Ab40 oligomers identified as a potential biomarker for the diagnosis of alzheimer’s disease

Ab40 Oligomers Identified as a Potential Biomarker for the Diagnosis of Alzheimer’s Disease
Carol Man Gao1., Alice Y. Yam1., Xuemei Wang1, Erika Magdangal1, Cleo Salisbury1, David Peretz1, Ronald N. Zuckermann1¤, Michael D. Connolly1¤, Oskar Hansson3, Lennart Minthon3, Henrik Zetterberg2, Kaj Blennow2, Joseph P. Fedynyshyn1*, Sophie Allauzen1
1 Research and Development, Novartis Vaccines andDiagnostics, Emeryville, California, United States of America, 2 Clinical Neurochemistry Laboratory, Department of ¨ ¨ Neuroscience and Physiology, Sahlgrenska University Hospital, Molndal, Sweden, 3 Clinical Memory Research Unit, Department of Clinical Sciences Malmo, Lund ¨ University, Malmo, Sweden

Abstract
Alzheimer’s Disease (AD) is the most prevalent form of dementia worldwide, yet thedevelopment of therapeutics has been hampered by the absence of suitable biomarkers to diagnose the disease in its early stages prior to the formation of amyloid plaques and the occurrence of irreversible neuronal damage. Since oligomeric Ab species have been implicated in the pathophysiology of AD, we reasoned that they may correlate with the onset of disease. As such, we have developed a novelmisfolded protein assay for the detection of soluble oligomers composed of Ab x-40 and x-42 peptide (hereafter Ab40 and Ab42) from cerebrospinal fluid (CSF). Preliminary validation of this assay with 36 clinical samples demonstrated the presence of aggregated Ab40 in the CSF of AD patients. Together with measurements of total Ab42, diagnostic sensitivity and specificity greater than 95% and 90%,respectively, were achieved. Although larger sample populations will be needed to confirm this diagnostic sensitivity, our studies demonstrate a sensitive method of detecting circulating Ab40 oligomers from AD CSF and suggest that these oligomers could be a powerful new biomarker for the early detection of AD.
Citation: Gao CM, Yam AY, Wang X, Magdangal E, Salisbury C, et al. (2010) Ab40 OligomersIdentified as a Potential Biomarker for the Diagnosis of Alzheimer’s Disease. PLoS ONE 5(12): e15725. doi:10.1371/journal.pone.0015725 Editor: Sergio T. Ferreira, Federal University of Rio de Janeiro, Brazil Received August 2, 2010; Accepted November 21, 2010; Published December 30, 2010 Copyright: ß 2010 Gao et al. This is an open-access article distributed under the terms of the Creative CommonsAttribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was funded by Novartis Vaccines and Diagnostics. Several of the authors are or were employed by the funder and, as such, the funders played a role in the study design, data collection and analysis, decision to publish, andpreparation of the manuscript. Competing Interests: Several of the authors are employed by Novartis Vaccines and Diagnostics and thus may have a conflict of interest. In addition, the submitted work is included in a pending patent application on amyloid-beta aggregates as biomarkers for Alzheimer’s Disease (patent #61/265,340, submitted by Novartis AG on Nov 30, 2009). This does not alter the authors’adherence to all the PLoS ONE policies on sharing data and materials. * E-mail: joseph.fedynyshyn@novartis.com ¤ Current address: Lawrence Berkeley National Laboratory, Molecular Foundry, Berkeley, California, United States of America . These authors contributed equally to this work.

Introduction
Alzheimer’s Disease (AD) is a neurodegenerative disorder characterized by progressive memory lossand cognitive dysfunction. It is the most prevalent form of dementia, estimated to affect 13 million people worldwide [1]. While the precise mechanism underlying the disease is not fully understood, the aggregation of amyloid beta (Ab) appears to play an important role [2–4]. Ab peptides of various lengths (typically 1–40 and 1–42) are cleavage products of the amyloid precursor protein that...