A soluble phosphorylated tau signature links tau, amyloid and the evolution of stages of dominantly inherited Alzheimer’s disease

May combine two claims.

Two general patterns emerged: at some sites phosphorylation fell significantly as cognitive decline began, while at other sites it rose continuously or did not change with disease progression.

“We identified two general patterns: for some sites, phosphorylation decreased significantly as cognitive decline began, whereas other sites showed a continuous increase or no change with disease progression”

May combine two claims.

pT181/T181 hyperphosphorylation had the weakest overall correlation with cortical atrophy and was limited to medial and lateral parietal lobes and medial dorsomedial frontal lobes.

“Hyperphosphorylation at pT181/T181 had the lowest overall correlation with cortical atrophy and was restricted to the medial and lateral parietal lobes and medial dorsomedial frontal lobes.”

May combine two claims.

In both DIAD and sAD, pT217/T217 and pT181/T181 ratios rose significantly with amyloid pathology and then rose less with more advanced symptom stages.

“In both DIAD and sAD, pT217/T217 and pT181/T181 ratios increase significantly with the presence of amyloid pathology and then less so with more advanced stages of symptoms.”

• AssumptionRests on an assumption: PiB-PET SUVR above 1.25 reliably identifies significant brain-aggregated Aβ.

May combine two claims.

When CSF-soluble Aβ was used to define abnormal amyloid levels in DIAD, the same ordering of soluble tau measures appeared, but each AUC was lower.

“When using CSF-soluble Aβ in DIAD to determine abnormal amyloid levels, we found the same order for the soluble tau measures in classifying participants as amyloid positive (Aβ 42/40 ≥ 0.0776) or amyloid negative (Aβ 42/40 < 0.0776), but lower AUC values for each”

May combine two claims.

In both DIAD and sAD, T205 phosphorylation rate and t-tau levels rose at later stages and continued to rise as clinical disease advanced.

“However, the rate of phosphorylation of T205 and levels of t-tau increase at later stages and continue increasing as clinical disease progresses.”

May combine two claims.

In a mixed-effects model of longitudinal cognition, t-tau rose monotonically with worsening cognition, pT217/T217 and pT181/T181 fell with worsening cognition, pT205/T205 changed less with cognitive decline, and pS202/S202 had no association with cognitive change.

“t-tau monotonically increased with worsening cognition and pT217/T217 and pT181/T181 decreased with worsening cognition, while pT205/T205 demonstrated less change relative to cognitive decline and pS202/S202 had no association with cognitive change.”

May combine two claims.

In the precuneus, after control for age, gender and EYO and adjustment for multiple comparisons, correlations with PiB-PET SUVR ranked pT217/T217 (r = 0.53; s.e.m. = 0.06; P < 10−30) > pT205/T205 (r = 0.37; s.e.m. = 0.075; P < 10−5) > pT181/T181 (r = 0.35; s.e.m. = 0.075; P < 10−6), all positive; pS202/S202 correlated inversely (r = −0.46; s.e.m. = 0.067; P < 10−7).

“We found an order of correlations from greatest to least of pT217/T217 (r = 0.53; s.e.m. = 0.06; P < 10−30) > pT205/T205 (r = 0.37; s.e.m. = 0.075; P < 10−5) > pT181/T181 (r = 0.35; s.e.m. = 0.075; P < 10−6), with positive correlations with PiB-PET SUVR. In contrast, pS202/S202 had an inverse correlation (r = −0.46; s.e.m. = 0.067; P < 10−7)”

• AssumptionRests on an assumption: PiB-PET SUVR above 1.25 reliably identifies significant brain-aggregated Aβ.

May combine two claims.

DIAD showed a larger magnitude of phosphorylation and higher t-tau levels for each category than sAD.

“Notably, there was evidence that in DIAD there is a greater magnitude of phosphorylation and higher levels of t-tau for each category compared with sAD.”

May combine two claims.

