Transcriptional risk scores in Alzheimer's disease: From pathology to cognition.

ABSTRACT

INTRODUCTION: Our previously developed blood-based transcriptional risk scores (TRS) showed associations with diagnosis and neuroimaging biomarkers for Alzheimer's disease (AD). Here, we developed brain-based TRS. METHODS: We integrated AD genome-wide association study summary and expression quantitative trait locus data to prioritize target genes using Mendelian randomization. We calculated TRS using brain transcriptome data of two independent cohorts (N = 878) and performed association analysis of TRS with diagnosis, amyloidopathy, tauopathy, and cognition. We compared AD classification performance of TRS with polygenic risk scores (PRS). RESULTS: Higher TRS values were significantly associated with AD, amyloidopathy, tauopathy, worse cognition, and faster cognitive decline, which were replicated in an independent cohort. The AD classification performance of PRS was increased with the inclusion of TRS up to 16% with the area under the curve value of 0.850. DISCUSSION: Our results suggest brain-based TRS improves the AD classification of PRS and may be a potential AD biomarker. HIGHLIGHTS Transcriptional risk score (TRS) is developed using brain RNA-Seq data. Higher TRS values are shown in Alzheimer's disease (AD). TRS improves the AD classification power of PRS up to 16%. TRS is associated with AD pathology presence. TRS is associated with worse cognitive performance and faster cognitive decline.