This review synthesizes evidence that disrupted endoplasmic reticulum–mitochondria contact sites (ERMCs/MAMs) alter Ca2+ homeostasis, lipid transfer, mitochondrial dynamics and ER stress to drive Alzheimer’s pathology including Aβ production and mitochondrial dysfunction.

Although AD-focused, the paper highlights mechanistic nodes (ER–mitochondria Ca2+ signaling, mitochondrial integrity, lipid metabolism, ER stress) that are shared with Parkinson’s disease and therefore point to actionable targets and biomarkers relevant for PD therapeutic discovery.

Alzheimer's disease (AD) remains a major, intractable neurodegenerative disorder and a serious threat to human health, characterized by a protracted clinical course, gradual progression, and irreversible cognitive decline. The current therapeutic landscape is characterized by a lack of disease-modifying agents, making the pursuit of early, effective interventions a global priority. Endoplasmic reticulum-mitochondria contact sites (ERMCs), also termed mitochondria-associated ER membranes (MAMs), constitute critical platforms for interorganellar communication, enabling material exchange and signal transduction. Key functions regulated at these junctions include calcium (Ca2+) homeostasis, mitochondrial dynamics, and lipid synthesis/transfer. Growing evidence implicates dysregulated ERMCs in the pathogenesis of neurodegenerative diseases, including AD and Parkinson's disease (PD). Recent advances in understanding the physiological and pathological roles of ERMCs have further illuminated their multifaceted contribution to AD, spanning amyloid-β (Aβ) production, Ca2+ signaling, energy and lipid metabolism, mitochondrial integrity, and endoplasmic reticulum stress (ERs). This review synthesizes current knowledge on ERMCs as a pivotal communication hub in AD and underscores their promising potential as targets for novel therapeutic strategies. Deeper insights into this axis may inform future approaches to improve clinical outcomes.