The impact of increasing levels of blood C‐reactive protein on the loci for inflammatory, SPI1 and CD33, for Alzheimer’s disease

Abstract

Background Previously, we found that elevated blood C‐reactive protein (CRP) increased the impact of the apolipoprotein ε4 allele (APOE ε4) on the risk of Alzheimer’s disease (AD).1 In this study, we hypothesized that interactions between CRP and other AD‐associated genes also increase AD risk. Method SNPs in 10 AD risk loci, which also encode proteins related to inflammation, were used to test interaction with CRP on AD risk using additive model or dominant model with Cox proportional hazards regression and survival analysis. Result There were 279,176 UKBB white participants with average age (mean±SD) 60.1 ± 5.5 years including 53.9% females and 803 (0.3%) incident AD cases among 8.3 ± 0.9 years follow‐up on average. We found that for higher concentrations of serum CRP, the AD risk increased for SNP genotypes in 3 AD associated genes (SPI1, CD33 and CLU). Using Cox proportional hazards model in stratified genotype analysis, the hazard ratios (HR) for the association between higher CRP level (≥ 10 vs < 10 mg/L) and the risk of incident AD were 1.94 (95% CI: 1.33‐2.84, p<0.001) among SPI1 rs1057233‐AA genotype, 1.75 (95% CI: 1.20‐2.55, p = 0.004) for CD33 rs3865444‐CC genotype, and 1.76 (95% CI: 1.25‐2.48, p = 0.001) for CLU rs9331896‐CC+CT genotype, respectively. All models adjusted for age at baseline, sex, years of education, APOE ε4 and population principal components. In contrast, these associations were not observed in the other genotypes of these genes. Similar results for SPI1 and CD33 genotypes impacted by elevated CRP levels were observed for MCI to AD conversion and CSF AD biomarkers including t‐Tau and p‐Tau in the ADNI cohort (p<0.01). Conclusion Elevated blood CRP released in peripheral inflammation may be an important mediator in the association of genetic variants in SPI1, CD33 and CLU in addition to APOE ε4 for AD risk. Monitoring of CRP levels may be useful for more precise intervention and prevention of AD for these genotype carriers. 1. Tao Q, Ang TFA, DeCarli C, et al. Association of Chronic Low‐grade Inflammation With Risk of Alzheimer Disease in ApoE4 Carriers. JAMA Netw Open. Oct 5 2018;1(6):e183597. https://doi.org/10.1001/jamanetworkopen.2018.3597