Figure 2.

CSF biomarkers of amyloid, tau and phosphorylated tau-related processes, astrogliosis/neuroinflammation, and neuronal, synaptic and axonal injury in adults with Down syndrome (orange), ADAD mutation carriers (green) and normal ADAD non-carrier controls (gray) as a function of age (increasing age left to right). Biomarkers include: A) Aβ40, B) Aβ42, C) Aβ42/Aβ40 ratio, D) tTau, E) pTau181, F) YKL-40, G) tTau/Aβ42 ratio, H) pTau181/Aβ42 ratio, I) log transformed NfL, J) VILIP-1, and K) SNAP-25. Actual age is not shown on the X axis in order to maintain blinding. Colored lines reflect the regression lines and 95% confidence intervals (CI) based on the linear regression, with each biomarker as the outcome and APOE ε4 status, sex and the group x age interaction as the covariates. Pair-wise comparisons of the change in biomarkers over age (slopes of the linear lines) controlling for APOE ε4 status and sex was performed based on the linear regressions, and p values for pre-specified subgroup comparisons were adjusted by the Benjamini-Hochberg method¹⁴. Significant (at least p<0.05) summary group differences in slope (colored asterisks, DS/DIAN-MC vs DIAN-NC; black dagger, DS vs DIAN-MC) were observed for the following biomarkers: Aβ42, DS vs DIAN-NC and DIAN-MC vs DIAN-NC; Aβ42/Aβ40, DIAN-MC vs DIAN-NC; tTau, DIAN-MC vs DIAN-NC; pTau181, DIAN-MC vs DIAN-NC and DS vs DIAN-NC; YKL-40, DS vs DIAN-NC and DS vs DIAN-MC; tTau/Aβ42, DIAN-MC vs DIAN-NC; pTau181/Aβ42, DIAN-MC vs DIAN-NC; SNAP-25, DIAN-MC vs DIAN-NC). Absolute mean differences in annualized slopes and associated p values are shown in Supplemental Table 5. Abbreviations: Aβ=amyloid-β; ADAD=autosomal dominant Alzheimer disease; CSF=cerebrospinal fluid; DIAN=Dominantly Inherited Alzheimer Network; DS=Down syndrome; MC=ADAD mutation carriers; NC=ADAD mutation non-carriers; NfL, neurofilament light chain; SNAP-25=synaptosomal-associated protein 25; tTau=total tau; VILIP-1=visinin-like protein 1; YKL-40=chitinase-3-like protein 1.