards, L., Contreras, W. R., Karydas, A., Cobigo, Y., et al. (2019) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2019.09.004 · Cited by 250 · see citing works
Neurofilament light as a biomarker in traumatic brain injury
Shahim, P., Politis, A., van der Merwe, A., Moore, B., Chou, Y., Pham, D. L., Butman, J. A., Diaz-Arrastia, R. R., Gill, J., Brody, D. L., et al. (2020) · Neurology · doi:10.1212/wnl.0000000000009983 · Cited by 261 · see citing works
Blood neuro‐exosomal synaptic proteins predict Alzheimer's disease at the asymptomatic stage
Jia, L., Zhu, M., Kong, C., Pang, Y., Zhang, H., Qiu, Q., Wei, C., Tang, Y., Wang, Q., Li, Y., et al. (2020) · Alzheimer s & Dementia · doi:10.1002/alz.12166 · Cited by 251 · see citing works
Molecular signatures underlying neurofibrillary tangle susceptibility in Alzheimer’s disease
Otero-Garcia, M., Mahajani, S. U., Wakhloo, D., Tang, W., Xue, Y.-Q., Morabito, S., Pan, J., Oberhauser, J., Madira, A. E., Shakouri, T., et al. (2022) · Neuron · doi:10.1016/j.neuron.2022.06.021 · Cited by 262 · see citing works
CNS-Derived Blood Exosomes as a Promising Source of Biomarkers: Opportunities and Challenges
Hornung, S., Dutta, S., & Bitan, G. (2020) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2020.00038 · Cited by 239 · see citing works
Advances in the development of new biomarkers for Alzheimer’s disease
Klyucherev, T. O., Olszewski, P., Shalimova, A. A., Chubarev, V. N., Tarasov, V. V., Attwood, M. M., Syvänen, S., & Schiöth, H. B. (2022) · Translational Neurodegeneration · doi:10.1186/s40035-022-00296-z · Cited by 241 · see citing works
“The NFL level in CSF has a good correlation with plasma NFL level, although the former is found in significantly higher concentrations [94, 95].”
BackgroundDiagnostic and prognostic plasma biomarkers for preclinical Alzheimer’s disease
Chatterjee, P., Pedrini, S., Ashton, N. J., Tegg, M., Goozee, K., Singh, A. K., Karikari, T. K., Simrén, J., Vanmechelen, E., Armstrong, N. J., et al. (2022) · Alzheimer's & Dementia · doi:10.1002/alz.12447 · Cited by 231 · see citing works
Self-citationEmerging Microglia Biology Defines Novel Therapeutic Approaches for Alzheimer’s Disease
Lewcock, J. W., Schlepckow, K., Di Paolo, G., Tahirovic, S., Monroe, K. M., & Haass, C. (2020) · Neuron · doi:10.1016/j.neuron.2020.09.029 · Cited by 221 · see citing works
Moving fluid biomarkers for Alzheimer’s disease from research tools to routine clinical diagnostics
Zetterberg, H., & Blennow, K. (2021) · Molecular Neurodegeneration · doi:10.1186/s13024-021-00430-x · Cited by 219 · see citing works
“However, the findings in familial AD are also quite clear; mutation carriers show a sudden change in their blood NfL levels 10–15 years before expected clinical onset, which probably marks the onset and intensity of the neurodegenerative process [54, 55].”
BackgroundVerberk, I. M. W., Laarhuis, M. B., van den Bosch, K. A., Ebenau, J. L., van Leeuwenstijn, M. S. S. A., Prins, N. D., Scheltens, P., Teunissen, C. E., & van der Flier, W. M. (2021) · The Lancet Healthy Longevity · doi:10.1016/s2666-7568(20)30061-1 · Cited by 203 · see citing works
Linguistic markers predict onset of Alzheimer's disease
Eyigoz, E., Mathur, S., Santamaria, M., Cecchi, G., & Naylor, M. (2020) · EClinicalMedicine · doi:10.1016/j.eclinm.2020.100583 · Cited by 206 · see citing works
“Most recently, very promising results were reported using Neurofilament light chain (NfL) for disease progression at the early pre-symptomatic stages of familial Alzheimer’s disease [43].”
