A Possible Explanation For Neurodegenerative Disease

Abstract

This review proposes an explanation for the pathogenesis of those neurodegenerative diseases which result in dementia and the resulting diversity of their disease phenotypes. The explanation is based on five principal observations, specifically: 1) neurodegenerative disease may be the direct consequence of neural ageing; 2) ageing may cause differential degeneration of neuroanatomical pathways; 3) breakdown of anatomical pathways may result in the formation of ‘reactive’ proteins; 4) these proteins may exhibit ‘prion-like’ behaviour and spread along anatomical pathways; and 5) neurodegenerative disease may be characterised by heterogeneity, overlapping phenotypes, and multiple pathology. The explanation proposes that genetic and environmental risk factors act cumulatively over a lifetime to increase an individual’s ‘allostatic load’, which determines the overall rate of neural ageing. This process results in the differential breakdown of neuro-anatomical pathways, influenced by their relative use or disuse during life, the consequence being the formation of one or more reactive proteins. Many of these proteins may spread through the brain from initial sites of ageing along neuro-anatomical pathways to affect specific neural networks. Variation in the proteins formed and in pathways of their spread result in the observed clinical and pathological diversity of disease phenotypes. Hence, minimising the factors that contribute to the allostatic load, together with cognitive and physical exercise to counter disuse of specific anatomical pathways over a lifetime, may be necessary to reduce the incidence of neurodegenerative disease.