Cerebrospinal fluid BACE1 activity and markers of amyloid precursor protein metabolism and axonal degeneration in Alzheimer's disease.
OBJECTIVE
The objective of this study was to assess cerebrospinal fluid (CSF) β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) activity in relation to Alzheimer's disease (AD) and to correlate the enzyme activity with protein markers of APP metabolism and axonal degeneration.


METHODS
BACE1 activity and protein concentrations were measured and analyzed in 342 participants of the Alzheimer's Disease Neuroimaging Initiative, including 99 normal control, 75 stable mild cognitive impairment (MCI), 87 progressive MCI, and 79 AD dementia cases. All statistical analyses were Bonferroni corrected for multiple comparisons.


RESULTS
No significant differences between controls and any of the three patient groups were detected for BACE1 activity and soluble APPβ (sAPPβ) concentrations in CSF. Significant correlations with BACE1 activity were found for CSF APPβ and total tau in all four groups and for CSF phosphorylated tau181 in all groups but the progressive MCI group. There were no correlations for CSF amyloid β (Aβ)1-42 or for plasma Aβ1-42 and Aβ1-40.


CONCLUSIONS
The consistent correlation between BACE1 activity and sAPPβ supports their role as biomarkers of target engagement in clinical trials on BACE1 inhibition.
Neuroepidemiology and Ageing Research Unit, School of Public Health, Faculty of Medicine, The Imperial College of Science, Technology, and Medicine, London, UK; West London Cognitive Disorders Treatment and Research Unit, West London Mental Health Trust, London, UK; Department of Psychiatry and Psychotherapy, Technische Universität München, Munich, Germany. Electronic address: r.perneczky@imperial.ac.uk.
Robert
R
Perneczky
Department of Psychiatry and Psychotherapy, Technische Universität München, Munich, Germany.
Panagiotis
P
Alexopoulos
D000368:Aged; D000544:Alzheimer Disease / Q000473:pathology / Q000503:physiopathology*; D053829:Amyloid Precursor Protein Secretases / Q000134:cerebrospinal fluid*; D016229:Amyloid beta-Peptides / Q000097:blood / Q000134:cerebrospinal fluid; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000134:cerebrospinal fluid*; D001369:Axons / Q000473:pathology / Q000502:physiology*; D015415:Biomarkers / Q000378:metabolism; D002986:Clinical Trials as Topic; D060825:Cognitive Dysfunction / Q000473:pathology / Q000503:physiopathology; D016208:Databases, Factual; D005260:Female; D006801:Humans; D008297:Male; D009410:Nerve Degeneration / Q000473:pathology / Q000503:physiopathology*; D010446:Peptide Fragments / Q000097:blood / Q000134:cerebrospinal fluid; D010766:Phosphorylation; D016875:tau Proteins / Q000134:cerebrospinal fluid
C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D015415:Biomarkers; C054369:MAPT protein, human; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
Amyloid precursor protein; Amyloid-β; Biomarker; Correlation; Dementia; Diagnosis; Mild cognitive impairment; Prognosis; Tau