ResultUntangling the association of amyloid-β and tau with synaptic and axonal loss in Alzheimer’s disease
Pereira, J. B., Janelidze, S., Ossenkoppele, R., Kvartsberg, H., Brinkmalm, A., Mattsson, N., Stomrud, E., Smith, R. A., Zetterberg, H., Blennow, K., et al. (2020) · Brain · doi:10.1093/brain/awaa395 · Cited by 201 · see citing works
“milial Alzheimer’s studies suggest that it is an early disease marker (Preische et al., 2019), they have not compared it to”
BackgroundJanelidze, S., Palmqvist, S., Leuzy, A., Stomrud, E., Verberk, I. M. W., Zetterberg, H., Ashton, N. J., Pesini, P., Sarasa, L., Allué, J. A., et al. (2022) · Alzheimer's & Dementia · doi:10.1002/alz.12395 · Cited by 188 · see citing works
An update on blood-based biomarkers for non-Alzheimer neurodegenerative disorders
Ashton, N. J., Hye, A., Rajkumar, A. P., Leuzy, A., Snowden, S. G., Suárez‐Calvet, M., Karikari, T. K., Schöll, M., Joie, R. L., Rabinovici, G. D., et al. (2020) · Nature Reviews Neurology · doi:10.1038/s41582-020-0348-0 · Cited by 182 · see citing works
Early-Onset Alzheimer’s Disease: What Is Missing in Research?
Ayodele, T., Rogaeva, E. A., Kurup, J. T., Beecham, G. W., & Reitz, C. (2021) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-020-01090-y · Cited by 198 · see citing works
“Studies in individuals withM-EOAD including the DIAN study further indicate that, similar to CSF, plasma NFL is elevated more than a decade prior to symptom onset, suggesting that it can serve as a sensitive diagnostic screening tool to identify individuals at risk [101].”
BackgroundCerebrospinal fluid immune dysregulation during healthy brain aging and cognitive impairment
Piehl, N., van Olst, L., Ramakrishnan, A., Teregulova, V., Simonton, B., Zhang, Z., Tapp, E., Channappa, D., Oh, H. S., Losada, P. M., et al. (2022) · Cell · doi:10.1016/j.cell.2022.11.019 · Cited by 195 · see citing works
“NEFL is a biomarker for neuroaxonal damage which predicts neurodegeneration and clinical progression in presymptomatic AD.44 CXCL16 also correlated with levels of CSF glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase L1 (UCHL1).”
BackgroundInfluentialSun, B., Tang, N., Peluso, M. J., Iyer, N. S., Torres, L., Donatelli, J. L., Munter, S. E., Nixon, C. C., Rutishauser, R. L., Rodríguez-Barraquer, I., et al. (2021) · Cells · doi:10.3390/cells10020386 · Cited by 187 · see citing works
“Increased plasma NFL has been associated with ongoing CNS injury in HIV [47], Parkinsons [48], and AD [49].”
BackgroundNeurofilament Light Chain as a Biomarker in Multiple Sclerosis
Varhaug, K. N., Torkildsen, Ø., Myhr, K., & Vedeler, C. A. (2019) · Frontiers in Neurology · doi:10.3389/fneur.2019.00338 · Cited by 184 · see citing works
“The important fact that serum NF-L levels correlate with CSF levels have been confirmed in several studies (9, 18, 19).”
