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Brain Advance Access originally published online on March 11, 2008
Brain 2008 131(5):1252-1258; doi:10.1093/brain/awn034
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© The Author (2008). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Increased CSF-BACE 1 activity is associated with ApoE-{varepsilon}4 genotype in subjects with mild cognitive impairment and Alzheimer's disease

Michael Ewers1,2, Zhenyu Zhong3, Katharina Bürger1, Anders Wallin4, Kaj Blennow4, Stefan J. Teipel5, Yong Shen3 and Harald Hampel1,2

1Department of Psychiatry, Alzheimer Memorial Center, Ludwig-Maximilian University, Munich, Germany, 2Trinity College Dublin, School of Medicine, Discipline of Psychiatry & Trinity College Institute of Neuroscience (TCIN) & The Adelaide and Meath Hospital Incorporating The National Children's Hospital (AMiNCH), Dublin, Ireland, 3Haldeman Laboratory of Molecular and Cellular Neurobiology, Sun Health Research Institute, Sun City, AZ, USA, 4Department of Clinical Neuroscience, University of Göteborg, Sahlgren's University Hospital, Göteborg, Sweden and 5Department of Psychiatry, University Rostock, Germany

Correspondence to: Prof. Harald Hampel, MD, MSc, Discipline of Psychiatry, School of Medicine, Trinity College Dublin, Trinity Centre for Health Sciences, The Adelaide and Meath Hospital Incorporating The National Children's Hospital (AMiNCH), Tallaght, Dublin 24, Ireland E-mail: Harald.Hampel{at}tcd.ie, Harald.Hampel{at}med.uni-muenchen.de

The Apolipoprotein (ApoE) {varepsilon}4 allele is a major genetic risk factor of Alzheimer's disease, and may affect the production of amyloid beta (Aβ1–42). Recently, we have shown that β-secretase (BACE 1) activity can be reliably detected within the brain and human CSF. Here, we have examined an association between the ApoE genotype and CSF-levels of BACE 1 activity in Alzheimer's disease and mild cognitive impairment (MCI). A total of 148 subjects were included: 60 Alzheimer's disease patients, 51 MCI subjects and 37 elderly healthy controls. The CSF-levels of Aβ1–42, BACE 1 activity and BACE protein were measured in all of these subjects. The differences between ApoE-{varepsilon}4 carriers and ApoE-{varepsilon}4 non-carriers in these CSF-based measures were determined controlling for gender, age and MMSE score. The ApoE-{varepsilon}4 genotype was associated with increased BACE 1 activity in both Alzheimer's disease (P = 0.03) and MCI (P = 0.04) subjects. Levels of Aβ1–42 were decreased in ApoE-{varepsilon}4 carriers in MCI (P = 0.004) but not Alzheimer's disease subjects. This study is the first to demonstrate the association between ApoE-{varepsilon}4 and CSF-BACE 1 activity in MCI and Alzheimer's disease subjects. The assessment of BACE 1 in CSF may provide a sensitive measure to detect in vivo alterations in the amyloidogenic processing potentially modified by the ApoE genotype.

Key Words: mild cognitive impairment; cerebrospinal fluid; Alzheimer's disease; ApoE{varepsilon}4, β-amyloid; biological marker; prediction; early detection; biological activity; cerebrospinal fluid; CSF

Abbreviations: ApoE, Apolipoprotein; APP, amyloid precursor protein; Aβ, beta-amyloid; CSF, cerebrospinal fluid; HC, healthy control; MCI, mild cognitive impairment

Received November 14, 2007. Revised January 25, 2008. Accepted February 13, 2008.


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