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Plasma phosphorylated tau217 strongly associates with memory deficits in the Alzheimer's disease spectrum

Fernández Arias, Jaime ; Brum, Wagner S. ; Salvadó, Gemma LU ; Therriault, Joseph ; Servaes, Stijn ; Wang, Yi Ting ; Aumont, Etienne ; Rahmouni, Nesrine ; Macedo, Arthur C. and Quispialaya, Kely Monica , et al. (2025) In Brain 148(7). p.2384-2399
Abstract

Plasma phosphorylated tau (p-tau) biomarkers open unprecedented opportunities for identifying carriers of Alzheimer's disease pathophysiology in early disease stages using minimally invasive techniques. Plasma p-tau biomarkers are believed to reflect tau phosphorylation and secretion. However, it remains unclear to what extent the magnitude of plasma p-tau abnormalities reflects neuronal network disturbance in the form of cognitive impairment. To address this question, we included 103 cognitively unimpaired elderly and 40 cognitively impaired, amyloid-β-positive individuals from the TRIAD cohort, in addition to 336 cognitively unimpaired and 216 cognitively impaired, amyloid-β-positive older adults from the BioFINDER-2 cohort.... (More)

Plasma phosphorylated tau (p-tau) biomarkers open unprecedented opportunities for identifying carriers of Alzheimer's disease pathophysiology in early disease stages using minimally invasive techniques. Plasma p-tau biomarkers are believed to reflect tau phosphorylation and secretion. However, it remains unclear to what extent the magnitude of plasma p-tau abnormalities reflects neuronal network disturbance in the form of cognitive impairment. To address this question, we included 103 cognitively unimpaired elderly and 40 cognitively impaired, amyloid-β-positive individuals from the TRIAD cohort, in addition to 336 cognitively unimpaired and 216 cognitively impaired, amyloid-β-positive older adults from the BioFINDER-2 cohort. Participants had tau PET scans, amyloid PET scans or amyloid CSF, p-tau217, p-tau181 and p-tau231 blood measures, structural T1-MRI and cognitive assessments. In this cross-sectional study, we used regression models and correlation analyses to assess the relationship between plasma biomarkers and cognitive scores. Furthermore, we applied receiver operating characteristic curves to assess cognitive impairment across plasma biomarkers. Finally, we categorized participants into amyloid (A), p-tau (T1) and tau PET (T2) positive (+) or negative (-) profiles and ran non-parametric comparisons to assess differences across cognitive domains. We found that plasma p-tau217 was more associated with cognitive performance than p-tau181 and p-tau231 and that this relationship was particularly strong for memory scores (TRIAD: βp-tau217 = -0.53, βp-tau181 = -0.35 and βp-tau231 = -0.24; BioFINDER-2: βp-tau217 = -0.52, βp-tau181 = -0.24 and βp-tau231 = -0.29). Associations in amyloid-β-positive participants resembled these results, but other cognitive scores also showed strong associations in cognitively impaired individuals. Moreover, plasma p-tau217 outperformed plasma p-tau181 and plasma p-tau231 in identifying memory impairment (area under the curve values for TRIAD: p-tau217 = 0.86, p-tau181 = 0.77 and p-tau231 = 0.75; and for BioFINDER-2: p-tau217 = 0.86, p-tau181 = 0.76 and p-tau231 = 0.81) and in identifying executive function impairment only in the BioFINDER-2 cohort (p-tau217 = 0.82, p-tau181 = 0.76 and p-tau231 = 0.76). Lastly, we showed that subtle memory deficits were present in A+T1+T2- participants for plasma p-tau217 (P = 0.007) and plasma p-tau181 (P = 0.01) in the TRIAD cohort and for all biomarkers across cognitive domains in A+T1+T2- and A+T1+T2- individuals (P < 0.001 in all) in the BioFINDER-2 cohort. The A+T1+T2- individuals showed cognitive deficits in both cohorts (P < 0.001 in all). Together, our results suggest that plasma p-tau217 stands out as a biomarker capable of identifying memory deficits attributable to Alzheimer's disease and that memory impairment certainly occurs in amyloid-β- and plasma p-tau-positive individuals who have no significant amounts of tau in the neocortex.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Alzheimer's disease, memory, plasma p-tau, tau discordance
in
Brain
volume
148
issue
7
pages
16 pages
publisher
Oxford University Press
external identifiers
  • pmid:39879633
  • scopus:105010077865
ISSN
0006-8950
DOI
10.1093/brain/awaf033
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2025 The Author(s). Published by Oxford University Press on behalf of the Guarantors of Brain.
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7a40030c-fbff-4616-a9bc-5ccd9b0d7cd8
date added to LUP
2025-12-15 15:51:37
date last changed
2025-12-16 03:20:47
@article{7a40030c-fbff-4616-a9bc-5ccd9b0d7cd8,
