The genetics of neurodegenerative diseases is the genetics of age-related damage clearance failure

Abstract

In this perspective we draw together the data from the genome wide association studies for Alzheimer's disease, Parkinson's disease and the tauopathies and reach the conclusion that in each case, most of the risk loci are involved in the clearance of the deposited proteins: in Alzheimer's disease, the microglial removal of Aβ, in the synucleinopathies, the lysosomal clearance of synuclein and in the tauopathies, the removal of tau protein by the ubiquitin proteasome. We make the point that most loci identified through genome wide association studies are not strictly pathogenic but rather relate to failures to remove age related damage. We discuss these issues in the context of copathologies in elderly individuals and the prediction of disease through polygenic risk score analysis at different ages. Finally, we discuss what analytic approaches are needed now that we have adequately sized case control analyses in white populations.

Fig. 1. Cartoon suggesting the possible relationships between the different disease pathologies: amyloid, cleared largely by the microglia: tau, clearly largely by the ubiquitin proteasome and synuclein, cleared mainy through the lysosome.

However, these clearance pathways are not mutually exclusive, and as one fails, it overloads the other pathways pushing them to fail and cause their substrates to build up. Thus, the different pathologes need not have direct connections, but rather be indirectly connected by clearance failure.

Fig. 2. Cartoon showing the reduction of clearance capacity by age (blue line), with the shading arpund the line suggesting variability.

Horizontal (orange lines) showing rate of production with shading around the line suggesting variability. Vertical (black lines) marking the intercept when production exceeds clearance and deposition starts.

Fig. 3. APOE4 allele frequency by age in cases (red) and controls (blue) showing that the odds ratio between cases and controls alters by age.

Since APOE4 has the largest effect on Alzheimer risk, it is likely that this allele shows the largest interaction with age but other risk alleles are likely to have the same type of age dependent effect.