Integrated Multi-Omics Analysis and Cross-Model Validation Reveal Mitochondrial Signatures in Alzheimer's Disease

Area of Science:

• Neuroscience
• Genetics
• Biochemistry

Background:

• Mitochondrial dysfunction is crucial in Alzheimer's disease (AD) pathogenesis.
• The precise molecular mechanisms linking mitochondrial issues to AD remain unclear.

Purpose of the Study:

• To identify and validate mitochondria-related biomarkers for AD risk and brain resilience.
• To elucidate molecular mechanisms of mitochondrial dysfunction in AD.

Main Methods:

• Integrated multi-omics (genomics, methylation, RNA-seq, miRNA) from ROSMAP and ADNI cohorts.
• Applied machine learning to identify and validate mitochondrial biomarkers.
• Validated findings in an AD mouse model and an in vitro oxidative stress model.

Main Results:

• Identified hsa-miR-129-5p and SLC6A12 as key regulators; highlighted the tricarboxylic acid (TCA) cycle's importance.
• Observed cognitive deficits and transcriptomic changes in the AD mouse model.
• Found a core signature of seven genes, including APOE and CLOCK, dysregulated in both models, linking them to AD pathology.

Conclusions:

• Provided functional validation of mitochondrial biomarkers and mechanisms in AD.
• Offers insights into AD pathogenesis and potential therapeutic strategies targeting mitochondrial dysfunction.