  abstract     = {{<p>Plasma phosphorylated tau (p-tau) biomarkers open unprecedented opportunities for identifying carriers of Alzheimer's disease pathophysiology in early disease stages using minimally invasive techniques. Plasma p-tau biomarkers are believed to reflect tau phosphorylation and secretion. However, it remains unclear to what extent the magnitude of plasma p-tau abnormalities reflects neuronal network disturbance in the form of cognitive impairment. To address this question, we included 103 cognitively unimpaired elderly and 40 cognitively impaired, amyloid-β-positive individuals from the TRIAD cohort, in addition to 336 cognitively unimpaired and 216 cognitively impaired, amyloid-β-positive older adults from the BioFINDER-2 cohort. Participants had tau PET scans, amyloid PET scans or amyloid CSF, p-tau<sub>217</sub>, p-tau<sub>181</sub> and p-tau<sub>231</sub> blood measures, structural T<sub>1</sub>-MRI and cognitive assessments. In this cross-sectional study, we used regression models and correlation analyses to assess the relationship between plasma biomarkers and cognitive scores. Furthermore, we applied receiver operating characteristic curves to assess cognitive impairment across plasma biomarkers. Finally, we categorized participants into amyloid (A), p-tau (T<sub>1</sub>) and tau PET (T<sub>2</sub>) positive (+) or negative (-) profiles and ran non-parametric comparisons to assess differences across cognitive domains. We found that plasma p-tau<sub>217</sub> was more associated with cognitive performance than p-tau<sub>181</sub> and p-tau<sub>231</sub> and that this relationship was particularly strong for memory scores (TRIAD: β<sub>p-tau217</sub> = -0.53, β<sub>p-tau181</sub> = -0.35 and β<sub>p-tau231</sub> = -0.24; BioFINDER-2: β<sub>p-tau217</sub> = -0.52, β<sub>p-tau181</sub> = -0.24 and β<sub>p-tau231</sub> = -0.29). Associations in amyloid-β-positive participants resembled these results, but other cognitive scores also showed strong associations in cognitively impaired individuals. Moreover, plasma p-tau<sub>217</sub> outperformed plasma p-tau<sub>181</sub> and plasma p-tau<sub>231</sub> in identifying memory impairment (area under the curve values for TRIAD: p-tau217 = 0.86, p-tau181 = 0.77 and p-tau231 = 0.75; and for BioFINDER-2: p-tau<sub>217</sub> = 0.86, p-tau<sub>181</sub> = 0.76 and p-tau<sub>231</sub> = 0.81) and in identifying executive function impairment only in the BioFINDER-2 cohort (p-tau<sub>217</sub> = 0.82, p-tau<sub>181</sub> = 0.76 and p-tau231 = 0.76). Lastly, we showed that subtle memory deficits were present in A+T<sub>1</sub>+T<sub>2</sub>- participants for plasma p-tau<sub>217</sub> (P = 0.007) and plasma p-tau<sub>181</sub> (P = 0.01) in the TRIAD cohort and for all biomarkers across cognitive domains in A+T<sub>1</sub>+T<sub>2</sub>- and A+T<sub>1</sub>+T<sub>2</sub>- individuals (P &lt; 0.001 in all) in the BioFINDER-2 cohort. The A+T<sub>1</sub>+T<sub>2</sub>- individuals showed cognitive deficits in both cohorts (P &lt; 0.001 in all). Together, our results suggest that plasma p-tau<sub>217</sub> stands out as a biomarker capable of identifying memory deficits attributable to Alzheimer's disease and that memory impairment certainly occurs in amyloid-β- and plasma p-tau-positive individuals who have no significant amounts of tau in the neocortex.</p>}},
  author       = {{Fernández Arias, Jaime and Brum, Wagner S. and Salvadó, Gemma and Therriault, Joseph and Servaes, Stijn and Wang, Yi Ting and Aumont, Etienne and Rahmouni, Nesrine and Macedo, Arthur C. and Quispialaya, Kely Monica and Hosseini, Seyyed Ali and Kunach, Peter and Jia, Wan Lu and Chan, Tevy and Trudel, Lydia and Hall, Brandon and Zheng, Yanseng and Mohapatra, Sejal and Mathotaarachchi, Sulantha S. and Vitali, Paolo and Tissot, Cécile and Bezgin, Gleb and Iturria-Medina, Yasser and Ashton, Nicholas J. and Benedet, Andréa Lessa and Karikari, Thomas K. and Triana-Baltzer, Gallen and Klostranec, Jesse M. and Kolb, Hartmuth C. and Zimmer, Eduardo R. and Janelidze, Shorena and Mattsson-Carlgren, Niklas and Stomrud, Erik and Palmqvist, Sebastian and Zetterberg, Henrik and Blennow, Kaj and Pascoal, Tharick and Montembeault, Maxime and Hansson, Oskar and Rosa-Neto, Pedro}},
  issn         = {{0006-8950}},
  keywords     = {{Alzheimer's disease; memory; plasma p-tau; tau discordance}},
  language     = {{eng}},
  month        = {{07}},
  number       = {{7}},
  pages        = {{2384--2399}},
  publisher    = {{Oxford University Press}},
  series       = {{Brain}},
  title        = {{Plasma phosphorylated tau<sub>217</sub> strongly associates with memory deficits in the Alzheimer's disease spectrum}},
  url          = {{http://dx.doi.org/10.1093/brain/awaf033}},
  doi          = {{10.1093/brain/awaf033}},
  volume       = {{148}},
  year         = {{2025}},
}