Uncorrected Author Proof Journal of Alzheimer’s Disease xx (20xx) x–xx DOI 10.3233/JAD-142136 IOS Press 1 Amyloid- Oligomers Relate to Cognitive Decline in Alzheimer’s Disease 1 2 Wesley Jongbloed a,b , Kim A. Bruggink c , Maartje I. Kester b , Pieter-Jelle Visser b,d , Philip Scheltens b , Marinus A. Blankenstein a , Marcel M. Verbeek c , Charlotte E. Teunissen a and Robert Veerhuis a,e,* 3 4 5 a Department of Clinical Chemistry, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands 6 7 b Alzheimer Center & Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands 8 9 c Department of Neurology, Department of Laboratory Medicine, Donders Institute for Brain, Cognition and behaviour, Alzheimer Centre Nijmegen, Radboud University Medical Centre, Nijmegen, The Netherlands 10 11 d Department of Psychiatry and Neuropsychology, Alzheimer Center Limburg, University of Maastricht, Maastricht, The Netherlands 12 13 e Department of Psychiatry, VU University Medical Center, Amsterdam, The Netherlands 14 Handling Associate Editor: Henrietta Nielsen 15 Accepted 7 November 2014 Abstract. 16 Background: Amyloid- (A)-oligomers are neurotoxic isoforms of A and are a potential diagnostic biomarker for Alzheimer’s disease (AD). 17 18 Objectives: 1) Analyze the potential of A-oligomer concentrations in cerebrospinal fluid (CSF) to diagnose and predict progression to AD in a large clinical study sample. 2) Monitor A-oligomer concentrations over-time, both in early and advanced stages of AD. 3) Examine the relation between A-oligomer levels in CSF and cognitive functioning. 19 20 21 Methods: 24 non-demented, 61 mild cognitive impairment (MCI), and 64 AD patients who underwent lumbar puncture and cognitive testing at baseline and follow-up were selected from the memory clinic based Amsterdam Dementia Cohort. CSF samples were analyzed for standard AD-biomarkers and A-oligomer levels using a validated in-house A-oligomer specific enzyme-linked immunosorbent assay. A-oligomer levels were analyzed as indicators of disease progression (follow-up AD diagnosis) and cognitive decline, respectively. 22 23 24 25 26 Results: Patient groups did not differ in A-oligomer concentrations at baseline or follow-up. Baseline CSF A-oligomer levels were similar in MCI patients that develop AD as in stable MCI patients. MCI and AD patients showed an annual decrease in A-oligomer levels of 9.4% and 6.8%, respectively. A decrease in A-oligomer levels over time was strongly associated with more severe cognitive decline in AD patients. 27 28 29 30 Conclusion: Despite the limited diagnostic potential of A-oligomer levels in CSF to differentiate between patient groups, and between MCI-AD and MCI-stable patients, changes in CSF A-oligomer levels were related to cognitive decline. Therefore, CSF A-oligomers may aid in the selection of patients with a more aggressive disease course. 31 32 33 Keywords: Alzheimer’s disease, amyloid- peptides, biological markers, cerebrospinal fluid, cognition, dementia, disease progression, mild cognitive impairment 34 35 * Correspondence to: Robert Veerhuis, PhD, VU Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands. Tel.: +31 20 444 3868; E-mail: r.veerhuis@vumc.nl. ISSN 1387-2877/14/$27.50 © 2014 – IOS Press and the authors. All rights reserved