Cytosolic calcium: Judge, jury and executioner of neurodegeneration in Alzheimer's disease and beyond

Abstract This review discusses the driving principles that may underlie neurodegeneration in dementia, represented most dominantly by Alzheimer's disease (AD). While a myriad of different disease risk factors contribute to AD, these ultimately converge to a common disease outcome. Based on decades of research, a picture emerges where upstream risk factors combine in a feedforward pathophysiological cycle, culminating in a rise of cytosolic calcium concentration ([Ca 2+ ] c ) that triggers neurodegeneration. In this framework, positive AD risk factors entail conditions, characteristics, or lifestyles that initiate or accelerate self‐reinforcing cycles of pathophysiology, whereas negative risk factors or therapeutic interventions, particularly those mitigating elevated [Ca 2+ ] c , oppose these effects and therefore have neuroprotective potential.