Models of precision medicine for neurodegeneration

The clinicopathologic model that defines neurodegenerative disorders has remained unchanged for over a century. According to it, clinical manifestations are defined and explained by a given pathology, that is, by the burden and distribution of selected proteins aggregated into insoluble amyloids. There are two logical consequences from this model: (1) a measurement of the disease-defining pathology represents a biomarker of that disease in everyone affected, and (2) the targeted elimination of that pathology should end that disease. But success in disease modification guided by this model has remained elusive. New technologies to probe living biology have been used to validate rather than question the clinicopathologic model, despite three important observations: (1) a disease-defining pathology in isolation (without other pathologies) is an exceptional autopsy finding; (2) many genetic and molecular pathways converge on the same pathology; (3) the presence of pathology without neurological disease is more common than expected by chance. We here discuss the rationale for abandoning the clinicopathologic model, review the competing biological model of neurodegeneration, and propose developmental pathways for biomarker development and disease-modifying efforts. Further, in justifying future disease-modifying trials testing putative neuroprotective molecules, a key inclusion criterion must be the deployment of a bioassay of the mechanism corrected by the therapy of interest. No improvements in trial design or execution can overcome the fundamental deficit created by testing experimental therapies in clinically defined recipients unselected for their biologically suitability. Biological subtyping is the key developmental milestone needed to launch precision medicine for patients living with neurodegenerative disorders.