BackgroundDiagnostic biomarkers of Alzheimer’s disease: A state-of-the-art review
Khoury, R., & Ghossoub, E. (2019) · Biomarkers in Neuropsychiatry · doi:10.1016/j.bionps.2019.100005 · Cited by 157 · see citing works
van der Ende, E. L., Meeter, L. H., Poos, J. M., Panman, J. L., Jiskoot, L. C., Dopper, E. G. P., Papma, J. M., de Jong, F. J., Verberk, I. M. W., Teunissen, C., et al. (2019) · The Lancet Neurology · doi:10.1016/s1474-4422(19)30354-0 · Cited by 181 · see citing works
Self-citationCullen, N. C., Leuzy, A., Palmqvist, S., Janelidze, S., Stomrud, E., Pesini, P., Sarasa, L., Allué, J. A., Proctor, N. K., Zetterberg, H., et al. (2020) · Nature Aging · doi:10.1038/s43587-020-00003-5 · Cited by 187 · see citing works
Novak, P., Kovacech, B., Katina, S., Schmidt, R., Scheltens, P., Kontsekova, E., Ropele, S., Fialova, L., Kramberger, M., Paulenka-Ivanovova, N., et al. (2021) · Nature Aging · doi:10.1038/s43587-021-00070-2 · Cited by 187 · see citing works
Fluid Biomarkers for Synaptic Dysfunction and Loss
Camporesi, E., Nilsson, J., Brinkmalm, A., Becker, B., Ashton, N. J., Blennow, K., & Zetterberg, H. (2020) · Biomarker Insights · doi:10.1177/1177271920950319 · Cited by 165 · see citing works
An accurate fully automated panel of plasma biomarkers for Alzheimer's disease
Palmqvist, S., Stomrud, E., Cullen, N. C., Janelidze, S., Manuilova, E., Jethwa, A., Bittner, T., Eichenlaub, U., Suridjan, I., Kollmorgen, G., et al. (2022) · Alzheimer s & Dementia · doi:10.1002/alz.12751 · Cited by 161 · see citing works
Late-onset vs nonmendelian early-onset Alzheimer disease
Reitz, C., Rogaeva, E. A., & Beecham, G. W. (2020) · Neurology Genetics · doi:10.1212/nxg.0000000000000512 · Cited by 171 · see citing works
Shared proteomic effects of cerebral atherosclerosis and Alzheimer’s disease on the human brain
Wingo, A. P., Fan, W., Duong, D. M., Gerasimov, E. S., Dammer, E. B., Liu, Y., Harerimana, N. V., White, B., Thambisetty, M., Troncoso, J. C., et al. (2020) · Nature Neuroscience · doi:10.1038/s41593-020-0635-5 · Cited by 161 · see citing works
Jiang, Y., Zhou, X., Ip, F. C. F., Chan, P., Chen, Y., Lai, N. C. H., Cheung, K., Lo, R. M. N., Tong, E. P. S., Wong, B. W. Y., et al. (2021) · Alzheimer s & Dementia · doi:10.1002/alz.12369 · Cited by 164 · see citing works
Cerebrospinal fluid proteomics define the natural history of autosomal dominant Alzheimer’s disease
Johnson, E. C. B., Bian, S., Haque, R. U., Carter, E. K., Watson, C. M., Gordon, B. A., Ping, L., Duong, D. M., Epstein, M. P., McDade, E., et al. (2023) · Nature Medicine · doi:10.1038/s41591-023-02476-4 · Cited by 170 · see citing works
“To better approximate the complex nonlinear relationships between the biomarkers and EYO, and according to previously published work 20 , we modeled EYO using a restricted cubic spline transformation with three knots at the 0.1, 0.5 and 0.9 quantiles (Formula 1).”
