BACKGROUND: Alzheimer's disease (AD) is characterized by complex molecular alterations that complicate its pathogenesis and contribute to the lack of effective treatments. Mesenchymal stem cell-derived extracellular vesicles (EVs) have shown promise in AD models, but results across different EV subpopulations remain inconsistent. OBJECTIVES: This study investigates proteomic and transcriptomic data from publicly available postmortem AD brain datasets to identify molecular changes at both the gene and protein levels. These findings are then compared with the proteomes of various EV subpopulations, differing in size and distribution, to determine the most promising subtype for compensating molecular degeneration in AD. DESIGN: We conducted a comprehensive analysis of 788 brain samples, including 481 AD cases and 307 healthy controls, examining protein and mRNA levels to uncover AD-associated molecular changes. These findings were then compared with the proteomes of different EV subpopulations to identify potential therapeutic candidates. METHODS: A multi-omics approach was employed, integrating proteomic and transcriptomic data analysis, miRNA and transcription factor profiling, protein-protein network construction, hub gene identification, and enrichment analyses. This approach aimed to explore molecular changes in AD brains and pinpoint the most relevant EV subpopulations for therapeutic intervention. RESULTS: We identified common alterations in the cAMP signaling pathway and coagulation cascade at both the protein and mRNA levels. Distinct changes in energy metabolism were observed at the protein level but not at the mRNA level. A specific EV subtype, characterized by a broader size distribution obtained through high-speed centrifugation, was identified as capable of compensating for dysregulated mitochondrial proteostasis in AD brains. Network biology analyses further highlighted potential regulators of key therapeutic proteins within this EV subtype. CONCLUSION: This study underscores the critical role of proteomic alterations in AD and identifies a promising EV subpopulation, enriched with proteins targeting mitochondrial proteostasis, as a potential therapeutic strategy for AD.