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Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive tau PET in Alzheimer's disease
Open accessAbstract
Aβ pathology may induce changes in soluble tau release and phosphorylation, which is later followed by tau aggregation.
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Written from the paper’s full text.
TL;DR
In the Swedish BioFINDER Tau PET substudy, Aβ deposition was associated with early increases in CSF soluble and phosphorylated tau, especially P-tau217, before Tau PET became positive. These soluble tau changes statistically mediated the relationship between Amyloid PET and Tau PET, suggesting a window before significant PHF-tau aggregation.
Key findings
- Among 131 participants, Aβ+ CU had higher CSF P-tau181, P-tau217, and T-tau than Aβ− CU (P ≤ 0.0001) but did not differ on Tau PET measures. In Aβ+ CU, positivity was 70.0% for CSF P-tau217, 55.0% for P-tau181, 22.5% for T-tau, and only 2.5% for Tau PET ITC.
- Isolated CSF P-tau positivity with negative Tau PET was common (28.2 to 51.1%), whereas isolated Tau PET positivity was rare (0.8 to 3.1%). In Tau PET–negative CU with an early CSF sample a median of 3.8 years before Tau PET, 56.3% of Aβ+ were positive for P-tau217, 25.0% for P-tau181, and 9.4% for T-tau; 0% of Aβ− CU were positive.
- Aβ+ CU showed greater yearly increases than Aβ− CU in CSF P-tau217 [median 13.42 ng/liter/year (IQR, 4.94 to 22.12)], P-tau181 [7.06 (3.09 to 14.29)], and T-tau [10.65 (1.96 to 22.78)]. Spline thresholds showed CSF P-tau217 increased at 0.679 SUVR, P-tau181 at 0.684 SUVR, and T-tau at 0.695 SUVR, before the Amyloid PET positivity threshold of 0.743 SUVR; Tau PET increased at 0.772 SUVR (ITC) or 0.859 SUVR (Braak V–VI).
- P-tau217 and P-tau181 mediated 82% and 68% of the Amyloid PET effect on Tau PET, respectively; T-tau mediated 41%. In 5xFAD mice, CSF T-tau increased at 4 months despite no tau aggregates, and 12 of 12 MAPT mutation carriers had normal CSF P-tau, with 10 of 12 normal CSF T-tau.
Methods
- Prospective Swedish BioFINDER Tau PET substudy of 131 participants: 18 Aβ− CU, 40 Aβ+ CU, 38 Aβ+ with mild cognitive deficits (CDR 0.5), and 35 Aβ+ AD dementia (CDR 1 to 3), plus 12 MAPT mutation carriers. Measures included CSF T-tau, P-tau181, P-tau217, Tau368, 18F-flutemetamol Amyloid PET, 18F-flortaucipir Tau PET, MRI, and longitudinal subsets.
- Main analyses used linear regression adjusted for age and sex, nonlinear spline models for continuous Amyloid PET thresholds, mediation analysis, and longitudinal models. Cut points were defined as mean plus two SDs in independent Aβ− CU cohorts. Mouse experiments used 5xFAD mice and nontransgenic littermates with CSF T-tau and Thioflavin S plaque quantification.
Limitations
- Stated in the paper: lack of neuropathology to verify correlations between tau measures and brain changes; the longitudinal part was relatively small and differed between CSF and Tau PET measures; sensitivity may differ across techniques, and future studies are needed to compare CSF P-tau with interstitial fluid or brain tissue P-tau.
- Evident from the text: the human findings are observational and do not prove causality; the 5xFAD mouse model does not develop tau aggregates and CSF P-tau could not be measured in mice; the cohort was drawn from a memory-clinic/BioFINDER setting, which may limit generalizability.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Aβ+ individuals with mild cognitive deficits had higher levels of all CSF and PET tau measures, compared with both Aβ− CU (CSF, P < 0.0001; PET, P ≤ 0.0032) and Aβ+ CU (P < 0.0001).”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > RESULTS > CSF tau proteins and Tau PET retention are elevated in different stages of AD
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“All Aβ− CU were negative on all tau biomarkers, except one individual who was positive for CSF P-tau181 and P-tau217.”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > RESULTS > CSF tau proteins and Tau PET retention are elevated in different stages of AD
Strength:plain· not yet calibratedSingle caseTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In symptomatic disease stages, positivity was common for all tau biomarkers (71 to 100% for all, except Tau PET Braak V–VI, which had 32 to 66% positivity in symptomatic disease stages).”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > RESULTS > CSF tau proteins and Tau PET retention are elevated in different stages of AD
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The ratios strongly mediated the effects of Amyloid PET on Tau PET (full mediation effects; fig. S6).”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > RESULTS > CSF P-tau/T-tau ratios are increased early and continue to increase as tau accumulates
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: Global cortical 18F-flutemetamol Amyloid PET represents Aβ fibrillar plaque load.
- Rests on an assumption: Tau PET represents PHF-tau.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Most individuals were either concordant negative (range, 22.1 to 29.0%) or positive (range, 25.2 to 48.9%) for CSF P-tau and Tau PET measures”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > RESULTS > CSF P-tau positivity without Tau PET positivity is common in early stages of AD
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“CSF T-tau concentrations correlated significantly positive with amyloid plaque load in cortex when assessed over all age groups in 5xFAD mice”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > RESULTS > CSF tau increases when Aβ pathology accumulates in 5xFAD mice
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: The 5xFAD transgenic mouse model's CSF tau changes in response to Aβ pathology are informative about the human relationship between Aβ pathology and soluble tau.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“CSF T-tau concentrations in 5xFAD mice were significantly higher than those in nontransgenic littermates at 4, 6, and 12 months of age (Mann-Whitney U test; **P < 0.05 and ***P < 0.001).”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > RESULTS > CSF tau increases when Aβ pathology accumulates in 5xFAD mice
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: The 5xFAD transgenic mouse model's CSF tau changes in response to Aβ pathology are informative about the human relationship between Aβ pathology and soluble tau.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Rates of increase for CSF P-tau181, P-tau217, and T-tau were higher in Aβ+ CU [median (IQR) yearly increase: 7.06 (3.09 to 14.29) ng/liter and year, 13.42 (4.94 to 22.12) ng/liter and year, and 10.65 (1.96 to 22.78) ng/liter and year for CSF P-tau181, P-tau217, and T-tau, respectively] compared with Aβ− CU individuals [0.33 (−0.35 to 1.62) ng/liter and year, 1.34 (−0.055 to 1.94) ng/liter and year”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > RESULTS > Longitudinal CSF tau levels increase in preclinical AD before Tau PET becomes positive
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“All Aβ− CU were negative on CSF P-tau217, P-tau181, and T-tau in the early sample (0% positive).”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > RESULTS > CSF P-tau is often positive even several years before a negative Tau PET scan
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Within Aβ+ individuals with cognitive deficits (analyzing mild deficits and dementia together), higher P-tau181, P-tau217, and T-tau were associated with more rapid increase in Tau PET in most regions (fig. S3, A to C and E to G).”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > RESULTS > CSF tau predicts future Tau PET accumulation in cognitively impaired people
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
- It may state two separate claims as one. 41
- Probably not a substantial claim. 20
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“For CSF tau biomarkers, the percentages of positive individuals did not differ markedly between Aβ+ with milder cognitive deficits and dementia, but for Tau PET, the proportion of positivity increased from milder cognitive deficits to dementia.”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > RESULTS > CSF tau proteins and Tau PET retention are elevated in different stages of AD
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Aβ+ CU had higher CSF P-tau181, P-tau217, and T-tau than Aβ− CU (P ≤ 0.0001), but did not differ on any of the Tau PET measures.”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > RESULTS > CSF tau proteins and Tau PET retention are elevated in different stages of AD
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Aβ+ AD dementia had higher levels of all tau measures compared with all other groups (CSF, P ≤ 0.035; Tau PET, P ≤ 0.0013), except that there was no difference for CSF T-tau between Aβ+ with milder cognitive deficits or dementia.”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > RESULTS > CSF tau proteins and Tau PET retention are elevated in different stages of AD
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“A large group of Aβ+ CU were positive for CSF tau biomarkers (ranging from 22% for CSF T-tau to 70% for CSF P-tau217; Table 1), but only one Aβ+ CU was positive for Tau PET [in inferior temporal cortex (ITC)].”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > RESULTS > CSF tau proteins and Tau PET retention are elevated in different stages of AD
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Tau PET measures increased at 18F-flutemetamol 0.772 (ITC) or 0.859 SUVR (Braak V–VI; Fig. 3, D and E).”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > RESULTS > CSF tau starts to increase in early stages of Aβ accumulation, but Tau PET increases when Aβ accumulation is already manifest
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: Global cortical 18F-flutemetamol Amyloid PET represents Aβ fibrillar plaque load.
