A genetic and proteomic comparison of key AD biomarkers across tissues

Abstract

Introduction: Plasma has been proposed as an alternative to cerebrospinal fluid (CSF) for measuring Alzheimer's disease (AD) biomarkers, but no studies have analyzed in detail which biofluid is more informative for genetics studies of AD.

Method: Eleven proteins associated with AD (α-synuclein, apolipoprotein E [apoE], CLU, GFAP, GRN, NfL, NRGN, SNAP-25, TREM2, VILIP-1, YKL-40) were assessed in plasma (n = 2317) and CSF (n = 3107). Both plasma and CSF genome-wide association study (GWAS) analyses were performed for each protein, followed by functional annotation. Additional characterization for each biomarker included calculation of correlations and predictive power.

Results: Eighteen plasma protein quantitative train loci (pQTLs) associated with 10 proteins and 16 CSF pQTLs associated with 9 proteins were identified. Plasma and CSF shared some genetic loci, but protein levels between tissues correlated weakly. CSF protein levels better associated with AD compared to plasma.

Discussion: The present results indicate that CSF is more informative than plasma for genetic studies in AD.

Highlights: The identification of novel protein quantitative trait loci (pQTLs) in both plasma and cerebrospinal fluid (CSF). Plasma and CSF levels of neurodegeneration-related proteins correlated weakly. CSF is more informative than plasma for genetic studies of Alzheimer's disease (AD). Neurofilament light (NfL), triggering receptor expressed on myeloid cells 2 (TREM2), and chitinase-3-like protein 1 (YKL-40) tend to show relatively strong inter-tissue associations. A novel signal in the apolipoprotein E (APOE) region was identified, which is an eQTL for APOC1.

Keywords: Alzheimer's disease; CSF; biomarkers; genomics; neurodegenerative disease; plasma; protein quantitative trait loci.

FIGURE 1

Study design flow chart and dot plot of top hits for plasma and CSF. (A) This image is a flowchart of the entire set of analyses that were performed for the present study. Proteins were selected as outcome variables based on their association with neurodegenerative disease and availability in the SOMAscan7k proteomics panel. Plasma and CSF protein measurements were used for association analyses. Several functional analyses were performed to prioritize likely functional variants and genes, compare associations between plasma and CSF (sections with dark green background in post‐GWAS analyses section), and compare associations between plasma or CSF and AD (sections with light green background in post‐GWAS analyses section). (B) This plot shows the genomic position of significant variants across all analyses with respect to the gene that codes for the respective protein aptamer. Each color indicates if a signal is cis or trans. Each shape represents the tissue in which a variant was found to be significant. (C) The Circos plots show which genes had aptamers with a top hit in the APOE region by connecting these regions with the APOE region with lines that are colored based on effect size direction (red: negative; blue: positive, black: essentially zero) and that have thickness determined by the effect size (magnitude multiplied by 10 to make the lines easier to see). The APOE region is the only unlabeled region. Protein aptamer levels were log₁₀ transformed before analysis. All participants were European in ethnicity based on principal component analysis. AD, Alzheimer's disease; CSF, cerebrospinal fluid; GWAS, genome‐wide association study; N, sample size; pQTL: protein quantitative trait locus.

FIGURE 2

Correlation between CSF and plasma measurements of various AD‐associated protein aptamers in Europeans. These correlation plots show the correlation in protein levels between CSF and plasma for 16 different aptamers in Europeans who had both their plasma and CSF measurements taken within 6 months of each other. The left‐hand plot shows the overall correlations, whereas the right‐hand plots show correlations for AD patients (top) and controls (bottom), respectively. Larger circles indicate a stronger correlation and color indicates both the magnitude and the direction of the effect, with blue indicating a positive correlation and red indicating a negative correlation. The white asterisks indicate correlations that had p ≤ 5 × 10⁻⁸ and the black asterisks indicate correlations that has p ≤ 5 × 10⁻⁵. Protein aptamer levels were log₁₀ transformed before analysis. All participants were European in ethnicity based on principal component analysis. AD n range = 62–71; Control n range = 201–216. AD, Alzheimer's disease; CSF, cerebrospinal fluid.

FIGURE 3

Predictive ability of protein aptamer levels on AD status in CSF and plasma in Europeans. (A) This dot plot shows the predictive ability of protein aptamer levels on AD status in plasma and CSF without covariates included. (B) This dot plot shows the predictive ability of protein aptamer levels on AD status in CSF with a top hit included as a covariate. The top hits were included by regressing protein aptamer levels on top hit genotype and then running an ROC analysis with AD status as the predictor and the residuals of the protein aptamer‐top hit model as the predictor. (C) This dot plots shows the predictive ability of protein aptamer levels on AD status in plasma with a top hit included as a covariate. For Plots B and C, the no‐covariate model is plotted for comparison and color indicates the presence or lack of a top hit covariate. Error bars represent 95% confidence intervals of the AUC. Protein aptamer levels were log₁₀ transformed before analysis. All participants were European in ethnicity based on principal component analysis. CSF n = 800; Plasma n = 2176. AD, Alzheimer's disease; AUC, area under the curve; CSF, cerebrospinal fluid; ROC, receiver‐operating characteristic.