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Henrik Zetterberg, MD, PhD; Ulf Andreasson, PhD; Oskar Hansson, MD, PhD; Guoxin Wu, PhD; Sethu Sankaranarayanan, PhD; Malin E. Andersson, MSc; Peder Buchhave, MD; Elisabet Londos, MD, PhD; Robert M. Umek, PhD; Lennart Minthon, MD, PhD; Adam J. Simon, PhD; Kaj Blennow, MD, PhD

Arch Neurol. 2008;65(8):1102-1107.

Background  We used a sensitive and specific β-site amyloid precursor protein (APP)–cleaving enzyme 1 (BACE1) assay to determine the relationship between BACE1 activity in cerebrospinal fluid (CSF) and markers of APP metabolism and axonal degeneration in early and late stages of Alzheimer disease (AD).

Objective  To assess CSF BACE1 activity in AD.

Design  Case-control and longitudinal follow-up study.

Setting  Specialized memory clinic.

Patients  Eighty-seven subjects with AD, 33 cognitively normal control subjects, and 113 subjects with mild cognitive impairment (MCI), who were followed up for 3 to 6 years.

Main Outcome Measures  Cerebrospinal fluid BACE1 activity in relation to diagnosis and CSF levels of secreted APP and amyloid β protein (Aβ) isoforms and the axonal degeneration marker total tau.

Results  Subjects with AD had higher CSF BACE1 activity (median, 30 pM [range, 11-96 pM]) than controls (median, 23 pM [range, 8-43 pM]) (P =.02). Subjects with MCI who progressed to AD during the follow-up period had higher baseline BACE1 activity (median, 35 pM [range, 18-71 pM]) than subjects with MCI who remained stable (median, 29 pM [range, 14-83 pM]) (P < .001) and subjects with MCI who developed other forms of dementia (median, 20 pM [range, 10-56 pM]) (P <.001). BACE1 activity correlated positively with CSF levels of secreted APP isoforms and Aβ₄₀ in the AD and control groups and in all MCI subgroups (P < .05) except the MCI subgroup that developed AD. Strong positive correlations were found between CSF BACE1 activity and total tau levels in all MCI subgroups (r  0.57, P  .009).

Conclusion  Elevated BACE1 activity may contribute to the amyloidogenic process in sporadic AD and is associated with the intensity of axonal degeneration.

Author Affiliations: Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, Sahlgrenska Academy at Göteborg University, Mölndal (Drs Zetterberg, Andreasson, and Blennow and Ms Andersson), and Clinical Memory Research Unit, Department of Clinical Sciences at Lund University, and Neuropsychiatric Clinic at Malmö University Hospital, Malmö (Drs Hansson, Buchhave, Londos, and Minthon), Sweden; Alzheimer's Research, Merck Research Laboratories, West Point, Pennsylvania (Drs Wu, Sankaranarayanan, and Simon); and Meso Scale Discovery, Gaithersburg, Maryland (Dr Umek).

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