Elevated cerebrospinal fluid BACE1 activity in incipient Alzheimer disease

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

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Weused a sensitive and specific beta-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 beta protein (A beta) 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, 23pM [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 A beta(40) 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.
Original languageEnglish
Pages (from-to)1102-1107
JournalArchives of Neurology
Volume65
Issue number8
Publication statusPublished - 2008

Subject classification (UKÄ)

  • Neurology

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