In asymptomatic mutation carriers, hyperphosphorylation was inversely related to cortical thickness: pT205/T205, and less so pT217/T217, had the strongest associations with reduced cortical and subcortical thickness across the brain, while t-tau had fewer regional associations and weaker correlations.

“Hyperphosphorylation was inversely associated with cortical thickness in asymptomatic mutation carriers: pT205/T205, and to a lesser extent pT217/T217, was most strongly associated with a decrease in cortical and subcortical thickness throughout the brain (Fig. 4a and Supplementary Table 7), while t-tau levels showed fewer regional associations and weaker correlations.”

May combine two claims.

pT217/T217, pT181/T181 and pT205/T205 phosphorylation correlated positively with PiB-PET SUVR across the brain, whereas pS202/S202 correlated negatively.

“pT217/T217, pT181/T181 and pT205/T205 phosphorylation was positively correlated with PiB-PET SUVR throughout the brain, but pS202/S202 was negatively correlated.”

• AssumptionRests on an assumption: PiB-PET SUVR above 1.25 reliably identifies significant brain-aggregated Aβ.

May combine two claims.

In Spearman correlations, higher tau-PET levels were associated with rising t-tau (r = 0.58; P = 0.08) and pT205/T205 (r = 0.74; P = 0.02), while there was a suggestion of decreases in pT217/T217 (r = −0.2; P = 0.58) and pT181/T181 (r = −0.27; P = 0.46).

“we found evidence that increasing levels of t-tau (r = 0.58; P = 0.08) but also pT205/T205 (r = 0.74; P = 0.02) were associated with higher tau-PET levels, whereas there was a suggestion of decreases in pT217/T217 (r = −0.2; P = 0.58) and pT181/T181 (r = −0.27; P = 0.46) with higher tau-PET levels”

• AssumptionRests on an assumption: Tau-PET SUVR measures aggregated tau burden.

May combine two claims.

Nearly all PiB-PET regions showed a similar rank ordering of p-tau correlations, with statistically significant differences between measures, most often pT217/T217 having the strongest associations.

“We found a similar rank ordering for nearly all regions of PiB-PET and p-tau isoform correlations and statistically significant differences between the different p-tau measure correlations, most commonly for pT217/T217 having the greatest associations.”

• AssumptionRests on an assumption: PiB-PET SUVR above 1.25 reliably identifies significant brain-aggregated Aβ.

May combine two claims.

Every phosphorylation site except S202 rose with higher PiB-PET SUVR, while pS202/S202 fell with higher PiB-PET SUVR.

“All phosphorylation sites except S202 demonstrated increased levels of phosphorylation with greater PiB-PET SUVR; in contrast, pS202/S202 had a decrease in phosphorylation with increasing PiB-PET SUVRs.”

• AssumptionRests on an assumption: PiB-PET SUVR above 1.25 reliably identifies significant brain-aggregated Aβ.

May combine two claims.

The mass spectrometry method outperformed the Roche Elecsys pT181 and t-tau CSF electrochemiluminescence assay, indicating greater sensitivity for early AD pathology in DIAD.

“we compared this mass spectrometry-based method with one of the most advanced immunoassays (the Roche Elecsys pT181 and t-tau CSF electrochemiluminescence method) and found the mass spectrometry method to be superior, indicating a greater sensitivity to detecting early AD pathology in DIAD”

May combine two claims.

pT217/T217 and pT181/T181 started a significant decline close to symptom onset, whereas pT205/T205 phosphorylation slowed and t-tau kept rising.

“Second, pT217/T217 and pT181/T181 began to decline significantly near the time of symptom onset, while phosphorylation at pT205/T205 slowed and t-tau levels continued to increase.”

May combine two claims.

In asymptomatic mutation carriers, pT205/T205 phosphorylation correlated with glucose hypometabolism throughout cortical and subcortical regions on FDG-PET, while other p-tau sites and t-tau showed minimal associations.

