Alzheimer's Imaging Consortium

Area of Science:

• Neuroscience
• Genomics
• Biomarker Discovery

Background:

• Existing Alzheimer's disease (AD) biomarkers primarily focus on central nervous system pathologies (amyloid, tau, neurodegeneration).
• AD pathogenesis is complex and heterogeneous, necessitating accessible blood-based biomarkers reflecting brain molecular changes beyond core pathologies.

Purpose of the Study:

• To identify blood transcriptome signatures associated with Alzheimer's disease (AD) and mild cognitive impairment (MCI).
• To explore associations between blood gene expression patterns and cognitive function and neuroimaging measures.
• To validate blood-brain molecular connections for novel biomarker development.

Main Methods:

• Analyzed peripheral blood transcriptome data from the Mayo Clinic Study of Aging (MCSA) and Alzheimer's Disease Neuroimaging Initiative (ADNI) cohorts.
• Utilized Weighted Gene Co-expression Network Analysis (WGCNA) to identify gene modules associated with AD/MCI, cognition, and neuroimaging.
• Confirmed module preservation in bulk brain RNA-seq data and performed cell-type enrichment and Gene Ontology (GO) analyses.

Main Results:

• Identified specific blood transcriptome modules (M5, M8 upregulated; M1, M10, M13, M16, M21 downregulated) associated with AD/MCI diagnosis and cognitive performance.
• Module M17 correlated with increased microhemorrhages.
• Cell-type enrichment revealed associations with immune cells (basophils, monocytes, neutrophils, natural killer cells, B cells, megakaryocytes); module M1 transcripts linked to better cognition and B cell metabolic activity.

Conclusions:

• Discovered blood transcripts and modules significantly associated with AD/MCI, cognition, and neuroimaging.
• Three modules demonstrated preservation across blood and brain, representing peripheral molecular signatures of central brain pathways.
• These findings highlight potential novel blood biomarkers and therapeutic targets for AD/MCI.