BackgroundMethodInfluentialSelf-citationQuiroz, Y. T., Zetterberg, H., Reiman, E. M., Chen, Y., Su, Y., Fox-Fuller, J. T., Garcia, G., Villegas, A., Sepulveda-Falla, D., Villada, M., et al. (2020) · The Lancet Neurology · doi:10.1016/s1474-4422(20)30137-x · Cited by 159 · see citing works
Self-citationCSF biomarkers of neuroinflammation in distinct forms and subtypes of neurodegenerative dementia
Abu‐Rumeileh, S., Steinacker, P., Polischi, B., Mammana, A., Bartoletti‐Stella, A., Oeckl, P., Baiardi, S., Zenesini, C., Huss, A. M., Cortelli, P., et al. (2019) · Alzheimer s Research & Therapy · doi:10.1186/s13195-019-0562-4 · Cited by 154 · see citing works
Serum neurofilament light as a biomarker in progressive multiple sclerosis
Kapoor, R., Smith, K. E., Allegretta, M., Arnold, D. L., Carroll, W. M., Comabella, M., Furlan, R., Harp, C. T., Kühle, J., Leppert, D., et al. (2020) · Neurology · doi:10.1212/wnl.0000000000010346 · Cited by 159 · see citing works
“In patients with Alzheimer disease and amyotrophic lateral sclerosis, increasing mean serum concentrations occur months or years before the emergence of the first clinical manifestations.(35,36) Similarly, an increased CSF NfL concentration in radiologically isolated syndrome is a risk factor for later transition to c…”
BackgroundSelf-citationBiel, D., Brendel, M., Rubinski, A., Büerger, K., Janowitz, D., Dichgans, M., Franzmeier, N., & Initiative, A. D. N. (2021) · Alzheimer s Research & Therapy · doi:10.1186/s13195-021-00880-x · Cited by 153 · see citing works
Remote Blood Biomarkers of Longitudinal Cognitive Outcomes in a Population Study
Rajan, K. B., Aggarwal, N. T., McAninch, E. A., Weuve, J., Barnes, L. L., Wilson, R. S., DeCarli, C. S., & Evans, D. A. (2020) · Annals of Neurology · doi:10.1002/ana.25874 · Cited by 147 · see citing works
“been associated with AD(13) and cognitive impairment.(14,15) However, less is known of how these biomarkers are related to longitudinal cognitive outcomes over a decade, including the time-dependent development of clinical AD, and longterm changes in cognitive functioning and brain morphology.”
BackgroundAn Update on Blood-Based Markers of Alzheimer’s Disease Using the SiMoA Platform
Li, D., & Mielke, M. M. (2019) · Neurology and Therapy · doi:10.1007/s40120-019-00164-5 · Cited by 147 · see citing works
Pais, M. V., Forlenza, O. V., & Diniz, B. S. (2023) · Journal of Alzheimer s Disease Reports · doi:10.3233/adr-230029 · Cited by 168 · see citing works
“This biomarker has shown consistently increased levels in patients with MCI and patients with AD dementia compared to cognitively unimpaired individuals [88, 89], and this is particularly true in patients with A pathology.”
BackgroundGiacomucci, G., Mazzeo, S., Bagnoli, S., Ingannato, A., Leccese, D., Berti, V., Padiglioni, S., Galdo, G., Ferrari, C., Sorbi, S., et al. (2022) · Journal of Neurology · doi:10.1007/s00415-022-11055-5 · Cited by 148 · see citing works
Biomarkers for Alzheimer’s Disease Early Diagnosis
Ausó, E., Gómez‐Vicente, V., & Esquiva, G. (2020) · Journal of Personalized Medicine · doi:10.3390/jpm10030114 · Cited by 149 · see citing works
“Recent studies have revealed that serum neurofilament protein levels correlated with AD [89].”
BackgroundMinikel, E. V., Zhao, H. T., Le, J., O’Moore, J., Pitstick, R., Graffam, S., Carlson, G. A., Kavanaugh, M. P., Križ, J., Kim, J. B., et al. (2020) · Nucleic Acids Research · doi:10.1093/nar/gkaa616 · Cited by 143 · see citing works
Schindler, S. E., Karikari, T. K., Ashton, N. J., Henson, R. L., Yarasheski, K. E., West, T., Meyer, M. R., Kirmess, K. M., Li, Y., Saef, B. A., et al. (2022) · Neurology · doi:10.1212/wnl.0000000000200358 · Cited by 140 · see citing works
“Plasma neurofilament light chain (NfL) may also be useful as a nonspecific marker of neuroaxonal injury.(24) It is critical to evaluate whether these assays accurately and consistently predict brain amyloidosis across various racial and ethnic groups.”
BackgroundSelf-citationArtificial Intelligence for Alzheimer’s Disease: Promise or Challenge?
Fabrizio, C., Termine, A., Caltagirone, C., & Sancesario, G. M. (2021) · Diagnostics · doi:10.3390/diagnostics11081473 · Cited by 156 · see citing works
“A possible turning point has emerged with the recent development of ultra-sensitive methods for the detection of brain-derived proteins in blood, making it possible to measure NFL [84], Aβ42, and Aβ40 [85,86], and tau and P-tau in plasma [87,88].”
