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Age-related and amyloid-beta-independent tau deposition and its downstream effects

Wuestefeld, Anika LU orcid ; Pichet Binette, Alexa LU ; Berron, David LU ; Spotorno, Nicola LU ; van Westen, Danielle LU orcid ; Stomrud, Erik LU orcid ; Mattsson-Carlgren, Niklas LU orcid ; Strandberg, Olof LU ; Smith, Ruben LU and Palmqvist, Sebastian LU orcid , et al. (2023) In Brain : a journal of neurology 146(8). p.3192-3205
Abstract

Amyloid-β (Aβ) is hypothesized to facilitate the spread of tau pathology beyond the medial temporal lobe. However, there is evidence that, independently of Aβ, age-related tau pathology might be present outside of the medial temporal lobe. We therefore aimed to study age-related Aβ-independent tau deposition outside the medial temporal lobe in two large cohorts and to investigate potential downstream effects of this on cognition and structural measures. We included 545 cognitively unimpaired adults (40-92 years) from the BioFINDER-2 study (in vivo) and 639 (64-108 years) from the Rush Alzheimer's Disease Center cohorts (ex vivo). 18F-RO948- and 18F-flutemetamol-PET standardized uptake value ratios were calculated... (More)

Amyloid-β (Aβ) is hypothesized to facilitate the spread of tau pathology beyond the medial temporal lobe. However, there is evidence that, independently of Aβ, age-related tau pathology might be present outside of the medial temporal lobe. We therefore aimed to study age-related Aβ-independent tau deposition outside the medial temporal lobe in two large cohorts and to investigate potential downstream effects of this on cognition and structural measures. We included 545 cognitively unimpaired adults (40-92 years) from the BioFINDER-2 study (in vivo) and 639 (64-108 years) from the Rush Alzheimer's Disease Center cohorts (ex vivo). 18F-RO948- and 18F-flutemetamol-PET standardized uptake value ratios were calculated for regional tau and global/regional Aβ in vivo. Immunohistochemistry was used to estimate Aβ load and tangle density ex vivo. In vivo medial temporal lobe volumes (subiculum, cornu ammonis 1) and cortical thickness (entorhinal cortex, Brodmann area 35) were obtained using Automated Segmentation for Hippocampal Subfields packages. Thickness of early and late neocortical Alzheimer's disease regions was determined using FreeSurfer. Global cognition and episodic memory were estimated to quantify cognitive functioning. In vivo age-related tau deposition was observed in the medial temporal lobe and in frontal and parietal cortical regions, which was statistically significant when adjusting for Aβ. This was also observed in individuals with low Aβ load. Tau deposition was negatively associated with cortical volumes and thickness in temporal and parietal regions independently of Aβ. The associations between age and cortical volume or thickness were partially mediated via tau in regions with early Alzheimer's disease pathology, i.e. early tau and/or Aβ pathology (subiculum/Brodmann area 35/precuneus/posterior cingulate). Finally, the associations between age and cognition were partially mediated via tau in Brodmann area 35, even when including Aβ-PET as covariate. Results were validated in the ex vivo cohort showing age-related and Aβ-independent increases in tau aggregates in and outside the medial temporal lobe. Ex vivo age-cognition associations were mediated by medial and inferior temporal tau tangle density, while correcting for Aβ density. Taken together, our study provides support for primary age-related tauopathy even outside the medial temporal lobe in vivo and ex vivo, with downstream effects on structure and cognition. These results have implications for our understanding of the spreading of tau outside the medial temporal lobe, also in the context of Alzheimer's disease. Moreover, this study suggests the potential utility of tau-targeting treatments in primary age-related tauopathy, likely already in preclinical stages in individuals with low Aβ pathology.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
ageing, amyloid-beta, autoradiography, medial temporal lobe subregions, MRI, PART, tau-PET imaging
in
Brain : a journal of neurology
volume
146
issue
8
pages
14 pages
