Biofluid markers of Alzheimer’s disease‐associated CNS inflammation in adults with Down syndrome

Abstract

AbstractBackgroundDown syndrome (DS) is a genetically determined form of Alzheimer’s disease (AD), and a priority population to study early AD changes. This study explores inflammatory markers in biofluids over the course of the AD continuum in adults with DS.MethodThis is a cross‐sectional study of the Olink Target 96 Inflammation (v.3022) panel in paired plasma and CSF from adults with DS from the DABNI cohort across the AD continuum (83 asymptomatic and 109 symptomatic), 60 cognitively unimpaired controls and 130 sporadic AD (sAD) patients. See Table for demographics. We used linear regression to compare group differences, including age and sex as covariates. Age was excluded and intellectual disability was added as a covariate when comparing across AD stages in DS. We controlled the false discovery rate using the Bonferonni‐Hochberg method and considered only statistically and biologically relevant changes (fold‐change+/‐10%, adj.p<0.05).ResultWe detected 59/96 inflammatory markers on the panel in CSF and 81/96 in plasma. In asymptomatic DS vs CN, 12 inflammatory markers were decreased (<0.84‐fold, adj.p<0.02) and 3 were increased (>1.27‐fold, adj.p<0.03) in CSF. In the same comparison in plasma, 2 were decreased (<0.84‐fold, adj.p<0.03) and 26 were increased (>1.13‐fold, adj.p<0.04). Over the AD continuum in DS, 29 inflammatory markers were increased (>1.1‐fold, adj.p<0.04) and 1 was decreased (0.78‐fold, adj.p = 0.003) in CSF. We did not see the same profile in sAD vs CN CSF (1 marker; 1.59‐fold, adj.p<0.0001). To focus on CNS inflammation, we restricted plasma analyses to the 11 inflammatory markers that showed AD‐associated changes in CSF and correlated between both biofluids (r2 = 0.03‐0.43; p<0.04). CCL23, CCL3, CXCL9 and CXCL10 were increased over AD stages in plasma (>1.15‐fold, adj.p<0.03) with similar effect sizes to those in CSF (>1.17‐fold, adj.p<0.02). We observed no change in those inflammatory markers in sAD vs CN plasma (all adj.p>0.14).ConclusionTrisomy 21 is associated with a distinct inflammatory profile in CSF and plasma. However, certain markers showed similar changes in both biofluids across the AD continuum in DS. CCL23, CCL3, CXCL9 and CXCL10 represent promising novel plasma biomarkers of AD‐related inflammation in DS. Table. Demographics (%/mean+sd) for the participants used in this study.