A Gene Expression Pattern in Blood for the Early Detection of Alzheimer's Disease

Article type: Research Article

Authors: Booij, Birgitte Boonstra^{a; 1} | Lindahl, Torbjørn^a | Wetterberg, Peter^b | Skaane, Nina Voss^b | Sæbø, Solve^c | Feten, Guri^c | Rye, Phil D.^{a; 2} | Kristiansen, Lena Iren^a | Hagen, Nina^a | Jensen, Marianne^a | Bårdsen, Ken^a | Winblad, Bengt^d | Sharma, Praveen^a | Lönneborg, Anders^{a; *}

Affiliations: [a] DiaGenic ASA, Grenseveien, Oslo, Norway | [b] Memory Clinic, Department of Geriatrics, Medical Division, Ullevål University Hospital, Oslo, Norway | [c] Department of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences, Ås, Norway | [d] Department of Neurobiology, Care Sciences and Society, Karolinska Institutet Alzheimer Disease Research Center, Huddinge, Sweden

Correspondence: [*] Correspondence to: Dr. A. Lönneborg, DiaGenic ASA, Grenseveien 92, 0663 Oslo, Norway. Email: [email protected].

Note: [1] Present address: Birgitte Boonstra Booij, Clavis Pharma ASA, Oslo, Norway.

Note: [2] Present address: Phil D. Rye, GE Healthcare Europe GmbH, Oslo, Norway.

Abstract: A whole genome screen was performed using oligonucleotide microarray analysis on blood from a large clinical cohort of Alzheimer's disease (AD) patients and control subjects as clinical sample. Blood samples for total RNA extraction were collected in PAXgene tubes, and gene expression analysis performed on the AB1700 Whole Genome Survey Microarrays. When comparing the gene expression of 94 AD patients and 94 cognitive healthy controls, a Jackknife gene selection based method and Partial Least Square Regression (PLSR) was used to develop a disease classifier algorithm, which gives a test score indicating the presence (positive) or absence (negative) of AD. This algorithm, based on 1239 probes, was validated in an independent test set of 63 subjects comprising 31 AD patients, 25 age-matched cognitively healthy controls, and 7 young controls. This algorithm correctly predicted the class of 55/63 (accuracy 87%), including 26/31 AD samples (sensitivity 84%) and 29/32 controls (specificity 91%). The positive likelihood ratio was 8.9 and the area under the receiver operating characteristic curve (ROC AUC) was 0.94. Furthermore, the algorithm also discriminated AD from Parkinson's disease in 24/27 patients (accuracy 89%). We have identified and validated a gene expression signature in blood that classifies AD patients and cognitively healthy controls with high accuracy and show that alterations specific for AD can be detected distant from the primary site of the disease.

Keywords: Alzheimer's disease, blood, biomarker, diagnostic test, microarray, RNA

DOI: 10.3233/JAD-2010-101518

Journal: Journal of Alzheimer's Disease, vol. 23, no. 1, pp. 109-119, 2011