- Rests on an assumption: Tau PET represents PHF-tau.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In sum, CSF Tau368 levels were slightly increased in Aβ+ individuals with mild cognitive deficits or AD dementia, but Tau368 levels were not significantly increased in Aβ+ CU compared with Aβ− CU, and there were no clear correlations between Tau368 and Tau PET uptake (fig. S7, A to C).”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > RESULTS > CSF levels of truncated tau
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: Tau PET represents PHF-tau.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The ratios also increased over time in Aβ+ CU, and spline models indicated that they started to increase before Amyloid PET became positive (fig. S5).”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > RESULTS > CSF P-tau/T-tau ratios are increased early and continue to increase as tau accumulates
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: Global cortical 18F-flutemetamol Amyloid PET represents Aβ fibrillar plaque load.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“When using T-tau instead, the mediation was more modest (41% mediation), and Amyloid PET retained an independent association with Tau PET.”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > RESULTS > CSF tau statistically mediates the association between Amyloid PET and Tau PET
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: Global cortical 18F-flutemetamol Amyloid PET represents Aβ fibrillar plaque load.
- Rests on an assumption: Tau PET represents PHF-tau.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We confirmed this hypothesis in a set of 12 MAPT mutation carriers (eight with cognitive impairment and four CU controls), where all 12 had normal levels of CSF P-tau, and 10 of 12 had normal levels of CSF T-tau (fig. S1).”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > RESULTS > CSF tau is not increased in MAPT mutation carriers, even with tau pathology
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Furthermore, the increase in Tau PET as a function of 18F-flutemetamol was only seen in individuals with high CSF P-tau levels, but not in individuals with low CSF P-tau (Fig. 3, H and I).”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > RESULTS > CSF tau starts to increase in early stages of Aβ accumulation, but Tau PET increases when Aβ accumulation is already manifest
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: Global cortical 18F-flutemetamol Amyloid PET represents Aβ fibrillar plaque load.
- Rests on an assumption: Tau PET represents PHF-tau.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“CSF P-tau217, P-tau181, and T-tau started to increase already at 18F-flutemetamol 0.679 SUVR [95% confidence interval (CI), 0.671 to 0.695], 0.684 SUVR (95% CI, 0.675 to 0.703), and 0.695 SUVR (95% CI, 0.682 to 0.721), respectively”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > RESULTS > CSF tau starts to increase in early stages of Aβ accumulation, but Tau PET increases when Aβ accumulation is already manifest
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: Global cortical 18F-flutemetamol Amyloid PET represents Aβ fibrillar plaque load.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“but isolated CSF P-tau positivity was also seen in several cases (28.2 to 51.1%). Isolated Tau PET positivity was very rare (0.8 to 3.1%).”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > RESULTS > CSF P-tau positivity without Tau PET positivity is common in early stages of AD
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Among the Aβ+ CU, 18 (56.3%) were positive for CSF P-tau217, 8 (25.0%) for CSF P-tau181, and 3 (9.4%) for CSF T-tau in the early sample.”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > RESULTS > CSF P-tau is often positive even several years before a negative Tau PET scan
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These ratios were also changed in Aβ+ CU and were often positive in individuals with negative Tau PET (but the opposite, a positive Tau PET with a negative CSF P-tau/T-tau ratio, was only seen in one individual, for P-tau181/T-tau; fig. S4).”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > RESULTS > CSF P-tau/T-tau ratios are increased early and continue to increase as tau accumulates
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In contrast to CSF tau, Tau PET increases occurred well into the phase of Amyloid PET positivity and only in individuals who also had increased CSF P-tau levels.”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: Global cortical 18F-flutemetamol Amyloid PET represents Aβ fibrillar plaque load.
- Rests on an assumption: Tau PET represents PHF-tau.
In the paper
“CSF T-tau levels (we did not measure CSF P-tau since, to our knowledge, there is no assay available to measure P-tau in the CSF of mice) started to increase slightly after extracellular Aβ plaques start to accumulate, and then continued to increase as the Aβ pathology progressed, despite a lack of formation of PHF-tau in these mice (25).”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > DISCUSSION
What the sources say
- Not checked yetcites [25] Oakley H., Cole S. L., Logan S., Maus E., Shao P., Craft J., Guillozet-Bongaarts A., Ohno M., Disterhoft J., Van Eldik L., Berry R., Vassar R., Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: potential factors in amyloid plaque formation. J. Neurosci. 26, 10129– 10140 (2006). 17021169 PMC6674618 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: The 5xFAD mouse model recapitulates aspects of Aβ-induced tau changes relevant to human AD.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This is also in line with our findings that Tau PET, but not CSF tau, predicted longitudinal cognitive decline”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Furthermore, baseline CSF tau (but not baseline Tau PET) predicted future increases in Tau PET in people with cognitive impairment.”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: Tau PET represents PHF-tau.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Although changes in T-tau were also seen early, P-tau (especially P-tau217) more strongly mediated the effect of Amyloid PET on Tau PET and was more clearly altered in the earliest stages of the disease (in Aβ+ CU several years before a negative Tau PET scan).”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“but correlations between in vivo CSF tau biomarkers and tau aggregates in postmortem tissue are weaker (11).”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > INTRODUCTION
What the sources say
- Not checked yetcites [11] Buerger K., Ewers M., Pirttila T., Zinkowski R., Alafuzoff I., Teipel S. J., DeBernardis J., Kerkman D., McCulloch C., Soininen H., Hampel H., CSF phosphorylated tau protein correlates with neocortical neurofibrillary pathology in Alzheimer’s disease. Brain 129, 3035– 3041 (2006). 17012293 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“Cell and animal experiments have verified that Aβ may induce pathologically relevant alterations in neuronal tau, including increased phosphorylation and release of tau (4, 5).”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > INTRODUCTION
What the sources say
- Not checked yetcites [4] Stancu I.-C., Vasconcelos B., Terwel D., Dewachter I., Models of β-amyloid induced Tau-pathology: The long and “folded” road to understand the mechanism. Mol. Neurodegener. 9, 51 (2014). 25407337 PMC4255655 source
- Not checked yetcites [5] Maia L. F., Kaeser S. A., Reichwald J., Hruscha M., Martus P., Staufenbiel M., Jucker M., Changes in amyloid-β and Tau in the cerebrospinal fluid of transgenic mice overexpressing amyloid precursor protein. Sci. Transl. Med. 5, 194re2 (2013). 23863834 source
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Accumulation of Aβ fibrils is thought to be an initiating factor in AD and necessary for the formation of tau aggregates (1).”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > INTRODUCTION
What the sources say
- Not checked yetcites [1] Goedert M., Tau filaments in neurodegenerative diseases. FEBS Lett. 592, 2383– 2391 (2018). 29790176 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
In the paper
“Neuropathological studies have shown that Tau PET correlates strongly to NFT and neuropil threads in the brain (10)”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > INTRODUCTION
What the sources say
- Not checked yetcites [10] Smith R., Wibom M., Pawlik D., Englund E., Hansson O., Correlation of in vivo [18F]Flortaucipir with postmortem alzheimer disease tau pathology. JAMA Neurol. 76, 310– 317 (2018). PMC6439731 30508025 source
Strength:boosted· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Cognitive measures (15, 16) and atrophy (15) are more strongly related to Tau PET than to CSF tau biomarkers.”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > INTRODUCTION
What the sources say
- Not checked yetcites [15] Mattsson N., Schöll M., Strandberg O., Smith R., Palmqvist S., Insel P. S., Hägerström D., Ohlsson T., Zetterberg H., Jögi J., Blennow K., Hansson O., 18F-AV-1451 and CSF T-tau and P-tau as biomarkers in Alzheimer’s disease. EMBO Mol. Med. 9, 1212– 1223 (2017). 28743782 PMC5582410 source