“In the asymptomatic mutation carriers, phosphorylation at pT205/T205 was correlated with glucose hypometabolism throughout the cortex and subcortical regions, as measured by FDG-PET (Fig. 4b and Supplementary Table 8). There were minimal associations identified for the other p-tau sites and t-tau levels in asymptomatic mutation carriers.”

May combine two claims.

In DIAD, t-tau and site-specific phosphorylation rose in a sequence: pT217/T217 near −21 EYO, followed by pT181/T181 near −19 EYO, t-tau near −17 EYO, and pT205/T205 near −13 EYO.

“there was evidence that increases in t-tau and phosphorylation at specific sites occurred in a relative order: phosphorylation of tau at threonine 217 (pT217/T217) (which occurred at around −21 EYO) was followed by that of threonine 181 (pT181/T181) (−19 EYO), then t-tau increase (−17 EYO), then phosphorylation of tau at threonine 205 (pT205/T205) (−13 EYO)”

May combine two claims.

Longitudinal measures show that soluble tau phosphorylation occupancy falls while tau rises, at least in DIAD, indicating an inverse correlation.

“In contrast, the more appropriate longitudinal measures indicate that soluble tau phosphorylation occupancy decreases during the time of tau increase25, at least in DIAD, demonstrating an inverse correlation.”

• cites [25] Quiroz, Y. T. et al. Association between amyloid and Tau accumulation in young adults with autosomal dominant Alzheimer disease. JAMA Neurol. 75, 548–556 (2018). sourceNot checked yet

  Not checked in the free run.

• AssumptionRests on an assumption: Tau-PET SUVR measures aggregated tau burden.

May combine two claims.

Neither pT205/T205 nor pS202/S202 showed a relationship with cognitive decline.

“and no associations with pT205/T205 or pS202/S202.”

• Also stated in: § Extended Data · plain

  “and no associations with pT205/T205 or pS202/S202.”

May combine two claims.

Cognitive decline is linked to falling pT217 and pT181 and rising total tau.

“with decreases in p-T217 and p-T181 and an increase in total tau associated with cognitive decline”

May combine two claims.

The progression patterns for each phosphorylation ratio and total tau are closely alike in DIAD and sAD, with a similar ordering.

“The figure demonstrates very similar patterns for each phosphorylation ratio and total tau levels across the progression of disease and indicate a similar ordering in DIAD and SAD”

• AssumptionRests on an assumption: DIAD mutations are nearly fully penetrant, and symptom onset age is fairly consistent for a given mutation and family.

May combine two claims.

Cognitive decline is linked to falling pT217/T217 and pT181/T181 and rising total tau.

“with decreases in pT217/T217 and pT181/T181 and an increase in total tau associated with cognitive decline”

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

Few samples fell below the lowest quantifiable level for CSF pT205 (4.7%) and pT217 (4.5%).

“A low percentage of the investigated samples had CSF pT205 and pT217 levels below the lowest limit of quantitation (4.7 and 4.5%, respectively)”

May combine two claims.

The results connect Aβ pathology to a distinct change in soluble tau levels and phosphorylation patterns, explaining why p-tau is significantly elevated in AD but not in other neurodegenerative tauopathies.

“Our results link Aβ pathology to a distinct change in soluble tau levels and phosphorylation patterns, shedding light on the phenomenon in which significant elevation of p-tau occurs in AD but not in other neurodegenerative tauopathies17,18.”

• cites [17] Hu, W. T. et al. Reduced CSF p-Tau181 to Tau ratio is a biomarker for FTLD-TDP. Neurology 81, 1945–1952 (2013). sourceNot checked yet

  Not checked in the free run.

• cites [18] Hampel, H. et al. Measurement of phosphorylated tau epitopes in the differential diagnosis of Alzheimer disease: a comparative cerebrospinal fluid study. Arch. Gen. Psychiatry 61, 95–102 (2004). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Although some of the rise in CSF tau and phosphorylated tau may come from passive release during neurodegeneration, its initial rise is probably due to other processes.

“which would indicate that although an increase in CSF tau and phosphorylated tau may in part be related to a passive release in neurodegeneration, their initial rise is probably the consequence of other processes.”

