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Plasma N-terminal containing tau fragments (NTA-tau) : a biomarker of tau deposition in Alzheimer’s Disease

Lantero-Rodriguez, Juan ; Salvadó, Gemma LU ; Snellman, Anniina ; Montoliu-Gaya, Laia ; Brum, Wagner S. ; Benedet, Andrea L. ; Mattsson-Carlgren, Niklas LU orcid ; Tideman, Pontus LU ; Janelidze, Shorena LU and Palmqvist, Sebastian LU orcid , et al. (2024) In Molecular Neurodegeneration 19(1).
Abstract
Background: Novel
phosphorylated-tau (p-tau) blood biomarkers (e.g., p-tau181, p-tau217 or
p-tau231), are highly specific for Alzheimer’s disease (AD), and can
track amyloid-β (Aβ) and tau pathology. However, because these
biomarkers are strongly associated with the emergence of Aβ pathology,
it is difficult to determine the contribution of insoluble tau
aggregates to the plasma p-tau signal in blood. Therefore, there remains
a need for a biomarker capable of specifically tracking insoluble tau
accumulation in brain. Methods: NTA is a novel ultrasensitive assay
targeting N-terminal containing tau fragments (NTA-tau) in cerebrospinal
fluid (CSF) and plasma, which is elevated in AD. Using two... (More)
Background: Novel
phosphorylated-tau (p-tau) blood biomarkers (e.g., p-tau181, p-tau217 or
p-tau231), are highly specific for Alzheimer’s disease (AD), and can
track amyloid-β (Aβ) and tau pathology. However, because these
biomarkers are strongly associated with the emergence of Aβ pathology,
it is difficult to determine the contribution of insoluble tau
aggregates to the plasma p-tau signal in blood. Therefore, there remains
a need for a biomarker capable of specifically tracking insoluble tau
accumulation in brain. Methods: NTA is a novel ultrasensitive assay
targeting N-terminal containing tau fragments (NTA-tau) in cerebrospinal
fluid (CSF) and plasma, which is elevated in AD. Using two
well-characterized research cohorts (BioFINDER-2, n = 1,294, and
BioFINDER-1, n = 932), we investigated the association between plasma
NTA-tau levels and disease progression in AD, including tau
accumulation, brain atrophy and cognitive decline. Results: We
demonstrate that plasma NTA-tau increases across the AD continuum¸
especially during late stages, and displays a moderate-to-strong
association with tau-PET (β = 0.54, p < 0.001) in Aβ-positive
participants, while weak with Aβ-PET (β = 0.28, p < 0.001). Unlike
plasma p-tau181, GFAP, NfL and t-tau, tau pathology determined with
tau-PET is the most prominent contributor to NTA-tau variance (52.5% of
total R2), while having very low contribution from Aβ
pathology measured with CSF Aβ42/40 (4.3%). High baseline NTA-tau levels
are predictive of tau-PET accumulation (R2 = 0.27), steeper atrophy (R2 ≥ 0.18) and steeper cognitive decline (R2
≥ 0.27) in participants within the AD continuum. Plasma NTA-tau levels
significantly increase over time in Aβ positive cognitively unimpaired
(βstd = 0.16) and impaired (βstd = 0.18) at
baseline compared to their Aβ negative counterparts. Finally,
longitudinal increases in plasma NTA-tau levels were associated with
steeper longitudinal decreases in cortical thickness (R2 = 0.21) and cognition (R2
= 0.20). Conclusion: Our results indicate that plasma NTA-tau
levels increase across the AD continuum, especially during mid-to-late
AD stages, and it is closely associated with in vivo tau tangle
deposition in AD and its downstream effects. Moreover, this novel
biomarker has potential as a cost-effective and easily accessible tool
for monitoring disease progression and cognitive decline in clinical
settings, and as an outcome measure in clinical trials which also need
to assess the downstream effects of successful Aβ removal. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Alzheimer’s disease, BioFINDER, Biomarkers, NTA, NTA-tau, Plasma, Tau, Tau pathology, Tau-PET
in
Molecular Neurodegeneration
volume
19
issue
1
article number
19
publisher
BioMed Central (BMC)
external identifiers
  • scopus:85185505521
ISSN
1750-1326
DOI
10.1186/s13024-024-00707-x
language
English
LU publication?