- Not checked yetcites [16] La Joie R., Bejanin A., Fagan A. M., Ayakta N., Baker S. L., Bourakova V., Boxer A. L., Cha J., Karydas A., Jerome G., Maass A., Mensing A., Miller Z. A., O’Neil J. P., Pham J., Rosen H. J., Tsai R., Visani A. V., Miller B. L., Jagust W. J., Rabinovici G. D., Associations between [18F]AV1451 tau PET and CSF measures of tau pathology in a clinical sample. Neurology 90, e282– e290 (2018). 29282337 PMC5798657
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“For example, transgenic animal experiments have shown that Aβ aggregates are associated with increased levels of soluble tau and increased tau phosphorylation (5, 6).”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > INTRODUCTION
What the sources say
- Not checked yetcites [5] Maia L. F., Kaeser S. A., Reichwald J., Hruscha M., Martus P., Staufenbiel M., Jucker M., Changes in amyloid-β and Tau in the cerebrospinal fluid of transgenic mice overexpressing amyloid precursor protein. Sci. Transl. Med. 5, 194re2 (2013). 23863834 source
- Not checked yetcites [6] Jin M., Shepardson N., Yang T., Chen G., Walsh D., Selkoe D. J., Soluble amyloid β-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration. Proc. Natl. Acad. Sci. U.S.A. 108, 5819– 5824 (2011). 21421841 PMC3078381
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“These previous studies suggest that CSF tau biomarkers and Tau PET reflect different aspects of tau pathology and may become abnormal at different stages of the disease.”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > INTRODUCTION
What the sources say
- Not checked yetcites [12] Brier M. R., Gordon B., Friedrichsen K., McCarthy J., Stern A., Christensen J., Owen C., Aldea P., Su Y., Hassenstab J., Cairns N. J., Holtzman D. M., Fagan A. M., Morris J. C., Benzinger T. L. S., Ances B. M., Tau and Aβ imaging, CSF measures, and cognition in Alzheimer’s disease. Sci. Transl. Med. 8, 338ra66 (2016). PMC5267531 27169802 source
- Not checked yetcites [13] Chhatwal J. P., Schultz A. P., Marshall G. A., Boot B., Gomez-Isla T., Dumurgier J., LaPoint M., Scherzer C., Roe A. D., Hyman B. T., Sperling R. A., Johnson K. A., Temporal T807 binding correlates with CSF tau and phospho-tau in normal elderly. Neurology 87, 920– 926 (2016). 27473132 PMC5035159 source
- Not checked yetcites [14] Gordon B. A., Friedrichsen K., Brier M., Blazey T., Su Y., Christensen J., Aldea P., McConathy J., Holtzman D. M., Cairns N. J., Morris J. C., Fagan A. M., Ances B. M., Benzinger T. L. S., The relationship between cerebrospinal fluid markers of Alzheimer pathology and positron emission tomography tau imaging. Brain 139, 2249– 2260 (2016). 27286736 PMC4958902
- Not checked yetcites [15] Mattsson N., Schöll M., Strandberg O., Smith R., Palmqvist S., Insel P. S., Hägerström D., Ohlsson T., Zetterberg H., Jögi J., Blennow K., Hansson O., 18F-AV-1451 and CSF T-tau and P-tau as biomarkers in Alzheimer’s disease. EMBO Mol. Med. 9, 1212– 1223 (2017). 28743782 PMC5582410 source
- Not checked yetcites [16] La Joie R., Bejanin A., Fagan A. M., Ayakta N., Baker S. L., Bourakova V., Boxer A. L., Cha J., Karydas A., Jerome G., Maass A., Mensing A., Miller Z. A., O’Neil J. P., Pham J., Rosen H. J., Tsai R., Visani A. V., Miller B. L., Jagust W. J., Rabinovici G. D., Associations between [18F]AV1451 tau PET and CSF measures of tau pathology in a clinical sample. Neurology 90, e282– e290 (2018). 29282337 PMC5798657
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These results demonstrate that CSF tau protein levels and phosphorylation are increased already in Aβ+ CU (in up to 70% of individuals for CSF P-tau217), a stage of the disease when insoluble PHF-tau deposition is rarely detected on Tau PET.”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > RESULTS > CSF tau proteins and Tau PET retention are elevated in different stages of AD
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Studies comparing CSF tau biomarkers with Tau PET have found that they are only moderately correlated, with the strongest correlations in symptomatic stages of AD, and no or weak correlations in cognitively unimpaired (CU) individuals (12–16).”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > INTRODUCTION
What the sources say
- Not checked yetcites [12] Brier M. R., Gordon B., Friedrichsen K., McCarthy J., Stern A., Christensen J., Owen C., Aldea P., Su Y., Hassenstab J., Cairns N. J., Holtzman D. M., Fagan A. M., Morris J. C., Benzinger T. L. S., Ances B. M., Tau and Aβ imaging, CSF measures, and cognition in Alzheimer’s disease. Sci. Transl. Med. 8, 338ra66 (2016). PMC5267531 27169802 source
- Not checked yetcites [13] Chhatwal J. P., Schultz A. P., Marshall G. A., Boot B., Gomez-Isla T., Dumurgier J., LaPoint M., Scherzer C., Roe A. D., Hyman B. T., Sperling R. A., Johnson K. A., Temporal T807 binding correlates with CSF tau and phospho-tau in normal elderly. Neurology 87, 920– 926 (2016). 27473132 PMC5035159 source
- Not checked yetcites [14] Gordon B. A., Friedrichsen K., Brier M., Blazey T., Su Y., Christensen J., Aldea P., McConathy J., Holtzman D. M., Cairns N. J., Morris J. C., Fagan A. M., Ances B. M., Benzinger T. L. S., The relationship between cerebrospinal fluid markers of Alzheimer pathology and positron emission tomography tau imaging. Brain 139, 2249– 2260 (2016). 27286736 PMC4958902
- Not checked yetcites [15] Mattsson N., Schöll M., Strandberg O., Smith R., Palmqvist S., Insel P. S., Hägerström D., Ohlsson T., Zetterberg H., Jögi J., Blennow K., Hansson O., 18F-AV-1451 and CSF T-tau and P-tau as biomarkers in Alzheimer’s disease. EMBO Mol. Med. 9, 1212– 1223 (2017). 28743782 PMC5582410 source
- Not checked yetcites [16] La Joie R., Bejanin A., Fagan A. M., Ayakta N., Baker S. L., Bourakova V., Boxer A. L., Cha J., Karydas A., Jerome G., Maass A., Mensing A., Miller Z. A., O’Neil J. P., Pham J., Rosen H. J., Tsai R., Visani A. V., Miller B. L., Jagust W. J., Rabinovici G. D., Associations between [18F]AV1451 tau PET and CSF measures of tau pathology in a clinical sample. Neurology 90, e282– e290 (2018). 29282337 PMC5798657
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“In AD, tau becomes truncated and hyperphosphorylated (3), which can increase the risk for tau to aggregate into the paired helical filaments (PHF) that are found in neurofibrillary tangles (NFT) and neuropil treads in the brains of patients with AD (1).”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > INTRODUCTION
What the sources say
- Not checked yetcites [3] Cicognola C., Brinkmalm G., Wahlgren J., Portelius E., Gobom J., Cullen N. C., Hansson O., Parnetti L., Constantinescu R., Wildsmith K., Chen H.-H., Beach T. G., Lashley T., Zetterberg H., Blennow K., Höglund K., Novel tau fragments in cerebrospinal fluid: Relation to tangle pathology and cognitive decline in Alzheimer’s disease. Acta Neuropathol. 137, 279– 296 (2019). 30547227 PMC6514201 source
- Not checked yetcites [1] Goedert M., Tau filaments in neurodegenerative diseases. FEBS Lett. 592, 2383– 2391 (2018). 29790176 source
Strength:plain· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Together, these results show that the P-tau217/T-tau and P-tau181/T-tau ratios increase before Tau PET and may link Aβ pathology to deposition of PHF-tau.”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > RESULTS > CSF P-tau/T-tau ratios are increased early and continue to increase as tau accumulates
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: Global cortical 18F-flutemetamol Amyloid PET represents Aβ fibrillar plaque load.
- Rests on an assumption: Tau PET represents PHF-tau.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In contrast, CSF tau levels increase in the presence of Aβ, but do not directly reflect an injury process leading to cognitive decline.”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > RESULTS > Tau PET, but not CSF tau, predicts cognitive impairment
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This suggests that Aβ pathology leads to increased neuronal phosphorylation and release of tau, which seems necessary for the formation of tau deposits.”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: The 5xFAD transgenic mouse model's CSF tau changes in response to Aβ pathology are informative about the human relationship between Aβ pathology and soluble tau.
- Rests on an assumption: Global cortical 18F-flutemetamol Amyloid PET represents Aβ fibrillar plaque load.
- Rests on an assumption: Tau PET represents PHF-tau.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“To our knowledge, this is the first study to demonstrate directly in humans that early Aβ pathology is associated with marked changes in levels and phosphorylation of tau, before deposition of PHF-tau is detected with Tau PET imaging, and that changes in soluble tau mediate the effects of Aβ pathology on downstream deposition of tau aggregates.”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: Global cortical 18F-flutemetamol Amyloid PET represents Aβ fibrillar plaque load.
