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The multiplex model of the genetics of Alzheimer’s disease

Sims, Rebecca, Hill, Matthew and Williams, Julie 2020. The multiplex model of the genetics of Alzheimer’s disease. Nature Neuroscience 23 , pp. 311-322. 10.1038/s41593-020-0599-5

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Abstract

Genes play a strong role in Alzheimer’s disease (AD) with late-onset AD showing heritability of 58-79% and early-onset AD over 90%. Genetic association provides a robust platform to build our understanding of the etiology of this complex disease. Over 40 loci are now implicated for AD, suggesting that AD is a disease of multiple components as supported by pathway analyses (immunity, endocytosis, cholesterol transport, ubiquitination, amyloid-β and tau processing). Over 50% of late-onset AD (LOAD) heritability has been captured and allows the calculation of the accumulation of AD genetic risk through polygenic risk scores (PRS). PRS predicts disease with up to 90% accuracy and is an exciting tool in our research armoury that could allow selection of those with high PRS for clinical trials and precision medicine, as well as the cellular modelling of the combined risk. Here we propose the multiplex model as a new perspective from which to understand AD. The multiplex model reflex’s the combination of some, or all, of these model components (genetic and environmental), in a tissue specific manner, to trigger or sustain a disease cascade, which ultimately results in the cell/synaptic loss observed in AD.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: Nature Publishing Group
ISSN: 1097-6256
Date of First Compliant Deposit: 14 February 2020
Date of Acceptance: 24 January 2020
Last Modified: 25 Nov 2020 03:57
URI: http://orca-mwe.cf.ac.uk/id/eprint/129659

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