The many roads to dementia: a systems view of Alzheimer's disease

Abstract: Alzheimer's disease is not the outcome of a single cause but the convergence of many. This review reframes dementia as a systemic failure, where amyloid plaques and tau tangles are not root causes but late-stage byproducts of the underlying metabolic collapse. We begin by tracing the historical merger of early- and late-onset Alzheimer's into a single disease category, a conceptual error that may have misdirected decades of research. We then synthesize evidence pointing to metabolic dysfunction - especially mitochondrial damage - as a more likely initiating event. Through this lens, we examine diverse contributing factors including type 2 diabetes, hyperglycemia-induced oxidative stress, infections and neuroinflammation. Finally, we assess current treatment limitations and argue that prevention, grounded in early metabolic and vascular interventions, holds the most promise for altering the course of this complex disease.