Alzheimer's disease (AD) presents a complex interplay of molecular alterations, yet understanding its pathogenesis remains a challenge. In this study, we delved into the intricate landscape of proteome and transcriptome changes in AD brains compared to healthy controls, examining 788 brain samples revealing common alterations at both protein and mRNA levels. Moreover, our analysis revealed distinct protein-level changes in aberrant energy metabolism pathways in AD brains that were not evident at the mRNA level. This suggests that the changes in protein expression could provide a deeper molecular representation of AD pathogenesis. Subsequently, using a comparative proteomic approach, we explored the therapeutic potential of mesenchymal stem cell-derived extracellular vehicles (EVs), isolated through various methods, in mitigating AD-associated changes at the protein level. Our analysis revealed a particular EV-subtype that can be utilized for compensating dysregulated mitochondrial proteostasis in the AD brain. By using network biology approaches, we further revealed the potential regulators of key therapeutic proteins. Overall, our study illuminates the significance of proteome alterations in AD pathogenesis and identifies the therapeutic promise of a specific EV subpopulation with reduced pro-inflammatory protein cargo and enriched proteins to target mitochondrial proteostasis.