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

Abstract

Development of tau-based therapies for Alzheimer’s disease requires an understanding of the timing of disease-related changes in tau. We quantified the phosphorylation state at multiple sites of the tau protein in cerebrospinal fluid markers across four decades of disease progression in dominantly inherited Alzheimer’s disease. We identified a pattern of tau staging where site-specific phosphorylation changes occur at different periods of disease progression and follow distinct trajectories over time. These tau phosphorylation state changes are uniquely associated with structural, metabolic, neurodegenerative and clinical markers of disease, and some (p-tau217 and p-tau181) begin with the initial increases in aggregate amyloid-β as early as two decades before the development of aggregated tau pathology. Others (p-tau205 and t-tau) increase with atrophy and hypometabolism closer to symptom onset. These findings provide insights into the pathways linking tau, amyloid-β and neurodegeneration, and may facilitate clinical trials of tau-based treatments.

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Fig. 1: Stages of tau pathology.
Fig. 2: Longitudinal changes of different p-tau sites are specific to disease stage and change in opposite directions as AD progresses in dominantly inherited mutation carriers.
Fig. 3: Specific soluble tau phosphorylation sites are differentially associated with amyloid plaques in DIAD and sAD.
Fig. 4: Tau phosphorylation positions are differentially related to brain atrophy and hypometabolism in DIAD.
Fig. 5: In DIAD, elevated levels of tau phosphorylation decline in some sites with the onset of dementia, in contrast with a continued rise in t-tau.

Data availability

The data that support the findings of this study can be requested from DIAN at https://dian.wustl.edu/our-research/observational-study/dian-observational-study-investigator-resources/.

Code availability

All codes used for data analyses are available upon request from the corresponding authors.

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Acknowledgements

Data collection and sharing for this project was supported by the DIAN (UF1AG032438), funded by the National Institute on Aging, German Center for Neurodegenerative Diseases and Raul Carrea Institute for Neurological Research (FLENI), with partial support via research and development grants for dementia from the Japan Agency for Medical Research and Development and the Korea Health Technology R&D Project, through the Korea Health Industry Development Institute, MRC Dementias Platform UK (MR/L023784/1 and MR/009076/1) and AOI Lady Biobank CHU. The development and performance of the mass spectrometry analyses was supported by the Alzheimer’s Association Research Fellowship (AARF-16-443265 to N.R.B.), Fondation Plan Alzheimer (to A.G. and S.L.), BrightFocus (A20143845 to R.J.B.), the National Institute of Neurological Disorders and Stroke (R01NS095773 to R.J.B.) and the National Institute on Aging (K23 AG046363 to E.M.). This manuscript has been reviewed by DIAN Study investigators for scientific content and consistency of data interpretation with previous DIAN Study publications. We acknowledge the altruism of the participants and their families and contributions of the DIAN research and support staff at each of the participating sites for their contributions to this study. We thank J. Ringman and B. Ghetti for reviewing the manuscript and making suggestions.

Author information

N.R.B. and C.S. performed the mass spectrometry analyses. Y.L., C.X., N.J.-M. and B.A.G. performed the statistical and imaging analyses. N.R.B., Y.L., R.J.B. and E.M. designed the study and wrote the initial draft of the manuscript. All authors collected samples and data, helped to interpret the results and reviewed drafts of the manuscript.

Correspondence to Randall J. Bateman or Eric McDade.

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Competing interests

R.J.B. has equity ownership interest in C2N Diagnostics and receives royalty income based on technology (stable isotope labeling kinetics and blood plasma assay) licensed by Washington University to C2N Diagnostics. R.J.B. receives income from C2N Diagnostics for serving on the scientific advisory board. Washington University, with R.J.B., E.M. and N.R.B. as co-inventors, has submitted the US nonprovisional patent application ‘Cerebrospinal fluid (CSF) tau rate of phosphorylation measurement to define stages of Alzheimer’s disease and monitor brain kinases/phosphatases activity’. R.J.B. has received honoraria from Janssen and Pfizer as a speaker, and from Merck and Pfizer as an advisory board member. E.M. has received royalty payments for an educational program supported by Eli Lilly and as a member of a scientific advisory board for Eli Lilly.

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Peer review information Brett Benedetti and Kate Gao were the primary editors on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 Individual longitudinal changes of different phosphorylated-tau sites and total tau highlights differences in the time of increase relative to disease onset.

Individual, z-transformed, longitudinal changes in the ratio of phosphorylation of a, pT217/T217, b, pT181/T181 c, total tau, d, pT205/T205, and e, pS202/S202 for mutation carriers (orange = asymptomatic mutation carriers, (n = 152), red = symptomatic mutation carriers (n = 77)) and non-carriers (blue, (n = 141)) across the estimated years to symptom onset (EYO). The vertical dashed line is the point of expected symptom onset, the vertical green line represents the model estimated time when the rate of change for each p-tau isoform becomes greater for mutation carriers compared to non-carriers.

Extended Data Fig. 2 Individual longitudinal changes of different unphosphorylated-tau sites.

Individual, z-transformed, longitudinal changes in the unphosphorylated levels of a, T217, b, T181 c, T205 for mutation carriers (orange = asymptomatic mutation carriers, (n = 152), red = symptomatic mutation carriers (n = 77)) and non-carriers (blue, (n = 141)) across the estimated years to symptom onset (EYO). The solid line represents a LOESS fit to cross-sectional and longitudinal data. The vertical dashed line is the point of expected symptom onset. Compared to the phosphorylation ratios of each site (Extended Data Fig. 1), the increase in the unphosphorylated levels appears to be more similar over the progression of disease.

