Pathology vs pathogenesis: Rationale and pitfalls in the clinicopathology model of neurodegeneration

In neurodegenerative disorders, the term pathology is often implicitly referred to as pathogenesis. Pathology has been conceived as a window into the pathogenesis of neurodegenerative disorders. This clinicopathologic framework posits that what can be identified and quantified in postmortem brain tissue can explain both premortem clinical manifestations and the cause of death, a forensic approach to understanding neurodegeneration. As the century-old clinicopathology framework has yielded little correlation between pathology and clinical features or neuronal loss, the relationship between proteins and degeneration is ripe for revisitation. There are indeed two synchronous consequences of protein aggregation in neurodegeneration: the loss of the soluble/normal proteins on one; the accrual of the insoluble/abnormal fraction of these proteins on the other. The omission of the first part in the protein aggregation process is an artifact of the early autopsy studies: soluble, normal proteins have disappeared, with only the remaining insoluble fraction amenable to quantification. We here review the collective evidence from human data suggesting that protein aggregates, known collectively as pathology, are the consequence of many biological, toxic, and infectious exposures, but may not explain alone the cause or pathogenesis of neurodegenerative disorders.