Work

Circulating C-reactive protein influences polygenic risk of inflammatory genes expressed in brain endothelia for Alzheimer’s disease

Year: 2026

Type: article

Abstract: C-reactive protein (CRP) is a key marker of systemic inflammation that affects blood vessel endothelial function, including in the brain. Since endothelial dysfunction is linked to Alzheimer’s disease (AD), we investigated whether elevated CRP level interacts with genetic pathways in brain endothelial cells to influence AD risk. Using AD genome-wide association study (GWAS) data, we developed multiple polygenic risk scores (PRSs) including single nucleotide polymorphisms (SNPs) in genes expressed in brain endothelial cells, excluding the APOE region, that are involved in inflammation, synaptic transmission, and other pathways. Analysis across three independent cohorts revealed that individuals with low inflammatory PRSs (<50%) and elevated blood CRP level were associated with an increased risk of AD; in contrast, those with high inflammatory PRSs (≥50%) did not exhibit this CRP-related AD risk increase. Further examination of individuals with a low inflammatory PRS showed that elevated CRP was associated with lower cerebrospinal fluid (CSF) Aβ42 level and temporal lobe atrophy. Among individuals with a high inflammatory PRS, elevated CRP level was negatively correlated with CSF pTau181 and brain tauopathy, suggesting a potential protective mechanism against tau pathology. Key inflammatory PRS genes, which were impacted by circulating CRP for AD, included APP , IL6ST , and FN1 , are involved in amyloid pathology, wound healing, and coagulation. Our findings highlight two distinct genetic-dose dependent backgrounds: "vulnerable" (<50% inflammatory PRS) and "resilient" (≥50% inflammatory PRS), and support a Genome-Internal Environment (G × IE) interaction model, linking peripheral inflammation to AD risk. • A Genome–Internal Environment (G×IE) interaction model was constructed. • CRP interacts with inflammatory polygenic variation in endothelial-expressed genes to influence AD risk. • Low inflammatory PRS group was vulnerable to CRP-associated AD risk and biomarker changes. • Individuals with high inflammatory PRS appeared resilient. • Elevated CRP was linked to amyloid pathology and brain atrophy in the low inflammatory PRS (vulnerable) group.

Source: Neurobiology of Disease

DOI: 10.1016/j.nbd.2026.107257