Extended Data Fig. 3 Change in tau phosphorylation state is site dependent and related to amyloid PET and disease stage in DIAD and sAD.

Bar charts illustrating the proportion of participants that have p-tau ratios and total tau levels that exceed the normal values (biomarker + (red)) (a- d) as the stage of disease progresses from cognitively normal/PiB-PET normal to cognitively normal/PiB-PET positive then to mild dementia (CDR 0.5) and greater (CDR > 0.5). The top row is DIAD (n = 210) and the bottom row sAD (n = 83). 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, generalizing these findings to AD.

Extended Data Fig. 4 Elevated levels of tau phosphorylation decline in some sites with atrophy of hippocampal volumes in contrast to a continued rise in total tau.

Estimated individual annual rates of change of p-tau isoforms and total tau, standardized by the mean and standard deviation of the estimated rate of change for all mutation carriers, (y-axis) for mutation carriers were correlated with the annual change in hippocampal volumes (a-d). The linear regression was fit to those with no dementia (CDR 0, black circle, n = 48) and dementia (CDR > 0, red triangle, n = 27). A decline in pT217/T217 (a), r = 0.74(p < 0.0001), pT181/T181 (b), r = 0.84 (p < 0.0001) and pT205/T205, r = 0.25 (p = 0.03) phosphorylation rate was associated with hippocampal volume decline. For total tau there was an inverse correlation with atrophy (d), r = −0.79(p < 0.0001). (e) A linear fit for all mutation carriers demonstrates there are distinct associations between declining cognition and changes in the different p-tau isoforms and total tau: with decreases in pT217/T217 and pT181/T181 and an increase in total tau associated with cognitive decline; and no associations with pT205/T205 or pS202/S202. This suggests that soluble tau species are not equivalent in AD (pS202/S202) is shown here to demonstrate the lack of association with cognition, r = -0.07 (p = 0.57). Statistical significance of the correlations was calculated using z test.

Extended Data Fig. 5 Elevated levels of tau phosphorylation decline in some sites with atrophy of precuneus cortex in contrast to a continued rise in total tau.

Estimated individual annual rates of change of p-tau isoforms and total tau, standardized by the mean and standard deviation of the estimated rate of change for all mutation carriers, (y-axis) for mutation carriers were correlated with the annual change in hippocampal volumes (a-d). The linear regression was fit to those with no dementia (CDR 0, black circle, n = 48) and dementia (CDR > 0, red triangle, n = 27). A decline in pT217/T217 (a), r = 0.75 (p < 0.0001), pT181/T181 (b), r = 0.83 (p < 0.0001) and pT205/T205, r = 0.19 (p= 0.09) phosphorylation rate was associated with precuneus cortical decline. For total tau there was an inverse correlation with atrophy (d), r = -0.77(p < 0.0001). (e) A linear fit for all mutation carriers demonstrates there are distinct associations between declining cognition and changes in the different p-tau isoforms and total tau: with decreases in p-T217 and p-T181 and an increase in total tau associated with cognitive decline; and no associations with pT205/T205 or pS202/S202. This suggests that soluble tau species are not equivalent in AD (pS202/S202 is shown here to demonstrate the lack of association with cognition, r = -0.04 (p= 0.72). Statistical significance of the correlations was calculated using two-sided t tests.

Extended Data Fig. 6 Tau PET increases near symptom onset in DIAD mutation carriers.

The mean cortical standardized unit value ratio (SUVR), y-axis, for mutation carriers (red, n = 12) and non-carriers (blue, n = 9) over estimated years to symptom onset (EYO), x-axis, for those participants with a longitudinal CSF evaluation preceding the time of tau-PET. The plot shows that for mutation carriers there is little elevation in tau-PET until the point of estimated symptom onset (EYO=0). This figure shows that the neurofibrillary tangle (NFT) pathology detected by AV-1451 occurs much later than the increase in multiple soluble phosphotau sites suggesting that these soluble markers of tau are likely a marker of NFT pathology, but rather might predispose to the development of the hyperphosphorylated, insoluble tau deposits characteristic of AD pathology.

Extended Data Fig. 7 Longitudinal change in tau and tau phosphorylation sites are differentially related to neurofibrillary tau (tau-PET) in dominantly inherited AD.

Individual, rates of change of phosphorylation and total tau (y-axis) in mutation carriers only leading up to the time of tau-PET scan (x-axis) (n = 12). The vertical line is an SUVR of 1.22 and represents a conservative estimate of the point when cortical tau-PET is considered elevated for tau aggregates compared to non-carriers. The plots suggest that increases in soluble tau and p-T205 are associated with higher levels of aggregated tau, whereas the rate of phosphorylation at p-T217 and p-T181 decrease as levels of aggregated tau increase. These findings suggest that there are differences between increasing levels of tau and phosphorylation at different sites and may indicate that, in some instances, soluble p-tau maybe sequestered as the burden of hyperphosphorylated aggregates increase with the spreading of tau pathology. 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.

Extended Data Fig. 8 Spearman correlation of the cross-sectional association of p-tau phosphorylation, total tau (y-axis) and tau PET (x-axis) for mutation carriers (n = 12).

The vertical line is an SUVR of 1.22 and represents a conservative estimate of the point when cortical tau-PET is considered elevated for tau aggregates compared to non-carriers.

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Barthélemy, N.R., Li, Y., Joseph-Mathurin, N. et al. A soluble phosphorylated tau signature links tau, amyloid and the evolution of stages of dominantly inherited Alzheimer’s disease. Nat Med 26, 398–407 (2020). https://doi.org/10.1038/s41591-020-0781-z

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