Association of blood-based transcriptional risk scores with biomarkers for Alzheimer disease

Abstract

Objective: To determine whether transcriptional risk scores (TRSs), a summation of polarized expression levels of functional genes, reflect the risk of Alzheimer disease (AD).

Methods: Blood transcriptome data were from Caucasian participants, which included AD, mild cognitive impairment, and cognitively normal controls (CN) in the Alzheimer's Disease Neuroimaging Initiative (ADNI, n = 661) and AddNeuroMed (n = 674) cohorts. To calculate TRSs, we selected functional genes that were expressed under the control of the AD risk loci and were identified as being responsible for AD by using Bayesian colocalization and mendelian randomization methods. Regression was used to investigate the association of the TRS with diagnosis (AD vs CN) and MRI biomarkers (entorhinal thickness and hippocampal volume). Regression was also used to evaluate whether expression of each functional gene was associated with AD diagnosis.

Results: The TRS was significantly associated with AD diagnosis, hippocampal volume, and entorhinal cortical thickness in the ADNI. The association of the TRS with AD diagnosis and entorhinal cortical thickness was also replicated in AddNeuroMed. Among functional genes identified to calculate the TRS, CD33 and PILRA were significantly upregulated, and TRAPPC6A was significantly downregulated in patients with AD compared with CN, all of which were identified in the ADNI and replicated in AddNeuroMed.

Conclusions: The blood-based TRS is significantly associated with AD diagnosis and neuroimaging biomarkers. In blood, CD33 and PILRA were known to be associated with uptake of β-amyloid and herpes simplex virus 1 infection, respectively, both of which may play a role in the pathogenesis of AD.

Classification of evidence: The study is rated Class III because of the case control design and the risk of spectrum bias.

Figure 1. Violin plots for the TRS between CN, MCI, and AD

Target genes identified from SMR at p value of AD-associated SNPs less than 1 × 10⁻⁷ were used to calculate the TRS. The violin plot shows the probability density of the TRS data as well as median and interquartile ranges in ADNI (A) and AddNeuroMed (B). AD = Alzheimer disease; ADNI = Alzheimer's Disease Neuroimaging Initiative; CN = cognitively normal older adults; MCI = mild cognitive impairment; SMR = summary data–based mendelian randomization; TRS = transcriptional risk score.

Figure 2. Heatmaps of gene expression between CN and AD

Two genes (CD33 and PILRA) that were predicted to have increased expression in patients with AD from the integration of GWAS summary statistics and eQTL data showed significantly increased expression in patients with AD in ADNI (A). Among 3 genes predicted to have decreased expression in patients with AD, 1 gene (TRAPPC6A) showed significantly decreased expression in patients with AD in ADNI (B). In AddNeuroMed, the expression level of two genes (CD33 and PILRA) was significantly increased in patients with AD (C), whereas the expression level of two genes (B4GALT3 and TRAPPC6A) was significantly decreased in patients with AD (D). The gene expression values were transformed into a normal distribution with mean 0 and variance 1. AD = Alzheimer disease; ADNI = Alzheimer's Disease Neuroimaging Initiative; CN = cognitively normal older adults; eQTL = expression quantitative trait locus; GWAS = genome-wide association study.