Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

Longitudinal tau-PET accumulation and downstream effects in amyloid-beta negative cognitively unimpaired individuals

Wuestefeld, Anika LU orcid ; Spotorno, Nicola LU ; Binette, Alexa Pichet LU ; Mattsson-Carlgren, Niklas LU orcid ; Ossenkoppele, Rik LU ; Palmqvist, Sebastian LU orcid ; Smith, Ruben LU ; Stomrud, Erik LU orcid ; Strandberg, Olof LU and van Westen, Danielle LU orcid , et al. (2025) In Alzheimer's & dementia : the journal of the Alzheimer's Association 21. p.104826-104826
Abstract

BACKGROUND: Previous studies, including ours (Wuestefeld et al., Brain, 2023), showed tau positron emission tomography (PET) uptake in medial temporal and neocortical regions of amyloid-beta (Aβ)-negative cognitively unimpaired (CU) individuals, associated with neurodegeneration and worse memory performance. To further understand if tau-PET uptake is clinically relevant in this population, we characterized Aβ-negative CU individuals with higher longitudinal tau-PET accumulation and its associations with atrophy and cognitive decline. METHOD: We included 333 CU BioFINDER-2 participants, negative for both global [18F]flutemetamol Aβ-PET and cerebrospinal fluid (CSF) Aβ42/Aβ40 (age=63.8, 55% female, 2.28±1.36 years follow-up). Using linear... (More)

