The Impact of Complement Genes on the Risk of Late-Onset Alzheimer's Disease

Genes (Basel). 2021 Mar 20;12(3):443. doi: 10.3390/genes12030443.


Late-onset Alzheimer's disease (LOAD), the most common cause of dementia, and a huge global health challenge, is a neurodegenerative disease of uncertain aetiology. To deliver effective diagnostics and therapeutics, understanding the molecular basis of the disease is essential. Contemporary large genome-wide association studies (GWAS) have identified over seventy novel genetic susceptibility loci for LOAD. Most are implicated in microglial or inflammatory pathways, bringing inflammation to the fore as a candidate pathological pathway. Among the most significant GWAS hits are three complement genes: CLU, encoding the fluid-phase complement inhibitor clusterin; CR1 encoding complement receptor 1 (CR1); and recently, C1S encoding the complement enzyme C1s. Complement activation is a critical driver of inflammation; changes in complement genes may impact risk by altering the inflammatory status in the brain. To assess complement gene association with LOAD risk, we manually created a comprehensive complement gene list and tested these in gene-set analysis with LOAD summary statistics. We confirmed associations of CLU and CR1 genes with LOAD but showed no significant associations for the complement gene-set when excluding CLU and CR1. No significant association with other complement genes, including C1S, was seen in the IGAP dataset; however, these may emerge from larger datasets.

Keywords: clusterin; complement; complement receptor 1; genetics; late-onset Alzheimer’s disease; neuroinflammation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age of Onset
  • Alzheimer Disease / genetics*
  • Clusterin / genetics*
  • Complement Activation
  • Complement C1s / genetics*
  • Databases, Genetic
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Humans
  • Receptors, Complement 3b / genetics*


  • CLU protein, human
  • CR1 protein, human
  • Clusterin
  • Receptors, Complement 3b
  • Complement C1s