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 ] ) 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 ] , oppose these effects and therefore have neuroprotective potential.