- Rests on an assumption: Tau PET represents PHF-tau.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Slope differences were tested in linear regression models, adjusted for age, sex, and time span between the two lumbar punctures.”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > RESULTS > Longitudinal CSF tau levels increase in preclinical AD before Tau PET becomes positive
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These results show that CSF P-tau markers (especially P-tau217) not only start to increase but also, in many cases, reach clearly abnormal levels several years before PHF-tau deposition can be detected by Tau PET.”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > RESULTS > CSF P-tau is often positive even several years before a negative Tau PET scan
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This study presents converging results from human individuals in asymptomatic and symptomatic stages of AD, and from an AD mouse model (5xFAD) that increased release and phosphorylation of tau occur in response to fibrillar Aβ deposition, and that these alterations in tau metabolism link the accumulation of Aβ plaques to deposition of PHF-tau as seen by Tau PET in humans, but with a delay of”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: The 5xFAD transgenic mouse model's CSF tau changes in response to Aβ pathology are informative about the human relationship between Aβ pathology and soluble tau.
- Rests on an assumption: Global cortical 18F-flutemetamol Amyloid PET represents Aβ fibrillar plaque load.
- Rests on an assumption: Tau PET represents PHF-tau.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Together, these results support a model where Aβ pathology induces a change in brain metabolism of tau, including increased release and phosphorylation of tau at amino acid residues 217 and 181, where phosphorylation at position 217 may be a more pronounced early change, which later leads to accumulation of tau aggregates.”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: CSF concentrations of tau proteins reflect tau metabolism in the brain.
In the paper
“a recent mass spectrometry–based study found increased degree of phosphorylation at position 217 compared with position 181 in CSF from patients with AD (9).”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > DISCUSSION
What the sources say
- Not checked yetcites [9] Barthélemy N. R., Mallipeddi N., Moiseyev P., Sato C., Bateman R. J., Tau phosphorylation rates measured by mass spectrometry differ in the intracellular brain vs. extracellular cerebrospinal fluid compartments and are differentially affected by alzheimer’s disease. Front. Aging Neurosci. 11, 121 (2019). 31178717 PMC6537657 source
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These findings strengthen the amyloid cascade hypothesis and demonstrate in humans with sporadic (non–autosomal dominant) forms of AD that metabolism of soluble tau is altered in the presence of Aβ, and that this foreshadows significant tau deposition by several years.”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: Global cortical 18F-flutemetamol Amyloid PET represents Aβ fibrillar plaque load.
- Rests on an assumption: Tau PET represents PHF-tau.
In the paper
“A recently presented framework for AD research (the “ATN” framework) has suggested that Tau PET and CSF P-tau can be used to define tau pathology (“T”), while CSF T-tau can be used to define neurodegeneration (“N”) in AD (18).”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > DISCUSSION
What the sources say
- Not checked yetcites [18] Jack C. R. Jr., Bennett D. A., Blennow K., Carrillo M. C., Dunn B., Haeberlein S. B., Holtzman D. M., Jagust W., Jessen F., Karlawish J., Liu E., Molinuevo J. L., Montine T., Phelps C., Rankin K. P., Rowe C. C., Scheltens P., Siemers E., Snyder H. M., Sperling R., Contributors, NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 14, 535– 562 (2018). 29653606 PMC5958625 source
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“not only CSF P-tau217 but also P-tau181 may be increased very early (in preclinical stages) and then reach a plateau [and in very late stages, perhaps even a decrease, as has also been suggested by findings from autosomal dominant AD (35)].”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > DISCUSSION
What the sources say
- Not checked yetcites [35] McDade E., Wang G., Gordon B. A., Hassenstab J., Benzinger T. L. S., Buckles V., Fagan A. M., Holtzman D. M., Cairns N. J., Goate A. M., Marcus D. S., Morris J. C., Paumier K., Xiong C., Allegri R., Berman S. B., Klunk W., Noble J., Ringman J., Ghetti B., Farlow M., Sperling R. A., Chhatwal J., Salloway S., Graff-Radford N. R., Schofield P. R., Masters C., Rossor M. N., Fox N. C., Levin J., Jucker M., Bateman R. J.; Dominantly inherited alzheimer network, Longitudinal cognitive and biomarker changes in dominantly inherited alzheimer disease. Neurology 91, e1295– e1306 (2018). 30217935 PMC61772 source
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“Tau PET may continue to increase throughout the disease course, which gives it a very high diagnostic accuracy during the later stage of the disease (36).”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > DISCUSSION
What the sources say
- Not checked yetcites [36] Ossenkoppele R., Rabinovici G. D., Smith R., Cho H., Schöll M., Strandberg O., Palmqvist S., Mattsson N., Janelidze S., Santillo A., Ohlsson T., Jögi J., Tsai R., La Joie R., Kramer J., Boxer A. L., Gorno-Tempini M. L., Miller B. L., Choi J. Y., Ryu Y. H., Lyoo C. H., Hansson O., Discriminative accuracy of [18F]flortaucipir positron emission tomography for alzheimer disease vs other neurodegenerative disorders. JAMA 320, 1151– 1162 (2018). 30326496 PMC6233630 source
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“The first tau deposits that are initiated by Aβ may occur in dystrophic neurites surrounding the Aβ plaques, with the formation of widespread tangle pathology coming later (29), potentially spreading through functionally connected neurons.”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > DISCUSSION
What the sources say
- Not checked yetcites [29] He Z., Guo J. L., McBride J. D., Narasimhan S., Kim H., Changolkar L., Zhang B., Gathagan R. J., Yue C., Dengler C., Stieber A., Nitla M., Coulter D. A., Abel T., Brunden K. R., Trojanowski J. Q., Lee V. M.-Y., Amyloid-β plaques enhance Alzheimer’s brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation. Nat. Med. 24, 29– 38 (2018). 29200205 PMC5760353 source
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“comparisons of in vivo Tau PET versus neuropathology data have shown good correlations between Tau PET signal and tau neuropathology quantifications, although we note that individuals in those studies had substantial tau accumulation (10).”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > DISCUSSION
What the sources say
- Not checked yetcites [10] Smith R., Wibom M., Pawlik D., Englund E., Hansson O., Correlation of in vivo [18F]Flortaucipir with postmortem alzheimer disease tau pathology. JAMA Neurol. 76, 310– 317 (2018). PMC6439731 30508025 source
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“changes in CSF P-tau217 and P-tau181 would indicate “disease state,” i.e., the presence of a pathological process associated with AD from very early on in the disease, while the continuous increase in Tau PET [and the strong correlations between Tau PET and atrophy and cognitive decline; (39)] would make Tau PET a marker of “disease stage” throughout the symptomatic phases of AD.”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > DISCUSSION
What the sources say
- Not checked yetcites [38] Blennow K., Hampel H., CSF markers for incipient Alzheimer’s disease. Lancet Neurol. 2, 605– 613 (2003). 14505582 source
- Not checked yetcites [39] Mattsson N., Insel P. S., Donohue M., Jögi J., Ossenkoppele R., Olsson T., Schöll M., Smith R., Hansson O., Predicting diagnosis and cognition with 18F-AV-1451 tau PET and structural MRI in Alzheimer’s disease. Alzheimers Dement. 15, 570– 580 (2019). 30639421 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“T-tau levels may be increased also in other conditions with brain injury without tau aggregation (17).”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > DISCUSSION
What the sources say
- Not checked yetcites [17] Hesse C., Rosengren L., Vanmechelen E., Vanderstichele H., Jensen C., Davidsson P., Blennow K., Cerebrospinal fluid markers for Alzheimer’s disease evaluated after acute ischemic stroke. J. Alzheimers Dis. 2, 199– 206 (2000). 12214084
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The change in soluble tau metabolism (including hyperphosphorylation) is a link between the accumulation of Aβ and the widespread deposition of insoluble tau aggregates detectable by Tau PET imaging, with the latter following several years after detection of the first changes in soluble tau.”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: CSF concentrations of tau proteins reflect tau metabolism in the brain.