publisher
Oxford University Press
external identifiers
  • scopus:85166389553
  • pmid:37082959
ISSN
1460-2156
DOI
10.1093/brain/awad135
language
English
LU publication?
yes
id
b3246618-2a1d-4827-9bc3-d6dc2fbb17e5
date added to LUP
2023-04-24 20:44:37
date last changed
2024-06-29 03:21:58
@article{b3246618-2a1d-4827-9bc3-d6dc2fbb17e5,
  abstract     = {{<p>Amyloid-β (Aβ) is hypothesized to facilitate the spread of tau pathology beyond the medial temporal lobe. However, there is evidence that, independently of Aβ, age-related tau pathology might be present outside of the medial temporal lobe. We therefore aimed to study age-related Aβ-independent tau deposition outside the medial temporal lobe in two large cohorts and to investigate potential downstream effects of this on cognition and structural measures. We included 545 cognitively unimpaired adults (40-92 years) from the BioFINDER-2 study (in vivo) and 639 (64-108 years) from the Rush Alzheimer's Disease Center cohorts (ex vivo). <sup>18</sup>F-RO948- and <sup>18</sup>F-flutemetamol-PET standardized uptake value ratios were calculated for regional tau and global/regional Aβ in vivo. Immunohistochemistry was used to estimate Aβ load and tangle density ex vivo. In vivo medial temporal lobe volumes (subiculum, cornu ammonis 1) and cortical thickness (entorhinal cortex, Brodmann area 35) were obtained using Automated Segmentation for Hippocampal Subfields packages. Thickness of early and late neocortical Alzheimer's disease regions was determined using FreeSurfer. Global cognition and episodic memory were estimated to quantify cognitive functioning. In vivo age-related tau deposition was observed in the medial temporal lobe and in frontal and parietal cortical regions, which was statistically significant when adjusting for Aβ. This was also observed in individuals with low Aβ load. Tau deposition was negatively associated with cortical volumes and thickness in temporal and parietal regions independently of Aβ. The associations between age and cortical volume or thickness were partially mediated via tau in regions with early Alzheimer's disease pathology, i.e. early tau and/or Aβ pathology (subiculum/Brodmann area 35/precuneus/posterior cingulate). Finally, the associations between age and cognition were partially mediated via tau in Brodmann area 35, even when including Aβ-PET as covariate. Results were validated in the ex vivo cohort showing age-related and Aβ-independent increases in tau aggregates in and outside the medial temporal lobe. Ex vivo age-cognition associations were mediated by medial and inferior temporal tau tangle density, while correcting for Aβ density. Taken together, our study provides support for primary age-related tauopathy even outside the medial temporal lobe in vivo and ex vivo, with downstream effects on structure and cognition. These results have implications for our understanding of the spreading of tau outside the medial temporal lobe, also in the context of Alzheimer's disease. Moreover, this study suggests the potential utility of tau-targeting treatments in primary age-related tauopathy, likely already in preclinical stages in individuals with low Aβ pathology.</p>}},
  author       = {{Wuestefeld, Anika and Pichet Binette, Alexa and Berron, David and Spotorno, Nicola and van Westen, Danielle and Stomrud, Erik and Mattsson-Carlgren, Niklas and Strandberg, Olof and Smith, Ruben and Palmqvist, Sebastian and Glenn, Trevor and Moes, Svenja and Honer, Michael and Arfanakis, Konstantinos and Barnes, Lisa L and Bennett, David A and Schneider, Julie A and Wisse, Laura E M and Hansson, Oskar}},
  issn         = {{1460-2156}},
  keywords     = {{ageing; amyloid-beta; autoradiography; medial temporal lobe subregions; MRI; PART; tau-PET imaging}},
  language     = {{eng}},
  month        = {{08}},
  number       = {{8}},
  pages        = {{3192--3205}},
  publisher    = {{Oxford University Press}},
  series       = {{Brain : a journal of neurology}},
  title        = {{Age-related and amyloid-beta-independent tau deposition and its downstream effects}},
  url          = {{http://dx.doi.org/10.1093/brain/awad135}},
  doi          = {{10.1093/brain/awad135}},
  volume       = {{146}},
  year         = {{2023}},
}