Elevated cerebrospinal fluid BACE1 activity in incipient Alzheimer disease

Arch Neurol. 2008 Aug;65(8):1102-7. doi: 10.1001/archneur.65.8.1102.


Background: We used 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 (Abeta) 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 Abeta(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 >or= 0.57, P <or= .009).

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

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / cerebrospinal fluid*
  • Alzheimer Disease / enzymology*
  • Alzheimer Disease / pathology
  • Amyloid / adverse effects
  • Amyloid / physiology
  • Amyloid Precursor Protein Secretases / cerebrospinal fluid*
  • Amyloid Precursor Protein Secretases / physiology
  • Aspartic Acid Endopeptidases / cerebrospinal fluid*
  • Aspartic Acid Endopeptidases / physiology
  • Axons / enzymology
  • Axons / pathology
  • Biomarkers / cerebrospinal fluid
  • Case-Control Studies
  • Enzyme Activation / physiology
  • Female
  • Follow-Up Studies
  • Humans
  • Longitudinal Studies
  • Male
  • Middle Aged
  • Nerve Degeneration / cerebrospinal fluid
  • Nerve Degeneration / enzymology
  • Nerve Degeneration / pathology


  • Amyloid
  • Biomarkers
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human