MethodInfluentialThe accuracy and robustness of plasma biomarker models for amyloid PET positivity
Benedet, A. L., Brum, W. S., Hansson, O., Initiative, A. D. N., Karikari, T. K., Zimmer, E. R., Zetterberg, H., Blennow, K., & Ashton, N. J. (2022) · Alzheimer s Research & Therapy · doi:10.1186/s13195-021-00942-0 · Cited by 139 · see citing works
“Increases in plasma NfL are a widely reported finding in AD [20, 21] and are also observed in pre-symptomatic familial AD [22].”
BackgroundVermunt, L., Otte, M., Verberk, I. M. W., Killestein, J., Lemstra, A. W., van der Flier, W. M., Pijnenburg, Y. A. L., Vijverberg, E. G. B., Bouwman, F. H., Gravesteijn, G., et al. (2022) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.51676 · Cited by 138 · see citing works
“Within the included neurological diseases, blood NfL levels seemed to show a stronger age-related increase than CSF NfL levels, corroborating previous work.(2,8) Methodologically, involving a diverse group of physicians during the development of the interface is a strength.”
ResultChallenges in the practical implementation of blood biomarkers for Alzheimer’s disease
Schöll, M., Verberk, I. M. W., del Campo, M., Delaby, C., Therriault, J., Chong, J. R., Palmqvist, S., & Alcolea, D. A. (2024) · The Lancet Healthy Longevity · doi:10.1016/j.lanhl.2024.07.013 · Cited by 143 · see citing works
On the phantom-like appearance of bilingualism effects on neurocognition: (How) should we proceed?
Leivada, E., Westergaard, M. R., Duñabeitia, J. A., & Rothman, J. (2020) · Bilingualism Language and Cognition · doi:10.1017/s1366728920000358 · Cited by 134 · see citing works
Plasma tau complements CSF tau and P‐tau in the diagnosis of Alzheimer's disease
Fossati, S., Ramos‐Cejudo, J., Debure, L., Pirraglia, E., Sone, J. Y., Li, Y., Chen, J., Butler, T., Zetterberg, H., Blennow, K., et al. (2019) · Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring · doi:10.1016/j.dadm.2019.05.001 · Cited by 130 · see citing works
Bittner, S., Steffen, F., Uphaus, T., Muthuraman, M., Fleischer, V., Salmen, A., Luessi, F., Berthele, A., Klotz, L., Meuth, S. G., et al. (2020) · EBioMedicine · doi:10.1016/j.ebiom.2020.102807 · Cited by 130 · see citing works
“Neurofilament proteins are part of the neuronal cytoskeleton and are elevated in various neurological diseases associated with neuronal damage including neurodegenerative diseases [6] and stroke [7], as well as MS [8].”
Artificial intelligence for biomarker discovery in Alzheimer's disease and dementia
Winchester, L. M., Harshfield, E. L., Shi, L., Badhwar, A., Khleifat, A. A., Clarke, N., Dehsarvi, A., Lengyel, I., Lourida, I., Madan, C. R., et al. (2023) · Alzheimer's & Dementia · doi:10.1002/alz.13390 · Cited by 130 · see citing works
“41 Using data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), researchers performed a comparison between genomic and imaging variables using four different ML approaches to understand the potential of cost-effective, minimally invasive transition biomarkers.”
