A Unifying Theory of Alzheimer’s and Other Neurodegenerative Diseases
Background/Objectives The etiology and pathophysiology of neurodegenerative diseases are incompletely understood, and the treatments largely ineffective. A unifying theory that explains otherwise poorly understood observations may help to enhance therapeutic outcomes. Methods Here is proposed a unifying theory of neurodegenerative disease, the Pr2 theory, describing the origin, pathophysiology, optimal evaluation and treatment of patients, explanation of observations not explained by previous theories, and implications for further research and translation. The theory proposes that neurodegenerative diseases represent network insufficiencies, networks jeopardized by antagonistic pleiotropy. Through repeated evolutionary selection for performance over durability, highly functional and finely tuned neural subnetworks subserving key survival features such as lethal force and behavioral modification have evolved at the expense of durability and reserve. The Pr2 theory focuses on the physiology associated with the causes of neurodegeneration rather than the pathology that is largely reactive but has been the focus of the lion’s share of the research and attempted treatment of neurodegenerative diseases. Results Initial translation of the Pr2 theory to a precision medicine approach to cognitive decline has led to superior outcomes compared to other therapeutic approaches, and at least in some cases, sustained improvement for over a decade has been achieved. Conclusions The proposed theory explains key features of neurodegenerative disease pathophysiology and suggests novel therapeutic targets. Initial predictions have been validated in two proof-of-concept trials and one randomized controlled trial for patients with mild cognitive impairment or early-stage dementia.