Elevated cerebrospinal fluid BACE1 activity in incipient Alzheimer disease.
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.


METHODS
Case-control and longitudinal follow-up study.


METHODS
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.


METHODS
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).


CONCLUSIONS
Elevated BACE1 activity may contribute to the amyloidogenic process in sporadic AD and is associated with the intensity of axonal degeneration.
Zetterberg
Henrik
H
Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at Göteborg University, Mölndal, Sweden. henrik.zetterberg@gu.se
Andreasson
Ulf
U
Hansson
Oskar
O
Wu
Guoxin
G
Sankaranarayanan
Sethu
S
Andersson
Malin E
ME
Buchhave
Peder
P
Londos
Elisabet
E
Umek
Robert M
RM
Minthon
Lennart
L
Simon
Adam J
AJ
Blennow
Kaj
K
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000201:enzymology* / Q000473:pathology; D000682:Amyloid / Q000009:adverse effects / Q000502:physiology; D053829:Amyloid Precursor Protein Secretases / Q000134:cerebrospinal fluid* / Q000502:physiology; D016282:Aspartic Acid Endopeptidases / Q000134:cerebrospinal fluid* / Q000502:physiology; D001369:Axons / Q000201:enzymology / Q000473:pathology; D015415:Biomarkers / Q000134:cerebrospinal fluid; D016022:Case-Control Studies; D004789:Enzyme Activation / Q000502:physiology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009410:Nerve Degeneration / Q000134:cerebrospinal fluid / Q000201:enzymology / Q000473:pathology
D000682:Amyloid; D015415:Biomarkers; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human