Alzheimer's Imaging Consortium

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.