Personalised regional modelling predicts tau progression in the human brain

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Abstract
Aggregation of the hyperphosphorylated tau protein is a central driver of Alzheimer’s disease, and its accumulation exhibits a rich spatiotemporal pattern that unfolds during the course of the disease, sequentially progressing through the brain across axonal connections. It is unclear how this spatiotemporal process is orchestrated, namely, to what extent the spread of pathologic tau is governed by transport between brain regions, local production, or both. To address this, we develop a mechanistic model from tau PET data to describe tau dynamics along the Alzheimer’s disease timeline. Our analysis reveals longitudinal changes in production and transport dynamics in two independent cohorts, with subjects in the early stage of the disease exhibiting transport-dominated spread, consistent with an initial spread of pathological tau seeds, and subjects in the late stage disease characterized primarily by local tau production. Further, we demonstrate that the model can predict accurately subject-specific longitudinal tau accumulation at the regional level, potentially providing a new clinical tool to monitor and classify patient disease progression.
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Funding Information
  • Engineering and Physical Sciences Research Council (EP/L016044/1)
  • F. Hoffmann-La Roche
  • SciLifeLab and Wallenberg Data Driven Life Science Program (KAW 2020.0239)
  • Fonds de Recherche du Québec - Santé (298314)
  • Wellcome Trust (221933/Z/20/Z)
  • Wellcome Trust (215573/Z/19/Z)
  • F. Hoffmann-La Roche
  • F. Hoffmann-La Roche
  • National Institute of Aging (R01AG083740)
  • European Research Council (ADG-101096455)
  • Alzheimer’s Association (ZEN24-1069572)
  • Alzheimer's Association (SG-23-1061717)
  • GHR Foundation
  • Engineering and Physical Sciences Research Council (EP/R020205/1)
  • Swedish Research Council (2022-00775)
  • Swedish Research Council (2021-02219)
  • ERA PerMed (ERAPERMED2021-184)
  • Knut and Alice Wallenberg Foundation (2017-0383)
  • Knut and Alice Wallenberg Foundation (2022-0231)
  • Strategic Research Area MultiPark Lund University
  • swedish alzheimer foundation (AF-980907)
  • swedish alzheimer foundation (AF-994229)
  • swedish alzheimer foundation (AF-1011799)
  • Swedish brain foundation (FO2021-0293)
  • Swedish brain foundation (FO2023-0163)
  • Parkinson Foundation of Sweden (1412/22)
  • Cure Alzheimer's Fund
  • Rönström Family Foundation
  • Berg Family Foundation
  • Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse
  • Michael J Fox Foundation (MJFF-025507)
  • Lilly Research Award Program
  • SkÃ¥ne University Hospital Foundation (2020-O000028)
  • Regionalt Forskningsstöd (2022-1259)
  • WASP and DDLS Joint call for research projects (WASP/DDLS22-066)
  • Greta and Johan Kock Foundation
  • Swedish federal government under the ALF agreement (2022-Projekt0080)
  • Swedish federal government under the ALF agreement (2022-Projekt0107)
  • Engineering and Physical Sciences Research Council grant (EP/R020205/1)

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