- Rests on an assumption: Aβ status defined by the CSF Aβ42/Aβ40 ratio reflects brain Aβ pathology.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Limitations of the study include the lack of neuropathology to verify the correlations between the different tau measures and neuropathological changes in the brain.”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > DISCUSSION
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Another limitation was that the longitudinal part of the study was relatively small and differed between CSF and Tau PET measures.”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > DISCUSSION
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“The CSF Aβ42/Aβ40 ratio (using EUROIMMUN data) was used to define Aβ status, with a previously defined cut point (<0.1) to define positivity (42).”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > MATERIALS AND METHODS > CSF biomarkers
What the sources say
- Not checked yetcites [42] Janelidze S., Zetterberg H., Mattsson N., Palmqvist S., Vanderstichele H., Lindberg O., van Westen D., Stomrud E., Minthon L., Blennow K.; Swedish BioFINDER study group, Hansson O., CSF Aβ42/Aβ40 and Aβ42/Aβ38 ratios: Better diagnostic markers of Alzheimer disease. Ann. Clin. Transl. Neurol. 3, 154– 165 (2016). 27042676 PMC4774260 source
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our results therefore support that Aβ aggregation leads to both increased tau release (as shown in both the human individuals and the mouse model data) and phosphorylation, but it is primarily the altered tau hyperphosphorylation that is associated with the deposition of tau aggregates in humans.”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“A cut point for this global uptake was defined in a cohort of 428 BioFINDER participants using mixture modeling analysis as described elsewhere (SUVR 0.743; Mattsson, Leuzy et al., in press, Neurology).”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > MATERIALS AND METHODS > 18F-Flutemetamol PET imaging
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Analyses were done using a priori defined ROIs.”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > MATERIALS AND METHODS > 18F-flortaucipir PET imaging
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All regression models were adjusted for age, sex, and (when appropriate) the time-lag between lumbar puncture and Tau PET scan.”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > MATERIALS AND METHODS > Statistics
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“We defined cut points for tau biomarkers based on the mean levels plus two SDs of the respective biomarker in independent cohorts of Aβ− CU.”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > MATERIALS AND METHODS > Cut points
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Post hoc analysis for group comparisons between the youngest group and all other groups was performed using the Mann-Whitney U test, and corrected for multiple comparisons using the Bonferroni method.”
§ Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease > MATERIALS AND METHODS > Statistics
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
Only limited data exist from humans on the temporal relationships between development of Aβ plaques and altered release, phosphorylation, and aggregation of tau.
“but only limited data exist from humans on the temporal relationships between development of Aβ plaques and altered release, phosphorylation, and aggregation of tau.”
The paper relies on this without support.
The 5xFAD transgenic mouse model's CSF tau changes in response to Aβ pathology are informative about the human relationship between Aβ pathology and soluble tau.
“To corroborate the findings from humans, we studied changes in CSF tau in a transgenic mice model of AD (5xFAD).”
The paper relies on this without support.
Global cortical 18F-flutemetamol Amyloid PET represents Aβ fibrillar plaque load.
“continuous 18F-flutemetamol (Amyloid) PET (representing Aβ fibrillar plaque load; Fig. 3)”
The paper relies on this without support.
Tau PET represents PHF-tau.
“Tau PET (representing PHF-tau)”
The paper relies on this without support.
CSF concentrations of tau proteins reflect tau metabolism in the brain.
“To conclude, the CSF levels of tau proteins, especially P-tau217 and P-tau181, are increased in response to Aβ deposition in humans in early stages of AD.”
The paper relies on this without support.
The 5xFAD mouse model recapitulates aspects of Aβ-induced tau changes relevant to human AD.
“Some of the findings from humans could be translated back to 5xFAD mice”
The paper relies on this without support.
Aβ status defined by the CSF Aβ42/Aβ40 ratio reflects brain Aβ pathology.
“The CSF Aβ42/Aβ40 ratio (using EUROIMMUN data) was used to define Aβ status, with a previously defined cut point (<0.1) to define positivity (42).”
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 cited source says what the claim attributes to it.
In the citing paper
“Increases in CSF p-tau occur before both tau PET20,63,64 and established measures of neuronal death (e.g., neurofilament light, magnetic resonance imaging or [18F]FDG PET), thus CSF p-tau cannot merely reflect NFT leakage from dying neurons.”
From Cerebrospinal fluid p-tau231 as an early indicator of emerging pathology in Alzheimer's disease (2022) · cites this paper as [63]
In the citing paper
“The current in-vivo detection of tau positivity using 18F-flortaucipir PET seems to correspond only to widespread tau pathology in the brain (ie, Braak stages ≥IV),69 whereas CSF phosphorylated tau elevation can reflect earlier stages of tauopathy.70”
From Clinical diagnosis of Alzheimer’s disease: Recommendations of the International Working Group (2021) · cites this paper as [70]
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Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Longitudinal CSF statistical comparison is cited as Fig. 3 instead of Fig. 2
MinorThe text directs readers to Fig. 3 for the adjusted comparison of longitudinal CSF tau changes, but the Fig. 2 caption reports that comparison. Fig. 3 instead concerns tau measures in relation to Amyloid PET load.
“(see Fig. 3 for statistical comparison, adjusted for covariates)”
“Figure: Fig. 2 Longitudinal changes in CSF tau biomarkers. Longitudinal CSF P-tau217 (A and D), P-tau181 (B and E), and T-tau (C and F) in CU individuals with an additional early sample, preceding the main CSF sample. Slope differences were tested in linear regression models, adjusted for age, sex, and time span between the two lumbar punctures.”
Mouse CSF tau increase is cited to the wrong Fig. 5 panel
MinorThe text cites Fig. 5A for the increase in CSF tau at 4 months, but the figure caption identifies panel A as plaque staining and panel B as the CSF T-tau measurements.
“In this model, we observed clear increases in CSF tau already at 4 months of age (Fig. 5A).”
“(B) CSF T-tau concentrations in 5xFAD mice were significantly higher than those in nontransgenic littermates at 4, 6, and 12 months of age (Mann-Whitney U test; **P < 0.05 and ***P < 0.001).”
Citations
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Self-citationBlood‐based biomarkers for Alzheimer's disease
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“Although CSF p-tau181 is an highly accurate diagnostic biomarker for AD, tau PET better reflects the degree of NFT pathology [42] and is a superior diagnostic tool for AD [35].”
Self-citationBlood phospho-tau in Alzheimer disease: analysis, interpretation, and clinical utility
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Self-citationDeveloping the ATX(N) classification for use across the Alzheimer disease continuum
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Self-citationChallenges and hopes for Alzheimer’s disease
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Self-citationRole of tau protein in Alzheimer’s disease: The prime pathological player
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Self-citationSoluble P‐tau217 reflects amyloid and tau pathology and mediates the association of amyloid with tau
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“Additional valuable information could come from Ab overproducing mouse models that do not develop tau tangles, to characterize the extent to which Ab could promote tau secretion even in the absence of subsequent tau tangle deposition (Maia et al, 2015; Mattsson-Carlgren et al, 2020).”
BackgroundResultInfluentialSelf-citationCSF MTBR-tau243 is a specific biomarker of tau tangle pathology in Alzheimer’s disease
Horie, K., Salvadó, G., Barthélemy, N. R., Janelidze, S., Li, Y., He, Y., Saef, B., Chen, C. D., Jiang, H., Strandberg, O., et al. (2023) · Nature Medicine · doi:10.1038/s41591-023-02443-z · Cited by 249
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Self-citationTime course of phosphorylated-tau181 in blood across the Alzheimer’s disease spectrum
Moscoso, A., Grothe, M. J., Ashton, N. J., Karikari, T. K., Rodriguez, J. L., Snellman, A., Suárez-Calvet, M., Zetterberg, H., Blennow, K., Schöll, M., et al. (2021) · Brain · doi:10.1093/brain/awaa399 · Cited by 229
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Self-citationMEG3 activates necroptosis in human neuron xenografts modeling Alzheimer’s disease
Balusu, S., Horré, K., Thrupp, N., Craessaerts, K., Snellinx, A., Serneels, L., T’Syen, D., Chrysidou, I., Arranz, A. M., Sierksma, A. S. R., et al. (2023) · Science · doi:10.1126/science.abp9556 · Cited by 246
Self-citationUntangling the association of amyloid-β and tau with synaptic and axonal loss in Alzheimer’s disease
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Self-citationBiomarker-based staging of Alzheimer disease: rationale and clinical applications
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“63,96,123), become abnormal very early in AD and subsequently plateau, the use of single analytes might provide limited information regarding the severity of disease.”
