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.
Highlights
Alzheimer’s disease (AD) is a common, chronic neurodegenerative disease
Genetic variations within complement genes are extremely widespread in the general population; over the last 20 years, many common polymorphisms and rare mutations in complement genes have been linked with diverse inflammatory and infectious diseases, demonstrating the pivotal role of the complement pathway in determining disease risk (Table 1)
The AP gene variants conferring risk for age-related macular degeneration (AMD) and dense deposit disease (DDD) were not risk variants for another renal disease associated with complement dysregulation, atypical haemolytic uremic syndrome, a disease characterised by thrombocytopenia, microangiopathic haemolytic anaemia, and acute renal failure with complement deposition in the kidney [14]
Summary
Genetic variations within complement genes are extremely widespread in the general population; over the last 20 years, many common polymorphisms and rare mutations in complement genes have been linked with diverse inflammatory and infectious diseases, demonstrating the pivotal role of the complement pathway in determining disease risk (Table 1). The AP gene variants conferring risk for AMD and DDD were not risk variants for another renal disease associated with complement dysregulation, atypical haemolytic uremic syndrome (aHUS), a disease characterised by thrombocytopenia, microangiopathic haemolytic anaemia, and acute renal failure with complement deposition in the kidney [14]. This lack of concordance of risk suggests that the roles of complement are quite different in these superficially similar diseases; in support of this, a common genetic variation that causes deletion of the genes encoding FH-related proteins 1 and 3 (CFHR1/CFHR3) is protective for AMD but increases the risk of aHUS [14]. AD—Alzheimer’s disease, aHUS—atypical haemolytic uremic syndrome, AMD—age-related macular degeneration, bp—basepair, C3G—complement 3 glomerulopathy, CHAPLE—complement hyperactivity, angiopathic thrombosis, and protein-losing enteropathy, CNV—copy number variant, CVID—common variable immunodeficiency, DDD—dense deposit disease, GOF—gain of function, het—heterozygous, hom—homozygous, MPGN—membranoproliferative glomerulonephritis, LOF—loss of function, PCVP—polypoidal choroidal vasculopathy, PNH—paroxysmal nocturnal hemoglobinuria, SNP—single nucleotide polymorphism
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