Work

Synergistic effects of peripheral inflammation and neuroinflammation on amyloid, vascular, and neurodegeneration markers across the Alzheimer's disease spectrum

Year: 2025

Type: article

Abstract: BACKGROUND: Systemic inflammation and astrogliosis are relevant in Alzheimer's disease (AD). We evaluated whether peripheral inflammation has synergistic effects with astrogliosis on β-amyloid (Aβ), vascular, and neurodegeneration markers. METHOD: In the Ginkgo Evaluation of Memory Study, we evaluated the relationship between peripheral inflammation (TNF-R1, TNF-R2, IL-6, IL-2, CRP and sCD14) and astrogliosis (GFAP </≥196pg/mL) as to Aβ burden (</≥20centiloids) and accumulation (centiloids/year), white matter lesion (WML) volume, and neurodegeneration (NfL) across the AD spectrum. Participants underwent PiB-PET scans between 2009-2018. GFAP, NfL, and peripheral inflammatory markers were measured in 2009 by immunoassay; their values were standardized within the cohort. We used negative binomial regression models and adjusted for age, sex, education, APOEε4, cystatin C and baseline Aβ status. RESULT: 190 participants were included (mean age: 86±2.8 yrs., 40.8% women, 96.9% White). GFAP was higher among Aβ+ participants; it did not differ by levels of peripheral inflammation. Aβ accumulation was slower among those with high sCD14, particularly among Aβ+. There was a significant negative multiplicative interaction between GFAP and CRP on Aβ accumulation (RR;95%CI:0.61;.38-.99;p=0.047). WML were larger among GFAP+ individuals. There were significant additive and multiplicative interactions of GFAP with CRP (relative excess risk due to interaction (RERI);95%CI:0.47;0.12-0.83;p=0.008; RR;95%CI:1.76;1.11-2.81;p=0.016, respectively), with TNFR1 (RERI;95%CI:0.63;0.29-0.97;p<.001; RR;95%CI:1.93;1.24-3.01;p=0.004, respectively), and with TNFR2 (RERI;95%CI:0.52;0.22-0.82;p=0.001; RR;95%CI:1.82;1.18-2.82;p=0.006, respectively) on WML. Regarding neurodegeneration, there were significant joint effects of GFAP with CRP, sCD14 and/or TNFR1; and significant additive and/or multiplicative interactions of GFAP with CRP (RERI;95%CI:0.35;0.07-0.62;p=0.012, RR;95%CI:1.37;1.04-1.81;p=0.023, respectively) with TNFR1 (RERI;95%CI:0.29;0.08-0.50;p=.007, RR;95%CI:1.30;1.03-1.63;p=0.023, respectively) and with TNFR2 (RERI;95%CI:0.22;0.005-0.45;p=.045). CONCLUSION: In this 85+ population, with expected high levels of inflammation and more co-pathology; peripheral inflammation (CRP, TNFR1 and/or TNFR2) showed additive/multiplicative synergistic effects with astrogliosis resulting in less amyloid accumulation, greater vascular burden, and more neurodegeneration, particularly in Aβ+ participants. More inflammation may relate with more pathogenesis, bringing participants closer to the amyloid asymptote, slowing Aβ accumulation.

Source: Alzheimer s & Dementia

DOI: 10.1002/alz70856_099147