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Alzheimer's Imaging Consortium.

Min Su Kang1,2, Julie Ottoy3,4,5, Andrew Clappison6

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Plasma biomarkers like ptau181 and ptau217 reflect Alzheimer's disease (AD) pathology. This study links these biomarkers to specific molecular pathways, including mitochondrial metabolism and synaptic function, offering new insights into AD mechanisms.

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Area of Science:

  • Neuroscience
  • Biomarkers
  • Genomics

Background:

  • Plasma ptau181 and ptau217 are established indicators of Alzheimer's disease (AD) pathology, reflecting amyloid-beta (Aβ) and tau progression.
  • However, the underlying molecular mechanisms connecting AD pathology to plasma tau biomarkers remain unclear.

Purpose of the Study:

  • To elucidate the molecular pathways linking plasma ptau181 and ptau217 to AD pathology using imaging and transcriptomic data.
  • To identify key biological processes and cellular components associated with plasma tau biomarkers in AD.

Main Methods:

  • Utilized data from 549 participants across ADNI and TRIAD cohorts, including plasma ptau181/217 levels, Aβ-PET, and tau-PET imaging.
  • Employed linear regression and partial least squares (PLS) analysis to associate plasma ptau with PET imaging data and identified transcriptomic profiles from the Allen Human Brain Atlas (AHBA).
  • Conducted gene set enrichment analyses (GO, KEGG) and protein-protein interaction analyses (STRINGdb) to determine associated molecular pathways and biological processes.

Main Results:

  • Plasma ptau181-PET and ptau217-PET relationships significantly correlated with AHBA spatial distribution, explaining substantial variance (>90% and >82%, respectively).
  • Gene enrichment revealed mitochondrial metabolism for ptau181-PET and synaptic function for ptau217-PET as key AD-biodomains.
  • KEGG analysis identified neurodegeneration pathways for ptau181-PET and cytokine-cytokine receptor interactions for ptau217-PET, with AD pathways noted in the TRIAD cohort.

Conclusions:

  • Imaging-transcriptomic analysis identified distinct transcriptomic profiles linked to plasma ptau and AD pathology, highlighting mitochondrial metabolism and synaptic function.
  • The study emphasizes the roles of MAPT, SNCA, PINK1, and GSK3β proteins and intracellular signaling pathways in neurodegeneration and AD dementia.