MethodA combined miRNA-piRNA signature to detect Alzheimer’s disease
Jain, G., Stuendl, A., Rao, P., Berulava, T., Pena Centeno, T., Kaurani, L., Burkhardt, S., Delalle, I., Kornhuber, J., Hüll, M., et al. (2019) · Translational Psychiatry · doi:10.1038/s41398-019-0579-2 · Cited by 121 · see citing works
Preventing amyotrophic lateral sclerosis: insights from pre-symptomatic neurodegenerative diseases
Benatar, M. G., Wuu, J., McHutchison, C. A., Postuma, R. B., Boeve, B. F., Petersen, R. C., Ross, C. A., Rosen, H. J., Arias, J. J., Fradette, S., et al. (2021) · Brain · doi:10.1093/brain/awab404 · Cited by 118 · see citing works
Benedet, A. L., Leuzy, A., Pascoal, T. A., Ashton, N. J., Mathotaarachchi, S. S., Savard, M., Therriault, J., Kang, M. S., Chamoun, M., Schöll, M., et al. (2020) · Brain · doi:10.1093/brain/awaa342 · Cited by 123 · see citing works
“…plasma (Mattsson et al. , 2019) and CSF (Sjogren et al. , 2001) in sporadic, familial and preclinical Alzheimer’s disease (Weston et al. , 2017; Preische et al. , 2019; Quiroz et al. , 2020), and to correlate with cognitive, biochemical, imaging-based measures and post-mortem findings in…”
The role of innate immunity in Alzheimer's disease
Ennerfelt, H. E., & Lukens, J. R. (2020) · Immunological Reviews · doi:10.1111/imr.12896 · Cited by 121 · see citing works
O’Connor, A., Karikari, T. K., Poole, T., Ashton, N. J., Lantero Rodriguez, J., Khatun, A., Swift, I., Heslegrave, A. J., Abel, E., Chung, E., et al. (2021) · Molecular Psychiatry · doi:10.1038/s41380-020-0838-x · Cited by 122 · see citing works
Self-citationThe potential of blood neurofilament light as a marker of neurodegeneration for Alzheimer's disease
Jung, Y., & Damoiseaux, J. S. (2023) · Brain · doi:10.1093/brain/awad267 · Cited by 117 · see citing works
Neurofilaments in pre-symptomatic ALS and the impact of genotype
Benatar, M. G., Wuu, J., Lombardi, V., Jeromin, A., Bowser, R. P., Andersen, P. M., & Malaspina, A. (2019) · Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration · doi:10.1080/21678421.2019.1646769 · Cited by 115 · see citing works
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Early diagnosis and treatment of Alzheimer’s disease: new definitions and challenges
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Self-citationBiological age in healthy elderly predicts aging-related diseases including dementia
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“Importantly, plasma NFL increases early in the preclinical phase of AD [58, 59].”
BackgroundWilke, C., Haas, E., Reetz, K., Faber, J., García‐Moreno, H., Santana, M. M., van de Warrenburg, B. P. C., Hengel, H., Lima, M. C. F., Filla, A., et al. (2020) · EMBO Molecular Medicine · doi:10.15252/emmm.201911803 · Cited by 103 · see citing works
“…intraindividual temporal dynamics of Nfs might be even more sensitive to early stages of degeneration and better suited to capture individual disease progression, as indicated by longitudinal Nf studies of genetic FTD and Alzheimer’s disease (van der Ende et al, 2019; Preische et al, 2019).”
BackgroundSelf-citationEffects of acute sleep loss on diurnal plasma dynamics of CNS health biomarkers in young men
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“In humans, acute sleep loss increases levels of Aβ species and total tau (t-tau) in CSF.3,8 Furthermore, patients with obstructive sleep apnea exhibit increased Aβ levels in plasma, as well as higher levels of phosphorylated tau.9 The underlying mechanism may be a reduced functionality of the glymphatic system, which…”
BackgroundInfluentialNeurofilament Light Chain as a Biomarker of Hereditary Transthyretin-Mediated Amyloidosis
Ticau, S., Sridharan, G. V., Tsour, S., Cantley, W. L., Chan, A., Gilbert, J. A., Erbe, D. V., Aldinc, E., Reilly, M. M., Adams, D., et al. (2020) · Neurology · doi:10.1212/wnl.0000000000011090 · Cited by 108 · see citing works
“Elevated NfL levels in these diseases are thought to be caused by the release of NfL into the circulation from damaged neurons,(29) and it has been identified in both CSF(30) and blood.(31) In this study, the mean NfL levels described in patients with ATTRv amyloidosis with polyneuropathy (69.”
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Further understanding the connection between Alzheimer's disease and Down syndrome
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Biomarkers for parkinsonian disorders in CNS-originating EVs: promise and challenges
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“, neurofilament light chain (NfL), a highly useful biomarker of neurodegeneration, or the protein tau phosphorylated at Thr 217 (pT217-tau) as a specific marker for Alzheimer’s disease (AD) [16, 135, 141].”
