A Blood Gene Expression Marker of Early Alzheimer's Disease

Abstract

A marker of Alzheimer's disease (AD) that can accurately diagnose disease at the earliest stage would significantly support efforts to develop treatments for early intervention. We have sought to determine the sensitivity and specificity of peripheral blood gene expression as a diagnostic marker of AD using data generated on HT-12v3 BeadChips. We first developed an AD diagnostic classifier in a training cohort of 78 AD and 78 control blood samples and then tested its performance in a validation group of 26 AD and 26 control and 118 mild cognitive impairment (MCI) subjects who were likely to have an AD-endpoint. A 48 gene classifier achieved an accuracy of 75% in the AD and control validation group. Comparisons were made with a classifier developed using structural MRI measures, where both measures were available in the same individuals. In AD and control subjects, the gene expression classifier achieved an accuracy of 70% compared to 85% using MRI. Bootstrapping validation produced expression and MRI classifiers with mean accuracies of 76% and 82%, respectively, demonstrating better concordance between these two classifiers than achieved in a single validation population. We conclude there is potential for blood expression to be a marker for AD. The classifier also predicts a large number of people with MCI, who are likely to develop AD, are more AD-like than normal with 76% of subjects classified as AD rather than control. Many of these people do not have overt brain atrophy, which is known to emerge around the time of AD diagnosis, suggesting the expression classifier may detect AD earlier in the prodromal phase. However, we accept these results could also represent a marker of diseases sharing common etiology.

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].…”

“…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].…”

Validation of the Chinese Version of Addenbrooke's Cognitive Examination-Revised for Screening Mild Alzheimer's Disease and Mild Cognitive Impairment

“…For example, the sensitivity and specificity of ACE-R are 0.867 and 0.706 for screening for MCI, respectively, which means when a patient with suspected MCI obtains a score <85, the possibility of MCI is 0.867 (PPV) for him/her and the false positive rate is 0.133. The diagnosis of MCI or AD requires a detailed clinical history, a careful physical examination, comprehensive neuropsychological tests, biochemical blood tests, and neuroimaging studies [35,36]. …”

Altered Blood Gene Expression of Tumor-Related Genes (PRKCB, BECN1, and CDKN2A) in Alzheimer’s Disease

“…Several studies have tried to identify a gene expression signature in the peripheral blood that has diagnostic value for the detection of AD [4][5][6][7][8]. Although the validity of the blood transcriptome for the early diagnosis of AD has yet to be tested extensively, gene transcriptional profiles in the blood can reflect the complex pathophysiological status of AD, suggesting the potential of blood as a tissue for investigating causative factors, disease mechanisms, biomarkers, and novel therapeutic targets for AD [9][10]8].…”