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Self-citationCerebrospinal fluid p-tau231 as an early indicator of emerging pathology in Alzheimer's disease
Ashton, N. J., Benedet, A. L., Pascoal, T. A., Karikari, T. K., Lantero-Rodriguez, J., Brum, W. S., Mathotaarachchi, S., Therriault, J., Savard, M., Chamoun, M., et al. (2022) · eBioMedicine · doi:10.1016/j.ebiom.2022.103836 · Cited by 184
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Self-citationDissecting the clinical heterogeneity of early-onset Alzheimer’s disease
Sirkis, D. W., Bonham, L. W., Johnson, T. P., La Joie, R., & Yokoyama, J. S. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01531-9 · Cited by 151
Biomarker-Based Prediction of Longitudinal Tau Positron Emission Tomography in Alzheimer Disease
Leuzy, A., Smith, R., Cullen, N. C., Strandberg, O., Vogel, J. W., Binette, A. P., Borroni, E., Janelidze, S., Ohlsson, T., Jögi, J., et al. (2022) · JAMA Neurology · doi:10.1001/jamaneurol.2021.4654 · Cited by 149
Self-citationPlasma markers predict changes in amyloid, tau, atrophy and cognition in non-demented subjects
Pereira, J. B., Janelidze, S., Stomrud, E., Palmqvist, S., van Westen, D., Dage, J. L., Mattsson, N., & Hansson, O. (2021) · Brain · doi:10.1093/brain/awab163 · Cited by 147
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“In the discovery cohort, Aβ42, Mid-p-tau181, and total-tau were measured using the INNOTEST® β-AMYLOID(1-42), PHOSPHOTAU(181P), and hTAU Ag ELISAs.”
MethodSelf-citationRoles and Mechanisms of Gut Microbiota in Patients With Alzheimer’s Disease
Wu, S., Liu, X., Jiang, R., Yan, X., & Ling, Z. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.650047 · Cited by 150
“The neuropathological hallmarks of AD include the formation of senile plaques and neurofibrillary tangles in specific brain regions that lead to synaptic loss and neuronal death (Khan and Hegde, 2020; Mattsson-Carlgren et al., 2020; Konijnenberg et al., 2021).”
BackgroundAshton, N. J., Leuzy, A., Karikari, T. K., Mattsson-Carlgren, N., Dodich, A., Boccardi, M., Corre, J., Drzezga, A., Nordberg, A., Ossenkoppele, R., et al. (2021) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-021-05253-y · Cited by 142
Self-citationAlzheimer’s disease profiled by fluid and imaging markers: tau PET best predicts cognitive decline
Bucci, M., Chiotis, K., Nordberg, A., & Initiative, F. T. A. D. N. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01263-2 · Cited by 140
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Self-citationTauvid™: The First FDA-Approved PET Tracer for Imaging Tau Pathology in Alzheimer’s Disease
Jie, C. V. M. L., Treyer, V., Schibli, R., & Mu, L. (2021) · Pharmaceuticals · doi:10.3390/ph14020110 · Cited by 146
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“Altogether, these findings challenge the notion that the different tau biomarkers can be used interchangeably (Mattsson-Carlgren et al, 2020c).”
BackgroundInfluentialSelf-citationMattsson, N., Grinberg, L. T., Boxer, A. L., Ossenkoppele, R., Jonsson, M., Seeley, W., Ehrenberg, A. J., Spina, S., Janelidze, S., Rojas-Martinex, J., et al. (2022) · Neurology · doi:10.1212/wnl.0000000000200040 · Cited by 141
“Soluble P-tau may be increased in response to Aβ buildup as a first indicator of altered tau metabolism in individuals who are positive on Aβ PET but negative on tau PET.(46) However, we did not find that P-tau was altered in”
BackgroundSelf-citationMontoliu-Gaya, L., Benedet, A. L., Tissot, C., Vrillon, A., Ashton, N. J., Brum, W. S., Lantero-Rodriguez, J., Stevenson, J., Nilsson, J., Sauer, M., et al. (2023) · Nature Aging · doi:10.1038/s43587-023-00405-1 · Cited by 122
Self-citationLeuzy, A., Janelidze, S., Mattsson-Carlgren, N., Palmqvist, S., Jacobs, D., Cicognola, C., Stomrud, E., Vanmechelen, E., Dage, J. L., & Hansson, O. (2021) · Neurology · doi:10.1212/wnl.0000000000012727 · Cited by 128
Self-citationPlasma MTBR-tau243 biomarker identifies tau tangle pathology in Alzheimer’s disease
Horie, K., Salvadó, G., Koppisetti, R. K., Janelidze, S., Barthélemy, N. R., He, Y., Sato, C., Gordon, B. A., Jiang, H., Benzinger, T. L. S., et al. (2025) · Nature Medicine · doi:10.1038/s41591-025-03617-7 · Cited by 145
“For example, levels of CSF and plasma p-tau species are elevated in preclinical AD, many years before extensive insoluble tau aggregates are detectable in the cortex by tau-PET 17,18 .”
Self-citationDisease staging of Alzheimer’s disease using a CSF-based biomarker model
Salvadó, G., Horie, K., Barthélemy, N. R., Vogel, J. W., Binette, A. P., Chen, C. D., Aschenbrenner, A. J., Gordon, B. A., Benzinger, T. L. S., Holtzman, D. M., et al. (2024) · Nature Aging · doi:10.1038/s43587-024-00599-y · Cited by 129
“…of soluble amyloid species (that is, low Aβ42/40) may drive hyper-phosphorylation of tau in early phosphorylation site (pT217/T217), as previously suggested by human and animal data 52,53 , which would subsequently be followed by hyper-phosphorylation in later site (pT205/T205) and eventually”
BackgroundSelf-citationThe informed road map to prevention of Alzheimer Disease: a call to arms
McDade, E., Llibre-Guerra, J. J., Holtzman, D. M., Morris, J. C., & Bateman, R. J. (2021) · Molecular Neurodegeneration · doi:10.1186/s13024-021-00467-y · Cited by 89
Tsiknia, A. A., Edland, S. D., Sundermann, E. E., Reas, E. T., Brewer, J. B., Galasko, D. R., Banks, S. J., & Initiative, A. D. N. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01675-8 · Cited by 98
“Prior studies have shown that plasma p-tau181 levels are associated with markers of Aβ pathology particularly in preclinical and prodromal AD, and demonstrate that these associations become weaker at advanced clinical stages [20, 41, 42].”
BackgroundThe dynamics of plasma biomarkers across the Alzheimer’s continuum
Guo, Y., Shen, X., Wang, H.-F., Chen, S.-D., Zhang, Y.-R., Chen, S., Cui, M., Cheng, W., Dong, Q., Ma, T., et al. (2023) · Alzheimer s Research & Therapy · doi:10.1186/s13195-023-01174-0 · Cited by 91
Longitudinal changes in Alzheimer's‐related plasma biomarkers and brain amyloid
Bilgel, M., An, Y., Walker, K. A., Moghekar, A., Ashton, N. J., Kac, P. R., Karikari, T. K., Blennow, K., Zetterberg, H., Jedynak, B., et al. (2023) · Alzheimer s & Dementia · doi:10.1002/alz.13157 · Cited by 89
Self-citationCurrent advances in plasma and cerebrospinal fluid biomarkers in Alzheimer's disease
Leuzy, A., Cullen, N. C., Mattsson, N., & Hansson, O. (2021) · Current Opinion in Neurology · doi:10.1097/wco.0000000000000904 · Cited by 91
Self-citationConsiderations in the clinical use of amyloid PET and CSF biomarkers for Alzheimer's disease
Leuzy, A., Bollack, A., Pellegrino, D., Teunissen, C. E., Joie, R. L., Rabinovici, G. D., Franzmeier, N., Johnson, K. A., Barkhof, F., Shaw, L. M. J., et al. (2025) · Alzheimer s & Dementia · doi:10.1002/alz.14528 · Cited by 109
Self-citationTiming of Biomarker Changes in Sporadic Alzheimer's Disease in Estimated Years from Symptom Onset
Li, Y., Yen, D., Hendrix, R. D., Gordon, B. A., Dlamini, S. L., Barthélemy, N. R., Aschenbrenner, A. J., Henson, R. L., Herries, E. M., Volluz, K., et al. (2024) · Annals of Neurology · doi:10.1002/ana.26891 · Cited by 90
Longitudinal blood biomarker trajectories in preclinical Alzheimer's disease
Yakoub, Y., Ashton, N. J., Strikwerda‐Brown, C., Montoliu‐Gaya, L., Karikari, T. K., Kac, P. R., González‐Ortiz, F., Gallego-Rudolf, J., Meyer, P., St‐Onge, F., et al. (2023) · Alzheimer s & Dementia · doi:10.1002/alz.13318 · Cited by 91
Self-citationPlasma p‐tau immunoassays in clinical research for Alzheimer's disease
Teunissen, C. E., Kolster, R., Triana‐Baltzer, G., Janelidze, S., Zetterberg, H., & Kolb, H. C. (2024) · Alzheimer s & Dementia · doi:10.1002/alz.14397 · Cited by 96
Self-citationDelgado‐Peraza, F., Nogueras‐Ortiz, C. J., Volpert, O. V., Liu, D., Goetzl, E. J., Mattson, M. P., Greig, N. H., Eitan, E., & Kapogiannis, D. (2021) · Cells · doi:10.3390/cells10050993 · Cited by 81
An overview of the genes and biomarkers in Alzheimer’s disease
Krishnamurthy, H. K., Jayaraman, V., Krishna, K., Wang, T., Bei, K., Changalath, C., & Rajasekaran, J. J. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102599 · Cited by 89
Iaccarino, L., Burnham, S. C., Dell’Agnello, G., Dowsett, S. A., & Epelbaum, S. (2023) · The Journal of Prevention of Alzheimer s Disease · doi:10.14283/jpad.2023.43 · Cited by 87
“Of note, CSF P-tau181 concentrations and tau PET findings are likely a reflection of different aspects of tau pathology in AD, with CSF P-tau181 likely indicative of the early response to Aβ and preceding detectable elevation through tau PET (88).”