BackgroundChemical sensing platforms for detecting trace-level Alzheimer's core biomarkers
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“Strikingly, synapse loss was exacerbated, and neurofilament light chain (NfL), a sensitive fluid biomarker of neurodegeneration (Meeter et al , 2016; Rohrer et al , 2016; Preische et al , 2019), was also not reduced but unexpectedly increased in the cerebrospinal fluid (CSF).”
Self-citationNeurofilament-Light, a Promising Biomarker: Analytical, Metrological and Clinical Challenges
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“It also correlates highly with imaging and cognitive assessment results [14,15].”
BackgroundCurrent advances in plasma and cerebrospinal fluid biomarkers in Alzheimer's disease
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- Authors
- Dominantly Inherited Alzheimer Network, Preische, O., Schultz, S. A., Apel, A., Kuhle, J., Kaeser, S. A., Barro, C., Gräber, S., Kuder-Buletta, E., LaFougere, C., Laske, C., Vöglein, J., Levin, J., Masters, C. L., Martins, R., Schofield, P. R., Rossor, M. N., Graff-Radford, N. R., Salloway, S., Ghetti, B., Ringman, J. M., Noble, J. M., Chhatwal, J., Goate, A. M., Benzinger, T. L. S., Morris, J. C., Bateman, R. J., Wang, G., Fagan, A. M., McDade, E. M., Gordon, B. A., & Jucker, M.
- Affiliations
- German Center for Neurodegenerative Diseases (DE)
- Washington University in St. Louis (US)
- University of Basel (CH)
- The University of Melbourne (AU)
- Edith Cowan University (AU)
- UNSW Sydney (AU)
- Mayo Clinic (US)
- Brown University (US)
- Keck Hospital of USC (US)
- Columbia University Irving Medical Center (US)
- Harvard University (US)
- Corresponding author
- Jucker, Mathias
- ORCID
- Schultz, Stephanie A.
- Kaeser, Stephan A.
- Barro, Christian
- Laske, Christoph
- Vöglein, Jonathan
- Levin, Johannes
- Masters, Colin L.
- Martins, Ralph
- Schofield, Peter R.
- Rossor, Martin N.
- Salloway, Stephen
- Ghetti, Bernardino
- Ringman, John M.
- Noble, James M.
- Chhatwal, Jasmeer
- Goate, Alison M.
- Benzinger, Tammie L. S.
- Morris, John C.
- Bateman, Randall J.
- Wang, Guoqiao
- Fagan, Anne M.
- McDade, Eric M.
- Gordon, Brian A.
- Jucker, Mathias
- Venue
- Nature Medicine
- Published
- 2019-01-21
- Volume
- 25
- Issue
- 2
- Pages
- 277-283
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC6367005
- OpenAlex
- W2910313823
- Cited by
- 927
- References
- 49
- Citations by year
- 2026: 70 · 2025: 87 · 2024: 145 · 2023: 116 · 2022: 126 · 2021: 142 · 2020: 176 · 2019: 63
- FWCI
- 87.98
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion)
- Murdoch University Research Portal (submittedVersion)
- Edith Cowan University Research Online (Edith Cowan University) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- DZNE Pub (submittedVersion)
- Conicet (submittedVersion, cc-by)
- IUScholarWorks (Indiana University) (submittedVersion)
- PMC
- Funders
- National Institute for Health and Care Research (NF-SI-0512-10033)
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (320030)
- National Institutes of Health (UL1TR001873)
- Medical Research Council (MR/L023784/2, MR/L023784/1)
- Japan Society for the Promotion of Science (18K07385, 17H06498, 17K09794)
- National Institute on Aging (UF1AG032438, U19AG032438, U01AG032438, U24AG021886, K01AG053474)
- National Institute of Neurological Disorders and Stroke (P30NS098577)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- neurofilament light chain, serum biomarkers, preclinical Alzheimer's disease, familial Alzheimer's disease, mutation carriers, disease progression, neurodegeneration, cortical thinning, amyloid-beta, glucose metabolism, cerebrospinal fluid, longitudinal biomarker dynamics, cognitive decline
- MeSH terms
- Alzheimer Disease, Humans, Mutation, Nerve Degeneration, Neurofilament Proteins, Disease Progression
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.
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