Cerebrospinal fluid biomarkers of Alzheimer's disease in a cohort of adults with Down syndrome

Abstract

Introduction: Virtually all individuals with Down syndrome (DS) will develop Alzheimer's disease (AD) pathology by age 40. Cerebrospinal fluid (CSF) biomarkers have characterized AD pathology in cohorts of late-onset AD (LOAD) and autosomal-dominant AD (ADAD). Few studies have evaluated such biomarkers in adults with DS.

Methods: CSF concentrations of amyloid beta (Aβ)40, Aβ42, tau, phospho-tau181 (p-tau), neurofilament light chain (NfL), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), chitinase-3-like protein 1 (YKL-40), alpha synuclein (αSyn), neurogranin (Ng), synaptosomal-associated protein 25 (SNAP-25), and visinin-like protein 1 (VILIP-1) were assessed in CSF from 44 adults with DS from the Alzheimer's Biomarker Consortium-Down Syndrome study. Biomarker levels were evaluated by cognitive status, age, and apolipoprotein E gene (APOE) ε4 carrier status.

Results: Biomarker abnormalities indicative of amyloid deposition, tauopathy, neurodegeneration, synaptic dysfunction, and neuroinflammation were associated with increased cognitive impairment. Age and APOE ε4 status influenced some biomarkers.

Discussion: The profile of many established and emerging CSF biomarkers of AD in a cohort of adults with DS was similar to that reported in LOAD and ADAD, while some differences were observed.

Keywords: Alzheimer's disease; Down syndrome; amyloid; biomarkers; cerebrospinal fluid; tau.

FIGURE 1

Distribution of AD biomarkers in a cohort of adults with DS by cognitive status. Levels of (A) Aβ42, (B) total tau, (C) p‐tau, (D) Aβ42/Aβ40 ratio, (E) tau/Aβ42 ratio, (F) p‐tau/Aβ42 ratio, (G) YKL‐40, (H) SNAP‐25, and (I) logNfL are plotted as a function of cognitive status. Open symbols represent cognitively stable individuals (CS), gray symbols represent individuals with MCI (DS‐MCI), and black symbols represent individuals with AD dementia (DS‐AD) defined by consensus criteria. Horizontal lines represent mean ± SD. Outliers more than 2 SD from the mean (triangles) were excluded from statistical analysis. Group comparisons were conducted using Kruskal‐Wallis and Dunn tests with Holm‐Bonferroni correction for multiple comparisons. P values <.05 were considered statistically significant

FIGURE 2

Distribution of AD biomarkers in a cohort of adults with DS by age and cognitive status. Levels of (A) Aβ42, (B) total tau, (C) p‐tau, (D) Aβ42/Aβ40 ratio, (E) tau/Aβ42 ratio, (F) p‐tau/Aβ42 ratio, (G) YKL‐40, (H) SNAP‐25, and (I) logNfL are plotted as a function of age at LP. Open symbols represent cognitively stable individuals (CS), gray symbols represent individuals with MCI (DS‐MCI), and black symbols represent individuals with AD dementia (DS‐AD) defined by consensus criteria. Correlations coefficients represent Spearman rho (ρ). P values <.05 were considered statistically significant and are shown.

FIGURE 3

Distribution of CSF biomarkers by age and APOE ε4 carrier status. Levels of (A) Aβ42, (B) total tau, (C) the tau/Aβ42 ratio, and (D) SNAP‐25 are plotted as a function of age at LP. Open circles and dotted lines represent APOE ε4 non‐carriers (ε4‐). Black circles and solid lines represent APOE ε4 carriers (ε4+). Lines are linear regressions of biomarker data by age at LP. One individual did not have APOE genotype data and was excluded from this analysis. Group comparisons were performed by ANCOVA with age as a covariate. Adjusted P values <.05 were considered statistically significant

FIGURE 4

Scatter plots of select biomarker correlations. Plotted are the relationships between levels of (A) Aβ42 and Aβ40, (B) Aβ42 and total tau, (C) Aβ42 and p‐tau, (D) total tau and p‐tau, (E) total tau and log NfL, (F) p‐tau and YKL‐40, (G) Ng and αSyn, (H) Ng and VILIP‐1, and (I) p‐tau and SNAP‐25. Correlation coefficients represent Spearman rho (ρ). P values <.05 were considered statistically significant.