BackgroundChen, L., Liu, W., Lin, H., Lin, M., Yu, Y., Liu, H., Dai, Y., Chen, L.-W., Jia, W., He, X., et al. (2022) · Neural Regeneration Research · doi:10.4103/1673-5374.335832 · Cited by 76
“Furthermore, molecular imaging by positron emission tomography revealed that Aβ burden and tau accumulation in clinical AD patients are greater than those in clinically normal controls (Mattsson-Carlgren et al., 2020; Milà-Alomà et al., 2020).”
Rabinovici, G. D., Knopman, D. S., Arbizu, J., Benzinger, T. L. S., Donohoe, K. J., Hansson, O., Herscovitch, P., Kuo, P. H., Lingler, J. H., Minoshima, S., et al. (2025) · Journal of Nuclear Medicine · doi:10.2967/jnumed.124.268756 · Cited by 84
Self-citationMoloney, C. M., Labuzan, S. A., Crook, J. E., Siddiqui, H., Castanedes‐Casey, M., Lachner, C., Petersen, R. C., Duara, R., Graff‐Radford, N. R., Dickson, D. W., et al. (2022) · Alzheimer s & Dementia · doi:10.1002/alz.12749 · Cited by 76
Shen, X., Huang, Y., Chen, S.-D., Guo, Y., Tan, L., Dong, Q., Yu, J., Initiative, A. D. N., Weiner, M. W., Aisen, P., et al. (2021) · Translational Psychiatry · doi:10.1038/s41398-021-01709-9 · Cited by 74
“Other cohorts also explored the differences of plasma tau measures by both clinical diagnosis and Aβ PET [10, 14, 27], but they lacked analysis stratified by clinical conversion and observed no statistical difference between the CU A+ and A− groups or the CU and MCI A+ groups [10].”
Leuzy, A., Ashton, N. J., Mattsson, N., Dodich, A., Boccardi, M., Corre, J., Drzezga, A. E., Nordberg, A. K., Ossenkoppele, R., Zetterberg, H., et al. (2021) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-021-05258-7 · Cited by 73
Self-citationd’Abramo, C., D'adamio, L., & Giliberto, L. (2020) · Journal of Personalized Medicine · doi:10.3390/jpm10030116 · Cited by 71
Guo, T., Korman, D., Joie, R. L., Shaw, L. M. J., Trojanowski, J. Q., Jagust, W. J., Landau, S. M., & Initiative, A. D. N. (2020) · Alzheimer s Research & Therapy · doi:10.1186/s13195-020-00665-8 · Cited by 67
“Finally, consistent with three recent reports [14, 15, 66], we found that tau PET was more predictive of subsequent cognitive decline than CSF tau among Aβ+ individuals, suggesting brain tau may reflect a later tau stage closer to cognitive decline than CSF tau on the Alzheimer’s continuum.”
BackgroundResultInfluentialRegional correlation of biochemical measures of amyloid and tau phosphorylation in the brain
Horie, K., Barthélemy, N. R., Mallipeddi, N., Li, Y., Franklin, E. E., Perrin, R. J., Bateman, R. J., & Sato, C. (2020) · Acta Neuropathologica Communications · doi:10.1186/s40478-020-01019-z · Cited by 62
Groot, C., Smith, R. A., Collij, L. E., Mastenbroek, S. E., Stomrud, E., Binette, A. P., Leuzy, A., Palmqvist, S., Mattsson, N., Strandberg, O. T., et al. (2024) · JAMA Neurology · doi:10.1001/jamaneurol.2024.1612 · Cited by 68
Self-citationSanchez, J. S., Hanseeuw, B. J., Lopera, F., Sperling, R. A., Baena, A., Bocanegra, Y., Aguillon, D., Guzmán-Vélez, E., Pardilla-Delgado, E., Ramirez-Gomez, L., et al. (2021) · Alzheimer's Research & Therapy · doi:10.1186/s13195-020-00765-5 · Cited by 58
Towards clinical application of tau PET tracers for diagnosing dementia due to Alzheimer's disease
Ossenkoppele, R., & Hansson, O. (2021) · Alzheimer's & Dementia · doi:10.1002/alz.12356 · Cited by 62
Self-citationCellular localization of p-tau217 in brain and its association with p-tau217 plasma levels
Wennström, M., Janelidze, S., Nilsson, K. P. R., Bank, T. N. B., Serrano, G. E., Beach, T. G., Dage, J. L., & Hansson, O. (2022) · Acta Neuropathologica Communications · doi:10.1186/s40478-021-01307-2 · Cited by 59
Self-citationA Head-to-Head Comparison Between Plasma pTau181 and Tau PET Along the Alzheimer’s Disease Continuum
Coomans, E. M., Verberk, I. M. W., Ossenkoppele, R., Verfaillie, S. C. J., Visser, D., Gouda, M., Tuncel, H., Wolters, E. E., Timmers, T., Windhorst, A. D., et al. (2022) · Journal of Nuclear Medicine · doi:10.2967/jnumed.122.264279 · Cited by 63
Self-citationBiofluid Biomarkers of Alzheimer’s Disease: Progress, Problems, and Perspectives
Huang, S., Wang, Y., & Guo, J. (2022) · Neuroscience Bulletin · doi:10.1007/s12264-022-00836-7 · Cited by 63
Tau‐PET is superior to phospho‐tau when predicting cognitive decline in symptomatic AD patients
Smith, R., Cullen, N. C., Pichet Binette, A., Leuzy, A., Blennow, K., Zetterberg, H., Klein, G., Borroni, E., Ossenkoppele, R., Janelidze, S., et al. (2023) · Alzheimer's & Dementia · doi:10.1002/alz.12875 · Cited by 60
Self-citationComparison of CSF phosphorylated tau 181 and 217 for cognitive decline
Mielke, M. M., Aakre, J. A., Algeciras‐Schimnich, A., Proctor, N. K., Machulda, M. M., Eichenlaub, U., Knopman, D. S., Vemuri, P., Graff‐Radford, J., Jack, C. R., et al. (2022) · Alzheimer's & Dementia · doi:10.1002/alz.12415 · Cited by 55
Self-citationMander, B. A., Dave, A., Lui, K. K., Sprecher, K. E., Berisha, D. E., Chappel-Farley, M. G., Chen, I. Y., Riedner, B. A., Heston, M. B., Suridjan, I., et al. (2022) · SLEEP · doi:10.1093/sleep/zsac135 · Cited by 62
Self-citationShin, J., Park, S., Lee, H., & Kim, Y. (2021) · Scientific Reports · doi:10.1038/s41598-021-81304-6 · Cited by 56
Neitzel, J., Franzmeier, N., Rubinski, A., Dichgans, M., Brendel, M., (ADNI), A. D. N. I., Weiner, M., Aisen, P., Petersen, R., Jack, C. R., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-23755-z · Cited by 57
Biel, D., Suárez‐Calvet, M., Hager, P., Rubinski, A., Dewenter, A., Steward, A., Roemer, S. N., Ewers, M., Haass, C., Brendel, M., et al. (2023) · EMBO Molecular Medicine · doi:10.15252/emmm.202216987 · Cited by 56
Mundada, N. S., Rojas, J. C., VandeVrede, L. A., Thijssen, E. H., Iaccarino, L., Okoye, O., Shankar, R. P., Soleimani‐Meigooni, D. N., Lago, A. L., Miller, B. L., et al. (2023) · Alzheimer s Research & Therapy · doi:10.1186/s13195-023-01302-w · Cited by 54
“This difference would affect the timing of when each bio-marker elevates in the AD pathophysiological process and explains why studies have shown that plasma p-tau concentrations elevate before tau-PET signal [11, 32].”
