Cargando…

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

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 d...

Descripción completa

Detalles Bibliográficos
Autores principales: Wuestefeld, Anika, Pichet Binette, Alexa, Berron, David, Spotorno, Nicola, van Westen, Danielle, Stomrud, Erik, Mattsson-Carlgren, Niklas, Strandberg, Olof, Smith, Ruben, Palmqvist, Sebastian, Glenn, Trevor, Moes, Svenja, Honer, Michael, Arfanakis, Konstantinos, Barnes, Lisa L, Bennett, David A, Schneider, Julie A, Wisse, Laura E M, Hansson, Oskar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10393402/
https://www.ncbi.nlm.nih.gov/pubmed/37082959
http://dx.doi.org/10.1093/brain/awad135
_version_ 1785083149869383680
author Wuestefeld, Anika
Pichet Binette, Alexa
Berron, David
Spotorno, Nicola
van Westen, Danielle
Stomrud, Erik
Mattsson-Carlgren, Niklas
Strandberg, Olof
Smith, Ruben
Palmqvist, Sebastian
Glenn, Trevor
Moes, Svenja
Honer, Michael
Arfanakis, Konstantinos
Barnes, Lisa L
Bennett, David A
Schneider, Julie A
Wisse, Laura E M
Hansson, Oskar
author_facet Wuestefeld, Anika
Pichet Binette, Alexa
Berron, David
Spotorno, Nicola
van Westen, Danielle
Stomrud, Erik
Mattsson-Carlgren, Niklas
Strandberg, Olof
Smith, Ruben
Palmqvist, Sebastian
Glenn, Trevor
Moes, Svenja
Honer, Michael
Arfanakis, Konstantinos
Barnes, Lisa L
Bennett, David A
Schneider, Julie A
Wisse, Laura E M
Hansson, Oskar
author_sort Wuestefeld, Anika
collection PubMed
description 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). (18)F-RO948- and (18)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.
format Online
Article
Text
id pubmed-10393402
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Oxford University Press
record_format MEDLINE/PubMed
spelling pubmed-103934022023-08-02 Age-related and amyloid-beta-independent tau deposition and its downstream effects Wuestefeld, Anika Pichet Binette, Alexa Berron, David Spotorno, Nicola van Westen, Danielle Stomrud, Erik Mattsson-Carlgren, Niklas Strandberg, Olof Smith, Ruben Palmqvist, Sebastian Glenn, Trevor Moes, Svenja Honer, Michael Arfanakis, Konstantinos Barnes, Lisa L Bennett, David A Schneider, Julie A Wisse, Laura E M Hansson, Oskar Brain Original Article 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). (18)F-RO948- and (18)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. Oxford University Press 2023-04-21 /pmc/articles/PMC10393402/ /pubmed/37082959 http://dx.doi.org/10.1093/brain/awad135 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Original Article
Wuestefeld, Anika
Pichet Binette, Alexa
Berron, David
Spotorno, Nicola
van Westen, Danielle
Stomrud, Erik
Mattsson-Carlgren, Niklas
Strandberg, Olof
Smith, Ruben
Palmqvist, Sebastian
Glenn, Trevor
Moes, Svenja
Honer, Michael
Arfanakis, Konstantinos
Barnes, Lisa L
Bennett, David A
Schneider, Julie A
Wisse, Laura E M
Hansson, Oskar
Age-related and amyloid-beta-independent tau deposition and its downstream effects
title Age-related and amyloid-beta-independent tau deposition and its downstream effects
title_full Age-related and amyloid-beta-independent tau deposition and its downstream effects
title_fullStr Age-related and amyloid-beta-independent tau deposition and its downstream effects
title_full_unstemmed Age-related and amyloid-beta-independent tau deposition and its downstream effects
title_short Age-related and amyloid-beta-independent tau deposition and its downstream effects
title_sort age-related and amyloid-beta-independent tau deposition and its downstream effects
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10393402/
https://www.ncbi.nlm.nih.gov/pubmed/37082959
http://dx.doi.org/10.1093/brain/awad135
work_keys_str_mv AT wuestefeldanika agerelatedandamyloidbetaindependenttaudepositionanditsdownstreameffects
AT pichetbinettealexa agerelatedandamyloidbetaindependenttaudepositionanditsdownstreameffects
AT berrondavid agerelatedandamyloidbetaindependenttaudepositionanditsdownstreameffects
AT spotornonicola agerelatedandamyloidbetaindependenttaudepositionanditsdownstreameffects
AT vanwestendanielle agerelatedandamyloidbetaindependenttaudepositionanditsdownstreameffects
AT stomruderik agerelatedandamyloidbetaindependenttaudepositionanditsdownstreameffects
AT mattssoncarlgrenniklas agerelatedandamyloidbetaindependenttaudepositionanditsdownstreameffects
AT strandbergolof agerelatedandamyloidbetaindependenttaudepositionanditsdownstreameffects
AT smithruben agerelatedandamyloidbetaindependenttaudepositionanditsdownstreameffects
AT palmqvistsebastian agerelatedandamyloidbetaindependenttaudepositionanditsdownstreameffects
AT glenntrevor agerelatedandamyloidbetaindependenttaudepositionanditsdownstreameffects
AT moessvenja agerelatedandamyloidbetaindependenttaudepositionanditsdownstreameffects
AT honermichael agerelatedandamyloidbetaindependenttaudepositionanditsdownstreameffects
AT arfanakiskonstantinos agerelatedandamyloidbetaindependenttaudepositionanditsdownstreameffects
AT barneslisal agerelatedandamyloidbetaindependenttaudepositionanditsdownstreameffects
AT bennettdavida agerelatedandamyloidbetaindependenttaudepositionanditsdownstreameffects
AT schneiderjuliea agerelatedandamyloidbetaindependenttaudepositionanditsdownstreameffects
AT wisselauraem agerelatedandamyloidbetaindependenttaudepositionanditsdownstreameffects
AT hanssonoskar agerelatedandamyloidbetaindependenttaudepositionanditsdownstreameffects