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

Hardy, John and Escott-Price, Valentina ORCID: https://orcid.org/0000-0003-1784-5483 2025. The genetics of neurodegenerative diseases is the genetics of age-related damage clearance failure. Molecular Psychiatry 10.1038/s41380-025-02911-7

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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.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Medicine
Publisher:	Springer Nature [academic journals on nature.com]
ISSN:	1359-4184
Date of First Compliant Deposit:	4 February 2025
Date of Acceptance:	21 January 2025
Last Modified:	12 Feb 2025 12:08
URI:	https://orca.cardiff.ac.uk/id/eprint/175906

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