Genetic insights into the impact of complement in Alzheimer's disease

Torvell, Megan, Carpanini, Sarah M., Daskoulidou, Nikoleta, Byrne, Robert A. J., Sims, Rebecca ORCID: https://orcid.org/0000-0002-3885-1199 and Morgan, B. Paul ORCID: https://orcid.org/0000-0003-4075-7676 2021. Genetic insights into the impact of complement in Alzheimer's disease. Genes 12 (12) , 1990. 10.3390/genes12121990

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Abstract

The presence of complement activation products at sites of pathology in post-mortem Alzheimer’s disease (AD) brains is well known. Recent evidence from genome-wide association studies (GWAS), combined with the demonstration that complement activation is pivotal in synapse loss in AD, strongly implicates complement in disease aetiology. Genetic variations in complement genes are widespread. While most variants individually have only minor effects on complement homeostasis, the combined effects of variants in multiple complement genes, referred to as the “complotype”, can have major effects. In some diseases, the complotype highlights specific parts of the complement pathway involved in disease, thereby pointing towards a mechanism; however, this is not the case with AD. Here we review the complement GWAS hits; CR1 encoding complement receptor 1 (CR1), CLU encoding clusterin, and a suggestive association of C1S encoding the enzyme C1s, and discuss difficulties in attributing the AD association in these genes to complement function. A better understanding of complement genetics in AD might facilitate predictive genetic screening tests and enable the development of simple diagnostic tools and guide the future use of anti-complement drugs, of which several are currently in development for central nervous system disorders.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Additional Information:	This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/)
Publisher:	MDPI
ISSN:	2073-4425
Funders:	Dementia Research Institute, MRC
Date of First Compliant Deposit:	5 January 2022
Date of Acceptance:	13 December 2021
Last Modified:	19 Sep 2023 16:23
URI:	https://orca.cardiff.ac.uk/id/eprint/146380

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