Validation of AclarusDx™, a Blood-Based Transcriptomic Signature for the Diagnosis of Alzheimer's Disease

Abstract

Biomarkers have gained an increased importance in the past years in helping physicians to diagnose Alzheimer's disease (AD). This study was designed to identify a blood-based, transcriptomic signature that can differentiate AD patients from control subjects. The performance of the signature was then evaluated for robustness in an independent blinded sample population. RNA was extracted from 177 blood samples (90 AD patients and 87 controls) and gene expression profiles were generated using the human Genome-Wide Splice Array™. These profiles were used to establish a signature to differentiate AD patients from controls. Subsequently, prediction results were optimized by establishing grey zone boundaries that discount prediction scores near the disease status threshold. Signature validation was then performed on a blinded independent cohort of 209 individuals (111 AD and 98 controls). The AclarusDx™ signature consists of 170 probesets which map to 136 annotated genes, a significant number of which are associated with inflammatory, gene expression, and cell death pathways. Additional signature genes are known to interact with pathways involved in amyloid and tau metabolism. The validation sample set, after removal of 45 individuals with prediction profile scores within the grey zone, consisted of 164 subjects. The AclarusDx™ performance on this validation cohort had a sensitivity of 81.3% (95% CI: [73.3%; 89.3%]); and a specificity of 67.1% (95% CI: [56.3%; 77.9%]). AclarusDx™ is a non-invasive blood-based transcriptomic test that, in combination with standard assessments, can provide physicians with objective information to support the diagnosis of AD.

Prediction of Mild Cognitive Impairment that Evolves into Alzheimer's Disease Dementia within Two Years using a Gene Expression Signature in Blood: A Pilot Study

“…This suggests that these processes not only are affected in brain tissue but also are reflected in a systemic response that can be detected using gene expression in blood. This is also well in agreement with similar findings in previous AD studies [34][35][36][37][38]. The results also support the concept of AD as a multifactorial sporadic disorder [54] with multiple genes and alterations in gene expression involved [55,56].…”

“…We and others have previously shown that disease biomarkers to classify AD with dementia from cognitively healthy individuals are present in blood [16,23,35] and an algorithm based on the gene expression of a selected set of genes can be used to identify those with an AD dementia [34][35][36]. We have now further extended these findings to also include AD in the pre-dementia stage of the disease.…”

“…This test detects the blood-based gene expression signature in blood samples and adopts a combination of multiple gene expression assays to obtain a prediction value for disease classification. Alterations in a gene expression signature in peripheral blood are postulated as a result of a systemic disease response in AD as verified by many previous studies [34][35][36][37][38].…”

Small molecule biomarkers in Alzheimer’s disease

“…For example, application of Polymerase Chain Reaction (PCR) has proposed circulating microRNAs (Kumar et al, 2013;Tan et al, 2014); the most promising result showed a panel of 12 microRNAs which differentiated AD from controls with accuracy of 93% (Leidinger et al, 2013). Transcriptomic tests have also been applied on blood; a signature consisting of 170 probe sets has been identified to discriminate AD from controls with sensitivity and specificity of 81.3% and 67.1% respectively (Fehlbaum-Beurdeley et al, 2012).…”

Circulating Biomarker Panels in Alzheimer's Disease

“…Various studies [15,16,44,45,46,47] have shown that the gene expression blood test can aid in the diagnosis of mild to moderate AD. As for the other high-throughput approaches, further confirmation based on independent cohorts is required.…”