A Unifying Theory of Neurodegenerative Disease

A unifying theory of neurodegenerative disease, the Pr2 theory, is proposed, 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 the origin of the major neurodegenerative diseases is in antagonistic pleiotropy, which, through repeated evolutionary selection for performance over durability, has led to highly functional and finely tuned neural subnetworks subserving key survival features such as lethal force and behavioral modification, 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 has been the focus of the lion’s share of the research and attempted treatment of neurodegenerative diseases. 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.