Alzheimer's Disease and MERC Dysfunction: Integrating Mechanisms, Biomarkers, and Therapeutic Strategies

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, characterized by progressive cognitive decline, memory loss, and neuronal dysfunction. The pathological hallmarks are characterized by extracellular amyloid-β (Aβ) plaques, intracellular tau tangles, neuroinflammation, and synaptic failure. However, these only partially explain disease onset and progression. Recent evidence highlights mitochondria-endoplasmic reticulum contact sites (MERCs) as crucial hubs of cellular homeostasis, integrating calcium exchange, lipid metabolism, redox balance, and autophagy regulation. Dysregulation of MERC signaling is emerging as a central contributor to AD pathogenesis. MERCs orchestrate processes that intersect with amyloidogenic processing, tau hyperphosphorylation, mitochondrial dysfunction, and impaired clearance of protein aggregates. Aberrant tethering protein expression, disrupted calcium transfer, and altered lipid trafficking at MERCs have been reported in both familial and sporadic AD models, underscoring their pathogenic relevance. Moreover, MERCs influence neuroinflammatory cascades and synaptic remodeling, bridging molecular alterations with clinical manifestations. This review synthesizes current knowledge on MERC biology in the context of AD, highlighting molecular mechanisms, disease-specific perturubations, and therapeutic opportunities. In this review, we discussed pharmacological and genetic interventions targeting MERCs, including small molecules, natural compounds, and nanotechnology-based approaches. Taken together, this review outlines open research questions and future directions, underscoring MERC signaling as a promising frontier for therapeutic innovation in AD.