Synaptic mitochondrial dysfunction and Alzheimer’s disease: from molecular mechanisms to therapeutic strategies

Abstract

The ability of AD treatments targeting classic pathological proteins to achieve meaningful clinical outcomes has been severely limited, shifting attention to the earlier upstream pathways that drive disease progression. Increasing evidence indicates that synaptic mitochondrial dysfunction is an early pathological event that directly contributes to synaptic loss and cognitive decline. This review focuses on how four interrelated pathologies—disrupted energy metabolism, calcium overload, imbalanced mitochondrial fission/fusion, and defective autophagy—converge to impair synaptic function and plasticity. Emerging therapeutic strategies aimed at protecting and restoring synaptic mitochondrial health, including mitochondria-targeted antioxidants, metabolic modulators, calcium signaling inhibitors, dynamics regulators, and autophagy inducers, are also examined. A central focus of the review is clinical translation: we summarize the preclinical evidence and critically evaluate major obstacles such as the lack of synapse-specific biomarkers, challenges in blood–brain barrier penetration and targeted delivery, and substantial patient heterogeneity. Rather than proposing a fully defined translational framework, we highlight the essential requirements for building one, centered on synaptic mitochondrial bioenergetics and quality control. Specifically, early and accurate biomarkers must be developed, patients should be stratified promptly, and rational combination therapies with complementary mechanisms need to be implemented. This organelle-centered perspective will clarify AD pathogenesis and help guide the development of next-generation neuroprotective therapies.