May combine two claims.

Quantifying soluble tau phosphorylation occupancy can track the AD process from preclinical to symptomatic stages and provides a p-tau pathology signature for the disease.

“Together, these results indicate that this method of quantifying soluble tau phosphorylation occupancy can track the AD process across its preclinical to symptomatic stages, providing a signature of p-tau pathology for this disease”

May combine two claims.

The findings challenge the purported roles of tau/p-tau in DIAD, and possibly AD generally, and reproduce in humans animal findings that link Aβ pathology to tau hyperphosphorylation and active cellular release rather than release from dying neurons.

“Moreover, they challenge the purported roles of tau/p-tau in DIAD, and possibly AD in general, and recapitulate in humans those findings from animal studies that link Aβ pathology to tau hyperphosphorylation32,34,36,49 and active cellular release, rather than release of dying neurons.”

• cites [32] Maia, L. F. et al. Changes in amyloid-β and Tau in the cerebrospinal fluid of transgenic mice overexpressing amyloid precursor protein. Sci. Transl. Med. 5, 194re192 (2013).Not checked yet

  Not checked in the free run.

• cites [34] Schelle, J. et al. Prevention of tau increase in cerebrospinal fluid of APP transgenic mice suggests downstream effect of BACE1 inhibition. Alzheimers Dement. 13, 701–709 (2017). sourceNot checked yet

  Not checked in the free run.

• cites [36] Saman, S. et al. Exosome-associated Tau is secreted in tauopathy models and is selectively phosphorylated in cerebrospinal fluid in early Alzheimer disease. J. Biol. Chem. 287, 3842–3849 (2012). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The fall in the phosphorylation ratio for pT217/T217 and pT181/T181 was not caused by a disproportionate rise in unphosphorylated peptides at those two sites or by a fall in total tau protein.

“suggesting that the decrease in the phosphorylation ratio for pT217/T217 and pT181/T181 was not a result of a disproportionate rise in unphosphorylated peptides specifically related to these two sites, nor a decrease in total levels of tau protein”

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

A fall in the phosphorylation rate of some sites (for example, pT181 and pT217) while aggregated tau rises might reflect sequestration by hyperphosphorylated aggregates.

“these results might suggest that a reduction in the phosphorylation rate of some sites (for example, pT181 and pT217) when aggregated tau is increasing could represent a process of sequestration by hyperphosphorylated aggregates48.”

• cites [48] Yanamandra, K. et al. Anti-tau antibody administration increases plasma tau in transgenic mice and patients with tauopathy. Sci. Transl. Med. 9, eaal2029 (2017). sourceNot checked yet

  Not checked in the free run.

• AssumptionRests on an assumption: Tau-PET SUVR measures aggregated tau burden.

May combine two claims.

In DIAD, tau phosphorylation and release into CSF is dynamic: it starts after aggregated Aβ pathology (by PiB-PET) is established decades before symptoms and then unfolds over nearly two decades; it follows a pattern in which phosphorylation at different tau sites tracks disease progression as shown by other biomarkers; and it falls significantly in a site-dependent way near cognitive decline and,

“the process of tau phosphorylation and release into the CSF is a dynamic process that: (1) begins once aggregated Aβ pathology (as measured by PiB-PET) is established decades before symptoms, and subsequently unfolds over a period of nearly two decades”

• Also stated in: § Discussion · plain

  “(3) decreases significantly in a site-dependent manner near the onset of cognitive decline and the rise in aggregated tau (as measured by tau-PET).”

• AssumptionRests on an assumption: PiB-PET SUVR above 1.25 reliably identifies significant brain-aggregated Aβ.
• AssumptionRests on an assumption: Tau-PET SUVR measures aggregated tau burden.

May combine two claims.

A fall in T217 and T181 phosphorylation, like a rise in soluble t-tau, is an important marker of cognitive decline.

