Increased CSF-BACE1 Activity Associated with Decreased Hippocampus Volume in Alzheimer's Disease

Article type: Research Article

Authors: Ewers, Michael^{a; b; c; *} | Cheng, Xin^{d; e; #} | Zhong, Zhenyu^{d; #} | Nural, Hikmet F.^d | Walsh, Cathal^f | Meindl, Thomas^g | Teipel, Stefan J.^{h; i} | Buerger, Katharina^b | He, Ping^{d; j} | Shen, Yong^{d; j} | Hampel, Harald^k

Affiliations: [a] Discipline of Psychiatry, School of Medicine & Trinity College Institute of Neuroscience (TCIN), Laboratory of Neuroimaging & Biomarker Research, Trinity College, University of Dublin, The Adelaide and Meath Hospital Incorporating The National Children's Hospital (AMiNCH), Tallaght, Dublin, Ireland & Dementia Research Section and Memory Clinic, Dublin, Ireland | [b] Alzheimer Memorial Center, Department of Psychiatry, Ludwig Maximilian University, Munich, Germany | [c] Department of Radiology, University of California, San Francisco, CA, USA | [d] Haldeman Laboratory of Molecular and Cellular Neurobiology, Sun Health Research Institute, Sun City, AZ, USA | [e] Department of Neurology, Institute of Neurology, Huashan Hospital, Fudan University Shanghai Medical College, Shanghai, China | [f] Department of Statistics, Trinity College, University of Dublin, Dublin, Ireland | [g] Department of Radiology, Ludwig Maximilian University, Munich, Germany | [h] Department of Psychiatry, University of Rostock, Rostock, Germany | [i] Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Germany | [j] Center for Advanced Therapeutic Strategies for Brain Disorders, Roskamp Institute, Sarasota, FL, USA | [k] Department of Psychiatry, Psychosomatic Medicine & Psychotherapy, Goethe University, Frankfurt, Germany

Correspondence: [*] Correspondence to: Michael Ewers, Ph.D., University of California, San Francisco, Department of Radiology, VA Medical Center, Center for Neuroimaging of Neurodegenerative Diseases, San Francisco, CA 94121; Tel.:415-221-4810 x3831; fax: 415 668 2864. E-mail: michael.ewers@ucsf.edu; michael.ewers@va.gov.

Note: [#] Note: Both authors contributed equally to the study.

Abstract: The enzyme β-secretase (BACE1) is essentially involved in the production of cerebral amyloidogenic pathology in Alzheimer's disease (AD). The measurement of BACE1 activity in cerebrospinal fluid (CSF) has been reported, which may render CSF measurement of BACE1 a potential biomarker candidate of AD. In order to investigate whether BACE1 protein activity is correlated with regional brain atrophy in AD, we investigated the association between CSF levels of BACE1 and MRI-assessed hippocampus volume in patients with AD (n = 30). An increase in CSF-BACE1 activity was associated with decreased left and right hippocampus volume corrected for global head volume in the AD patients. Boot-strapped regression analysis showed that increased CSF levels of BACE1 activity were associated with increased CSF concentration of total tau but not amyloid-β1-42 in AD. White matter hyperintensities did not influence the results. BACE1 activity and protein levels were significantly increased in AD compared to 19 elderly healthy controls. Thus, the CSF biomarker candidate of BACE1 activity was associated with hippocampus atrophy in AD in a robust manner and may reflect neurotoxic amyloid-β-related processes.

Keywords: BACE1, β-secretase, cerebrospinal fluid, hippocampus

DOI: 10.3233/JAD-2011-091153

Journal: Journal of Alzheimer's Disease, vol. 25, no. 2, pp. 373-381, 2011