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

Abstract

Apolipoprotein ε4 (APOE ε4) is the most significant genetic risk factor for late-onset Alzheimer’s disease (AD). Elevated blood C-reactive protein (CRP) further increases the risk of AD for people carrying the APOE ε4 allele. We hypothesized that CRP, as a key inflammatory element, could modulate the impact of other genetic variants on AD risk. We selected ten single nucleotide polymorphisms (SNPs) in reported AD risk loci encoding proteins related to inflammation. We then tested the interaction effects between these SNPs and blood CRP levels on AD incidence using the Cox proportional hazards model in UK Biobank (n = 279,176 white participants with 803 incident AD cases). The five top SNPs were tested for their interaction with different CRP cutoffs for AD incidence in the Framingham Heart Study (FHS) Generation 2 cohort (n = 3009, incident AD = 156). 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 the Cox model in stratified genotype analysis, the hazard ratios (HRs) for the association between a 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) for the SPI1 rs1057233-AA genotype, 1.75 (95% CI: 1.20–2.55, p = 0.004) for the CD33 rs3865444-CC genotype, and 1.76 (95% CI: 1.25–2.48, p = 0.001) for the CLU rs9331896-C genotype. In contrast, these associations were not observed in the other genotypes of these genes. Finally, two SNPs were validated in 321 Alzheimer’s Disease Neuroimaging (ADNI) Mild Cognitive Impairment (MCI) patients. We observed that the SPI1 and CD33 genotype effects were enhanced by elevated CRP levels for the risk of MCI to AD conversion. Furthermore, the SPI1 genotype was associated with CSF AD biomarkers, including t-Tau and p-Tau, in the ADNI cohort when the blood CRP level was increased (p < 0.01). Our findings suggest that elevated blood CRP, as a peripheral inflammatory biomarker, is an important moderator of the genetic effects of SPI1 and CD33 in addition to APOE ε4 on AD risk. Monitoring peripheral CRP levels may be helpful for precise intervention and prevention of AD for these genotype carriers.

Inflammatory Processes in Alzheimer’s Disease—Pathomechanism, Diagnosis and Treatment: A Review

“…Genetic diagnostics include, among others, the detection of polymorphisms of genes related to inflammatory complement activation, including CLU, CR1, SERPINA3, CRP, C2, CFH, C3, and C4. The polymorphism of their genes and the identified mutations of these genes may be a helpful complement to the diagnosis of inflammation in AD, significantly facilitating the work of clinicians [ 160 ]. Interdisciplinary research used in the diagnosis of inflammation should mutually confirm these results and complement each other [ 161 ].…”

Is Drp1 a link between mitochondrial dysfunction and inflammation in Alzheimer’s disease?

“…Since the 1990s, researchers have demonstrated a significant presence of sustained inflammation in patients with AD (Aisen and Davis, 1994), confirmed by post-mortem tissues analysis (Gomez-Nicola and Boche, 2015). Epidemiological studies of largescale cohorts have shown that people showing enhanced pro-inflammatory proteins in the blood in mid-life are at higher risk of cognitive decline over the decades compared to subjects maintaining a low presence of pro-inflammatory factors in the blood (Leung et al, 2013;Huang et al, 2022). In addition, in their later life, these individuals are characterized by lower volume of brain with abnormal microstructure of white matter, increased myelin loss and the inability of the oligodendrocytes, the cells responsible for the production and maintenance of myelin, to repair myelin damages (Nasrabady et al, 2018;Collij et al, 2021).…”

Peripheral inflammation and neurocognitive impairment: correlations, underlying mechanisms, and therapeutic implications

“…Whereas populations with cognitive impairment also exhibit features of peripheral inflammatory activation, data from a cohort study of 2,479 patients ≥60 years of age in the United States showed that white blood cell counts (WBC), neutrophil counts, neutrophil-to-lymphocyte ratios, and neutrophil-to-albumin ratios in the peripheral blood of populations with cognitive impairment were significantly higher than those of normal populations ( Li W. et al, 2023 ). AD, the most prevalent neurodegenerative disease, has been reported to have enhanced genotypic effects of the proteins SPI1 and CD33 encoding proteins at the AD inflammation-related SNP locus as peripheral blood CRP levels increase, and an increased risk of conversion to AD in people with mild cognitive impairment (MCI) ( Huang J. et al, 2022 ). One study ( Lyu et al, 2023 ) demonstrated that by comparing diabetic (T2DM) patients aged 29–65 years who did not meet the criteria for a clinical diagnosis of cognitive impairment with the normal population (42.125 ± 10.436 years), although the difference did not gain statistical significance, the Montreal cognitive assessment scale (MoCA) scores of the T2DM patients showed a tendency to be lower than that of healthy controls and peripheral blood laboratory results showed significantly lower levels of peripheral blood IL-4 and brain-derived neurotrophic factor (BDNF) in the T2DM population compared to the healthy population.…”