Peripheral alterations of mitochondrial function and mitophagy in Alzheimer's disease: from fundamental research to clinical perspectives.

PURPOSE OF REVIEW: Alzheimer's disease (AD) is commonly defined by its hallmark brain pathologies, yet mounting evidence shows that metabolic impairment particularly linked to mitochondrial dysfunction, is a central and systemic feature of the disease. This review highlights consistent abnormalities in mitochondrial function, and turnover (mitophagy) across multiple AD-derived peripheral cells, including skin fibroblasts, lymphocytes, platelets, and peripheral blood mononuclear cells. We also report on potential peripheral AD biomarkers linked to mitochondria dysfunction in AD. RECENT FINDINGS: Mitochondrial abnormalities in peripheral cells from individuals with AD robustly correlate with disease development. These mitochondrial dysfunctions mostly include reduced respiratory chain activity, increased accumulation of reactive oxygen species (ROS), altered mitochondrial membrane potential, and consequently decreased ATP production. Studies have also identified a complex pattern of mitochondrial hyperactivity and hypoactivity in peripheral cells of AD patients that appears to depend on the stage of AD and whether the disease is sporadic or familial. Furthermore, multiple steps of the mitophagy pathway are disrupted in peripheral cells as AD progresses. Finally, biochemical and proteomic analyses of peripheral fluids further support the loss of mitochondrial homeostasis in AD patients. SUMMARY: Collectively, the reviewed findings support mitochondrial homeostasis disruption as a core pathophysiological component of AD and a promising target for biomarker development and therapeutic intervention.