Abstract
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.
Highlights
The gene set in which both CLU and complement receptor 1 (CR1) were excluded from the complement gene-set was not significantly associated with Late-onset Alzheimer’s disease (LOAD) (p = 0.170)
CLU and CR1 were removed (Table 2). These results suggest that the LOAD association signal in the complement gene-set is predominantly driven by CLU
We have demonstrated that the signal for the association of the complement gene-set with LOAD is explained by the genome-wide significant (GWS) genes CLU and CR1, and not by other complement genes tested here
Summary
Alzheimer’s disease (AD) is the most common cause of dementia in the elderly. AD is a chronic neurodegenerative disease underpinned by neuronal and synaptic loss, the accumulation of amyloid-β plaques, and neurofibrillary tangles composed of hyperphosphorylated tau. Evidence includes the presence of activated microglia in the brain innate immune cells, the presence of inflammatory markers, including complement proteins, in the brain, cerebrospinal fluid (CSF) and plasma, and the demonstration that chronic use of anti-inflammatory drugs may reduce disease incidence [1,2,3]. Perhaps the best evidence that inflammation may be involved in AD aetiology comes from genome-wide association studies (GWAS); many of the genes most strongly associated with AD risk are involved in inflammation and immunity
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