BackgroundSelf-citationAssociation of CSF Biomarkers With Hippocampal-Dependent Memory in Preclinical Alzheimer Disease
Trelle, A. N., Carr, V. A., Wilson, E. N., Swarovski, M. S., Hunt, M. P., Toueg, T. N., Tran, T., Channappa, D., Corso, N. K., Thieu, M. K., et al. (2021) · Neurology · doi:10.1212/wnl.0000000000011477 · Cited by 52
Insights into the use of biomarkers in clinical trials in Alzheimer's disease
Pascoal, T. A., Aguzzoli, C. S., Lussier, F. Z., Crivelli, L., Suemoto, C. K., Fortea, J., Rosa‐Neto, P., Zimmer, E. R., Ferreira, P. C. L., & Bellaver, B. (2024) · EBioMedicine · doi:10.1016/j.ebiom.2024.105322 · Cited by 60
“While individuals at an earlier stage may show abnormal tau phosphorylation in the absence of detectable tau PET abnormality, 37 later stages are characterised by the regional progression of tau PET accumulation.”
Moscoso, A., Karikari, T. K., Grothe, M. J., Ashton, N. J., Lantero‐Rodriguez, J., Snellman, A., Zetterberg, H., Blennow, K., & Schöll, M. (2022) · Alzheimer s & Dementia · doi:10.1002/alz.12570 · Cited by 50
Self-citationSalvadó, G., Grothe, M. J., Groot, C., Moscoso, A., Schöll, M., Gispert, J. D., Ossenkoppele, R., & Initiative, A. D. N. (2021) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-021-05192-8 · Cited by 57
“On the other hand, tau abnormalities might be detected earlier in CSF than on PET [50].”
BackgroundSelf-citationAssociation of amyloid-β CSF/PET discordance and tau load 5 years later
Reimand, J., Collij, L. E., Scheltens, P., Bouwman, F. H., Ossenkoppele, R., & Initiative, A. D. N. (2020) · Neurology · doi:10.1212/wnl.0000000000010739 · Cited by 50
Self-citationGroot, C., Smith, R. A., Stomrud, E., Binette, A. P., Leuzy, A., Wuestefeld, A., Wisse, L. E. M., Palmqvist, S., Mattsson, N., Janelidze, S., et al. (2022) · Brain · doi:10.1093/brain/awac329 · Cited by 53
“15,44 For tau-PET, neuropathology studies have revealed that it mainly reflects aggregated tau proteins into neuritic tau and neurofibrillary tangles, especially in the later stages of Alzheimer’s disease.”
InfluentialSelf-citationWang, Y., Therriault, J., Servaes, S., Tissot, C., Rahmouni, N., Macedo, A. C., Arias, J. F., Mathotaarachchi, S. S., Benedet, A. L., Stevenson, J., et al. (2023) · Brain · doi:10.1093/brain/awad397 · Cited by 53
“22 Levels of soluble p-tau have also been shown to correlate with neuropathological levels of NFTs, 23-25 and some evidence indicates that synergistic interaction between A β and p-tau predicts cognitive decline and progression to dementia.”
Self-citationErickson, P., Simrén, J., Brum, W. S., Ennis, G. E., Kollmorgen, G., Suridjan, I., Langhough, R. E., Jonaitis, E. M., Hulle, C. A. V., Betthauser, T. J., et al. (2023) · JAMA Neurology · doi:10.1001/jamaneurol.2023.2338 · Cited by 48
Self-citationMcFarland, K. N., & Chakrabarty, P. (2022) · Neurotherapeutics · doi:10.1007/s13311-021-01179-3 · Cited by 48
Dark, H. E., An, Y., Duggan, M. R., Joynes, C. M., Davatzikos, C. A., Erus, G., Lewis, A., Moghekar, A., Resnick, S. M., & Walker, K. A. (2024) · Alzheimer s Research & Therapy · doi:10.1186/s13195-024-01459-y · Cited by 52
“Increases in plasma NfL are thought to coincide with brain atrophy and occur after elevations in pTau-181, Aβ 42 , and GFAP [50, 52, 53].”
BackgroundWolters, E. E., Dodich, A., Boccardi, M., Corre, J., Drzezga, A. E., Hansson, O., Nordberg, A. K., Frisoni, G. B., Garibotto, V., & Ossenkoppele, R. (2021) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-020-05118-w · Cited by 48
Self-citationWhat’s the cut-point?: a systematic investigation of tau PET thresholding methods
Weigand, A. J., Maaß, A., Eglit, G. L., & Bondi, M. W. (2022) · Alzheimer s Research & Therapy · doi:10.1186/s13195-022-00986-w · Cited by 49
APOEε4 potentiates amyloid β effects on longitudinal tau pathology
Ferrari-Souza, J. P., Bellaver, B., Ferreira, P. C. L., Benedet, A. L., Povala, G., Lussier, F. Z., Leffa, D. T., Therriault, J., Tissot, C., Soares, C., et al. (2023) · Nature Aging · doi:10.1038/s43587-023-00490-2 · Cited by 43
Self-citationLantero‐Rodriguez, J., Salvadó, G., Snellman, A., Montoliu‐Gaya, L., Brum, W. S., Benedet, A. L., Mattsson, N., Tideman, P., Janelidze, S., Palmqvist, S., et al. (2024) · Molecular Neurodegeneration · doi:10.1186/s13024-024-00707-x · Cited by 43
Self-citationAlzheimer’s Disease Biomarkers Revisited From the Amyloid Cascade Hypothesis Standpoint
Alawode, D. O. T., Fox, N. C., Zetterberg, H., & Heslegrave, A. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.837390 · Cited by 41
Self-citationCharacterization of Alzheimer’s tau biomarker discordance using plasma, CSF, and PET
Initiative, T. A. D. N., Guo, Y., Huang, Y., Shen, X., Chen, S.-D., Hu, H., Wang, Z.-T., Tan, L., & Yu, J. (2021) · Alzheimer s Research & Therapy · doi:10.1186/s13195-021-00834-3 · Cited by 45
“” Synthesizing the findings in this study, together with previous literatures [33, 36], a model of biomarker trajectories in AD may therefore be updated (Fig.”
BackgroundResultInfluentialBiomarker A+T−: is this Alzheimer’s disease or not? A combined CSF and pathology study
Vromen, E. M., de Boer, S. C. M., Teunissen, C. E., Rozemüller, A. J. M., Sieben, A., Bjerke, M., Initiative, A. D. N., Visser, P. J., Bouwman, F. H., Engelborghs, S., et al. (2022) · Brain · doi:10.1093/brain/awac158 · Cited by 45
Metadata
- Authors
- Mattsson-Carlgren, N., Andersson, E., Janelidze, S., Ossenkoppele, R., Insel, P., Strandberg, O., Zetterberg, H., Rosen, H. J., Rabinovici, G., Chai, X., Blennow, K., Dage, J. L., Stomrud, E., Smith, R., Palmqvist, S., & Hansson, O.
- Affiliations
- Clinical Memory Research Unit, Faculty of Medicine, Lund University, Lund, Sweden.
- Lund University (SE)
- Sahlgrenska University Hospital (SE)
- University of California, San Francisco (US)
- Eli Lilly (United States) (US)
- Corresponding author
- Hansson, Oskar
- ORCID
- Venue
- Science Advances
- Published
- 2020-04-17
- Volume
- 6
- Issue
- 16
- Pages
- eaaz2387-eaaz2387
- ISSN
- 2375-2548 (ISSN-L)
- PMC
- PMC7159908
- OpenAlex
- W3016877536
- Semantic Scholar
- 474138087e67e9eaed4ae5baf6485f7c164d79cc
- Cited by
- 359
- References
- 48
- Citations by year
- 2026: 43 · 2025: 64 · 2024: 64 · 2023: 55 · 2022: 55 · 2021: 54 · 2020: 23
- FWCI
- 28.11
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Science Advances (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, cc-by)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion, other-oa)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc)
- UCL Discovery (University College London) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- Parkinson Research Foundation
- H2020 European Research Council
- Swedish Research Council Formas
- Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse
- Region Skåne
- Marianne and Marcus Wallenberg Foundation
- Swedish Brain Foundation
- Swedish Alzheimer Foundation
- the Knut and Alice Wallenberg Foundation
- Medical Faculty at Lund University
- Strategic Research Area MultiPark
- Swedish Medical Association
- Skåne University Hospital Foundation
- Parkinson foundation of Sweden
- Torsten Söderberg Foundation
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, amyloid-beta deposition, tau phosphorylation, soluble tau, tau PET, cerebrospinal fluid biomarkers, tau aggregation, 5xFAD mice, amyloid-beta aggregation
- MeSH terms
- Alzheimer Disease, Animals, Phosphorylation, Biomarkers, Amyloid beta-Peptides, tau Proteins, Positron-Emission Tomography, Mice
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