BACKGROUND: Previous studies, including ours (Wuestefeld et al., Brain, 2023), showed tau positron emission tomography (PET) uptake in medial temporal and neocortical regions of amyloid-beta (Aβ)-negative cognitively unimpaired (CU) individuals, associated with neurodegeneration and worse memory performance. To further understand if tau-PET uptake is clinically relevant in this population, we characterized Aβ-negative CU individuals with higher longitudinal tau-PET accumulation and its associations with atrophy and cognitive decline. METHOD: We included 333 CU BioFINDER-2 participants, negative for both global [18F]flutemetamol Aβ-PET and cerebrospinal fluid (CSF) Aβ42/Aβ40 (age=63.8, 55% female, 2.28±1.36 years follow-up). Using linear mixed-effects models, we calculated the rate of change (ROC) in [18F]RO948 tau-PET SUVR in composite regions of interest (ROI), recapitulating the Braak stages. Individuals were classified as "tau-accumulators" vs. "non-accumulators" based on the mean+standard deviation of Braak I-IV tau-PET ROC in young controls (20-40 years, n = 29; Figure 1A). Tau-PET ROC and thickness of the entorhinal cortex, Brodmann area (BA)35 and neocortical AD-regions (precuneus/posterior cingulate, lateral occipital, superior frontal) were extracted. Group differences and associations with CSF AD biomarkers, delayed word-list recall, and modified Preclinical Alzheimer Cognitive Composite were tested. RESULT: 16% of individuals were identified as tau-accumulators. They were older, had lower levels of Aβ as indicated by a higher CSF Aβ42/40 ratio (no difference on Aβ-PET) and numerically higher CSF MTBR-tau243/Aβ40 (not significant, note missingness; Figure 1B+C). Tau-accumulators showed significantly greater tau-PET at baseline and accumulation in regions not included in Braak I-IV (all p <0.001). Additionally, we observed more atrophy in BA35 (Figure 2A, not after age-adjustment) and numerically worse baseline cognitive performance, but no difference in decline over time (Figure 2B). In the whole sample, Braak I-IV tau-PET accumulation was significantly associated with increased age, more BA35 atrophy and at trend-level with higher levels of CSF Aβ42/40 and CSF MTBR-tau243/Aβ40 (Figure 3). CONCLUSION: A subgroup of Aβ- CU individuals show longitudinal tau accumulation across the neocortex. Preliminary results suggest an association with a tau-specific CSF biomarker and focal atrophy, which did not translate to changes in cognition. We will complement our analyses with a data-driven approach of classifying tau-accumulators.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; ; and , et al. (More)
; ; ; ; ; ; ; ; ; ; and (Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Alzheimer's & dementia : the journal of the Alzheimer's Association
volume
21
pages
104826 - 104826
publisher
Wiley
external identifiers
  • scopus:105026840995
  • pmid:41498671
ISSN
1552-5279
DOI
10.1002/alz70856_104826
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2025 The Alzheimer's Association. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.
id
5bed7bb6-c166-4ff8-9dc2-93ed2e92a3a2
date added to LUP
2026-02-12 15:01:00
date last changed
2026-02-13 03:40:42
@misc{5bed7bb6-c166-4ff8-9dc2-93ed2e92a3a2,
  abstract     = {{<p>BACKGROUND: Previous studies, including ours (Wuestefeld et al., Brain, 2023), showed tau positron emission tomography (PET) uptake in medial temporal and neocortical regions of amyloid-beta (Aβ)-negative cognitively unimpaired (CU) individuals, associated with neurodegeneration and worse memory performance. To further understand if tau-PET uptake is clinically relevant in this population, we characterized Aβ-negative CU individuals with higher longitudinal tau-PET accumulation and its associations with atrophy and cognitive decline. METHOD: We included 333 CU BioFINDER-2 participants, negative for both global [18F]flutemetamol Aβ-PET and cerebrospinal fluid (CSF) Aβ42/Aβ40 (age=63.8, 55% female, 2.28±1.36 years follow-up). Using linear mixed-effects models, we calculated the rate of change (ROC) in [18F]RO948 tau-PET SUVR in composite regions of interest (ROI), recapitulating the Braak stages. Individuals were classified as "tau-accumulators" vs. "non-accumulators" based on the mean+standard deviation of Braak I-IV tau-PET ROC in young controls (20-40 years, n = 29; Figure 1A). Tau-PET ROC and thickness of the entorhinal cortex, Brodmann area (BA)35 and neocortical AD-regions (precuneus/posterior cingulate, lateral occipital, superior frontal) were extracted. Group differences and associations with CSF AD biomarkers, delayed word-list recall, and modified Preclinical Alzheimer Cognitive Composite were tested. RESULT: 16% of individuals were identified as tau-accumulators. They were older, had lower levels of Aβ as indicated by a higher CSF Aβ42/40 ratio (no difference on Aβ-PET) and numerically higher CSF MTBR-tau243/Aβ40 (not significant, note missingness; Figure 1B+C). Tau-accumulators showed significantly greater tau-PET at baseline and accumulation in regions not included in Braak I-IV (all p &lt;0.001). Additionally, we observed more atrophy in BA35 (Figure 2A, not after age-adjustment) and numerically worse baseline cognitive performance, but no difference in decline over time (Figure 2B). In the whole sample, Braak I-IV tau-PET accumulation was significantly associated with increased age, more BA35 atrophy and at trend-level with higher levels of CSF Aβ42/40 and CSF MTBR-tau243/Aβ40 (Figure 3). CONCLUSION: A subgroup of Aβ- CU individuals show longitudinal tau accumulation across the neocortex. Preliminary results suggest an association with a tau-specific CSF biomarker and focal atrophy, which did not translate to changes in cognition. We will complement our analyses with a data-driven approach of classifying tau-accumulators.</p>}},
  author       = {{Wuestefeld, Anika and Spotorno, Nicola and Binette, Alexa Pichet and Mattsson-Carlgren, Niklas and Ossenkoppele, Rik and Palmqvist, Sebastian and Smith, Ruben and Stomrud, Erik and Strandberg, Olof and van Westen, Danielle and Hansson, Oskar and Wisse, Laura E.M.}},
  issn         = {{1552-5279}},
  language     = {{eng}},
  month        = {{12}},
  note         = {{Conference Abstract}},
  pages        = {{104826--104826}},
  publisher    = {{Wiley}},
  series       = {{Alzheimer's & dementia : the journal of the Alzheimer's Association}},
  title        = {{Longitudinal tau-PET accumulation and downstream effects in amyloid-beta negative cognitively unimpaired individuals}},
  url          = {{http://dx.doi.org/10.1002/alz70856_104826}},
  doi          = {{10.1002/alz70856_104826}},
  volume       = {{21}},
  year         = {{2025}},
}