Peripheral blood microarray-based transcriptomic and epigenetic analyses identify immune, inflammation, and metabolic dysregulation in Alzheimer's disease.

Leveraging multi-omics to better understand the molecular signatures and pathways underlying Alzheimer's disease (AD) pathogenesis is critical for early diagnosis and disease modifying interventions. We performed peripheral blood transcriptome (N = 669) and epigenome microarray analyses (N = 553) on non-Hispanic white participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to identify molecular signatures of AD. We identified specific transcripts (e.g., MAPK14, GM2A, CD177) and co-expression networks that were dysregulated in AD, marked by a strong influence of APOE ε4 genotype, and characterized by a consistent pattern of immune activation, inflammation, and metabolic suppression. Further, these peripheral signatures were linked to central AD pathology (amyloid PET, CSF p-tau181) and neurodegeneration (plasma NfL, regional atrophy), with two genes, MXD3 and NR4A1, identified as protective against progression from MCI to AD. Our work emphasizes the importance of APOE genotypes in AD pathophysiology and highlights potential targets for biomarker discovery and personalized therapeutic strategies.