Complement dysregulation and Alzheimer's disease in Down syndrome

Introduction Down syndrome (DS) is associated with immune dysregulation and a high risk of early onset Alzheimer's disease (AD). Complement is a key part of innate immunity and driver of pathological inflammation, including neuroinflammation in AD. Complement dysregulation has been reported in DS; however, the pattern of dysregulation and its relationship to AD risk is unclear. Methods Plasma levels of 14 complement biomarkers were measured in 71 adults with DS and 46 controls to identify DS-associated dysregulation; impact of apolipoprotein E (APOE) epsilon 4 genotype, single nucleotide polymorphisms (SNPs) in CLU and CR1, and dementia on complement biomarkers was assessed. Results Plasma levels of complement activation products (TCC, iC3b), proteins (C1q, C3, C9), and regulators (C1 inhibitor, factor H, FHR4, clusterin) were significantly elevated in DS versus controls while FI and sCR1 were significantly lower. In DS with AD (n = 13), C3 and FI were significantly decreased compared to non-AD DS (n = 58). Neither APOE genotype nor CLU SNPs impacted complement levels, while rs6656401 in CR1 significantly impacted plasma sCR1 levels. Conclusions Complement is dysregulated in DS, likely reflecting the generalized immune dysregulation state; measurement may help identify inflammatory events in individuals with DS. Complement biomarkers differed in DS with and without AD and may aid diagnosis and/or prediction. Highlights Complement is significantly dysregulated in plasma of people with DS who show changes in levels of multiple complement proteins compared to controls. People with DS and dementia show evidence of additional complement dysregulation with significantly lower levels of C3 and factor I compared to those without dementia. rs6656401 in CR1 was associated with significantly elevated sCR1 plasma levels in DS.

Automated summary

Complement dysregulation is present in individuals with Down syndrome, likely indicating a generalized immune dysregulation state; complement biomarkers differ in individuals with Down syndrome with and without Alzheimer's disease and may be used for diagnosis and/or prediction.