yes
id
4c062d39-4ff8-4429-beb9-5fdb8aa0c239
date added to LUP
2024-03-15 12:35:13
date last changed
2024-03-15 12:36:25
@article{4c062d39-4ff8-4429-beb9-5fdb8aa0c239,
  abstract     = {{Background: Novel <br>
phosphorylated-tau (p-tau) blood biomarkers (e.g., p-tau181, p-tau217 or<br>
 p-tau231), are highly specific for Alzheimer’s disease (AD), and can <br>
track amyloid-β (Aβ) and tau pathology. However, because these <br>
biomarkers are strongly associated with the emergence of Aβ pathology, <br>
it is difficult to determine the contribution of insoluble tau <br>
aggregates to the plasma p-tau signal in blood. Therefore, there remains<br>
 a need for a biomarker capable of specifically tracking insoluble tau <br>
accumulation in brain. Methods: NTA is a novel ultrasensitive assay <br>
targeting N-terminal containing tau fragments (NTA-tau) in cerebrospinal<br>
 fluid (CSF) and plasma, which is elevated in AD. Using two <br>
well-characterized research cohorts (BioFINDER-2, n = 1,294, and <br>
BioFINDER-1, n = 932), we investigated the association between plasma <br>
NTA-tau levels and disease progression in AD, including tau <br>
accumulation, brain atrophy and cognitive decline. Results: We <br>
demonstrate that plasma NTA-tau increases across the AD continuum¸ <br>
especially during late stages, and displays a moderate-to-strong <br>
association with tau-PET (β = 0.54, p &lt; 0.001) in Aβ-positive <br>
participants, while weak with Aβ-PET (β = 0.28, p &lt; 0.001). Unlike <br>
plasma p-tau181, GFAP, NfL and t-tau, tau pathology determined with <br>
tau-PET is the most prominent contributor to NTA-tau variance (52.5% of <br>
total R<sup>2</sup>), while having very low contribution from Aβ <br>
pathology measured with CSF Aβ42/40 (4.3%). High baseline NTA-tau levels<br>
 are predictive of tau-PET accumulation (R<sup>2</sup> = 0.27), steeper atrophy (R<sup>2</sup> ≥ 0.18) and steeper cognitive decline (R<sup>2</sup><br>
 ≥ 0.27) in participants within the AD continuum. Plasma NTA-tau levels <br>
significantly increase over time in Aβ positive cognitively unimpaired <br>
(β<sub>std</sub> = 0.16) and impaired (β<sub>std</sub> = 0.18) at <br>
baseline compared to their Aβ negative counterparts. Finally, <br>
longitudinal increases in plasma NTA-tau levels were associated with <br>
steeper longitudinal decreases in cortical thickness (R<sup>2</sup> = 0.21) and cognition (R<sup>2</sup><br>
 = 0.20). Conclusion: Our results indicate that plasma NTA-tau <br>
levels increase across the AD continuum, especially during mid-to-late <br>
AD stages, and it is closely associated with in vivo tau tangle <br>
deposition in AD and its downstream effects. Moreover, this novel <br>
biomarker has potential as a cost-effective and easily accessible tool <br>
for monitoring disease progression and cognitive decline in clinical <br>
settings, and as an outcome measure in clinical trials which also need <br>
to assess the downstream effects of successful Aβ removal.}},
  author       = {{Lantero-Rodriguez, Juan and Salvadó, Gemma and Snellman, Anniina and Montoliu-Gaya, Laia and Brum, Wagner S. and Benedet, Andrea L. and Mattsson-Carlgren, Niklas and Tideman, Pontus and Janelidze, Shorena and Palmqvist, Sebastian and Stomrud, Erik and Ashton, Nicholas J. and Zetterberg, Henrik and Blennow, Kaj and Hansson, Oskar}},
  issn         = {{1750-1326}},
  keywords     = {{Alzheimer’s disease; BioFINDER; Biomarkers; NTA; NTA-tau; Plasma; Tau; Tau pathology; Tau-PET}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{Molecular Neurodegeneration}},
  title        = {{Plasma N-terminal containing tau fragments (NTA-tau) : a biomarker of tau deposition in Alzheimer’s Disease}},
  url          = {{http://dx.doi.org/10.1186/s13024-024-00707-x}},
  doi          = {{10.1186/s13024-024-00707-x}},
  volume       = {{19}},
  year         = {{2024}},
}