“This suggests that decreased phosphorylation of T217 and T181, as much as increased soluble t-tau, presents an important marker of cognitive decline.”

May combine two claims.

A multivariate LME approach can control for EYO and for within-family correlation.

“Compared with the simple correlation estimation method (Pearson or Spearman correlation), the multivariate LME model can adjust for covariates such as EYO, as well as accounting for the correlation within the family cluster63,64.”

• cites [63] Luo, J., D’Angelo, G., Gao, F., Ding, J. & Xiong, C. Bivariate correlation coefficients in family-type clustered studies. Biom. J. 57, 1084–1109 (2015). sourceNot checked yet

  Not checked in the free run.

• cites [64] Xiong, C. et al. Longitudinal relationships among biomarkers for Alzheimer disease in the Adult Children Study. Neurology 86, 1499–1506 (2016). sourceNot checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

Correlation P values were adjusted with the Benjamini-Hochberg procedure to limit false discoveries from multiple tests.

“P values for testing the correlations were corrected using the Benjamini–Hochberg method65, to control the false discovery rate due to multiple testing.”

• cites [65] Benjamini, Y. & Hochberg, Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. R. Stat. Soc. B 57, 289–300 (1995). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Early phosphorylation changes suggest that hyperphosphorylation is a marker of pathophysiology but not necessarily a marker of tau-related NFTs.

“In addition, early phosphorylation modifications suggest that hyperphosphorylation, although a marker of pathophysiology, is not necessarily a marker of tau-related NFTs.”

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

A recent study found that new tau production and CSF tau levels do not appear to change when tau-PET is elevated.

“Similarly, a recent study has shown that the new production of tau and levels in the CSF do not appear to change in the presence of elevated tau (tau-PET)33.”

• cites [33] Sato, C. et al. Tau kinetics in neurons and the human central nervous system. Neuron 98, 861–864 (2018). sourceNot checked yet

  Not checked in the free run.

• AssumptionRests on an assumption: Tau-PET SUVR measures aggregated tau burden.

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

One possible explanation is that the large rise in aggregated tau sequesters phosphorylated tau in the brain, lowering CSF levels.

“One possible explanation for this is similar to what has been observed with soluble/aggregated Aβ52: that the dramatic increase of aggregated tau sequesters phosphorylated tau53 in the brain, decreasing CSF levels.”

• cites [52] Potter, R. et al. Increased in vivo amyloid-β42 production, exchange, and loss in presenilin mutation carriers. Sci. Transl. Med. 5, 189ra177 (2013). sourceNot checked yet

  Not checked in the free run.

• cites [53] Yamada, K. et al. In vivo microdialysis reveals age-dependent decrease of brain interstitial fluid tau levels in P301S human tau transgenic mice. J. Neurosci. 31, 13110–13117 (2011). sourceNot checked yet

  Not checked in the free run.

• AssumptionRests on an assumption: Tau-PET SUVR measures aggregated tau burden.

Classified as probably not a substantial claim.

Random effects comprised family-cluster intercepts plus individual intercepts and slopes with an unstructured covariance structure, addressing repeated-measures correlation.

“The random effects included in the models were the random intercepts for family clusters, individual random intercept and random slope with unstructured covariance matrix, to account for the within-subject correlation due to repeated measures.”

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

The tau-PET analysis had a small number of participants, which limits interpretation.

“Given the small number of participants available for this analysis, there are limits to the interpretation of these results.”

Classified as probably not a substantial claim.

The baseline cortical PiB-PET SUVR threshold was selected at the point where the longitudinal change rate first became significantly different between mutation carriers and non-carriers.

“The cut point for baseline cortical PiB-PET SUVR was chosen such that the difference in the longitudinal rate of change of cortical PiB-PET between mutation carriers and non-carriers first starts to differ significantly from 0.”

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

Data collection at all DIAN sites followed standard procedures intended to ensure consistency.

“Standard procedures were used to ensure consistency in the data collection of all DIAN sites38.”

• cites [38] 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). sourceNot checked yet

  Not checked in the free run.

