Dysregulation of Calcium Signaling Homeostasis in the Onset and Progression of Alzheimer's Disease and Its Therapeutic Potential

Abstract

Alzheimer's disease (AD), the most common neurodegenerative disorder, accounts for 60–70% of all dementia cases and is clinically characterized by progressive memory impairment, executive dysfunction, and neuropsychiatric symptoms. The traditional pathogenic framework has focused on β-amyloid (Aβ) deposition and Tau neurofibrillary tangles; however, recent trials of Aβ-targeting monoclonal antibodies (e.g., aducanumab, lecanemab) have shown that plaque reduction does not consistently translate into robust neurocognitive benefit, suggesting that AD pathogenesis extends far beyond protein aggregation alone. The "calcium hypothesis" posits that Aβ and Tau aggregation represent downstream events, whereas disruption of neuronal calcium homeostasis is an upstream driver that may precede overt pathology. Disturbances in calcium signaling act as a central hub linking proteinopathy, synaptic dysfunction, neuronal hyperexcitability, glial activation, vascular dysregulation, and metabolic failure. Dysregulated calcium homeostasis in AD encompasses coordinated abnormalities at the level of membrane channels (e.g., L-type voltage-gated calcium channels [L-VGCCs], TRPC family), endoplasmic reticulum (ER; ryanodine receptors [RyRs]), mitochondria, lysosomes, and glial cells, thereby coupling protein pathology to synaptic failure, energy deficits, neuroinflammation, and impaired cerebral perfusion. Notably, all currently approved symptomatic AD treatments — including the noncompetitive NMDA receptor antagonist memantine and acetylcholinesterase inhibitors — impinge on calcium signaling pathways. Emerging agents targeting RyRs (e.g., dantrolene, S107), TRPC3 antagonists (Pyr3, Pyr10), and lysosomal calcium channel inhibitors (e.g., Ned-19) have also demonstrated therapeutic potential in preclinical models. Here, we systematically review (i) the physiological roles of calcium signaling homeostasis in neuronal function, (ii) the manifestations and mechanisms of calcium dyshomeostasis in AD, (iii) the impact of abnormal calcium signaling on cognition and neuronal network function, and (iv) the therapeutic potential and drug development progress of calcium channel–related targets. We further discuss the challenges and prospects of cross-channel network analysis and genotype-informed combination strategies, with the goal of providing a theoretical foundation for calcium homeostasis–targeted therapies in AD.