Transcriptomic predictors of rapid progression from mild cognitive impairment to Alzheimer's disease.

BACKGROUND: Effective treatment for Alzheimer's disease (AD) remains an unmet need. Thus, identifying patients with mild cognitive impairment (MCI) who are at high-risk of progressing to AD is crucial for early intervention. METHODS: Blood-based transcriptomics analyses were performed using a longitudinal study cohort to compare progressive MCI (P-MCI, n = 28), stable MCI (S-MCI, n = 39), and AD patients (n = 49). Statistical DESeq2 analysis and machine learning methods were employed to identify differentially expressed genes (DEGs) and develop prediction models. RESULTS: We discovered a remarkable gender-specific difference in DEGs that distinguish P-MCI from S-MCI. Machine learning models achieved high accuracy in distinguishing P-MCI from S-MCI (AUC 0.93), AD from S-MCI (AUC 0.94), and AD from P-MCI (AUC 0.92). An 8-gene signature was identified for distinguishing P-MCI from S-MCI. CONCLUSIONS: Blood-based transcriptomic biomarker signatures show great utility in identifying high-risk MCI patients, with mitochondrial processes emerging as a crucial contributor to AD progression.