May combine two claims.

t-tau appears to rise to similar levels as disease progresses, suggesting that differences in phosphorylation occupancy in DIAD are less likely to reflect differences in the amount of intraneuronal tau produced and released into CSF.

“Importantly, we have shown that t-tau levels appear to rise to similar levels with disease progression (Supplementary Fig. 2). This would indicate that the differences we have detected in the phosphorylation occupancy in DIAD are less likely to just reflect a difference in the amount of intraneuronal tau protein produced and released into the CSF compartment.”

Classified as probably not a substantial claim.

Every model included a random family term to handle within-family correlation of outcomes.

“All of the models incorporated a random family effect to account for the correlations on the outcome measures between participants within the same family.”

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

Data were quality-controlled with annual quality assessments for irregular results and missing data from 26 January 2009 to 30 June 2017.

“Data were obtained from quality-controlled data (annual quality assessments for irregular results and missing data from 26 January 2009 to 30 June 2017)”

Classified as probably not a substantial claim.

Precuneus correlation analyses controlled for age, gender and EYO and adjusted for multiple comparisons.

“controlling for age, gender and EYO and adjusted for multiple comparisons.”

May combine two claims.

In AD caused by autosomal dominant mutations, CSF tau hyperphosphorylation occurs very early and shows site-specific changes at different disease stages.

“In summary, we have demonstrated that in AD associated with autosomal dominant mutations, CSF tau hyperphosphorylation occurs very early and exhibits pattern of site-specific changes at different stages of the disease.”

Classified as probably not a substantial claim.

Imaging correlation analyses controlled for sex, age and EYO.

“controlling for sex, age and EYO.”

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

In the DIAD study, evaluating clinicians did not know participants' genetic status.

“Evaluating clinicians were blind to genetic status.”

Classified as probably not a substantial claim.

The mixed-effects model adjusted for age, sex, education and familial relation.

“adjusting for age, sex, education and familial relation (participants of the same family).”

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

Assay variability was usually under 20% in both studies.

“In both studies, the inter-assay coefficient of variation was typically below 20%.”

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

Because participant numbers were small, the tau-PET prediction regressions omitted a family-cluster term.

“Due to the limited number of participants, a family cluster was not included.”

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

The very early rise in pT217/T217 and pT181/T181 may reflect an early tau response to aggregated Aβ and may explain the global association of PiB-PET SUVR with these isoforms.

“It is possible that the very early increase we find in pT217/T217 and pT181/T181 may reflect this ‘early’ tau response to aggregated Aβ and might explain the global association of PiB-PET SUVR with these isoforms that we identified.”

• AssumptionRests on an assumption: PiB-PET SUVR above 1.25 reliably identifies significant brain-aggregated Aβ.

May combine two claims.

Greater aggregated tau burden coincides with higher soluble tau, possibly from passive or active release.

“They also suggest that with the increase in aggregated tau there is a rise in soluble tau levels which could represent either passive or active release with greater burden of aggregated tau pathology.”

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

The models considered sex, education and APOE ε4 as covariates, retaining only those with significant effects.

“Sex, years of education and apolipoprotein-E ε4 status were considered as covariates, but only those effects that were significant were retained in the models.”

May combine two claims.

A reduction of tau through proteostatic mechanisms cannot be ruled out as a cause of the phosphorylation decrease, but the continued rise in t-tau suggests it is probably not the cause for the falling phosphorylation rate at some sites.

“A reduction of tau through proteostatic mechanisms cannot be excluded54 as a cause for the decrease in phosphorylation, but the continued increase of t-tau (Supplementary Fig. 3) would suggest that this is probably not the cause for the decreasing rate of phosphorylation for some sites.”

• cites [54] Van der Kant, R. et al. Cholesterol metabolism is a druggable axis that independently regulates tau and amyloid-β in iPSC-derived Alzheimer’s disease neurons. Cell Stem Cell 24, 363–375.e9 (2019). sourceNot checked yet

  Not checked in the free run.