Levels of beta-secretase (BACE1) in cerebrospinal fluid as a predictor of risk in mild cognitive impairment.
BACKGROUND
Elevated beta-secretase (beta-site amyloid precursor protein-cleaving enzyme 1 [BACE1]) activity has been found in the brains of patients with sporadic Alzheimer disease (AD) compared with controls. Now we are particularly interested in whether BACE1 can be identified in the cerebrospinal fluid (CSF) of patients with mild cognitive impairment (MCI), a population at high risk for AD. The possible presence of BACE1 in the CSF of patients with AD and MCI has so far gone unreported.


OBJECTIVE
To examine whether BACE1 can be identified in the CSF of patients with MCI.


METHODS
We evaluated CSF BACE1 levels using 2 sandwich enzyme-linked immunosorbent assays, BACE1 enzymatic activities by means of synthetic fluorescence substrate, and total amyloid-beta peptide levels using a sandwich enzyme-linked immunosorbent assay.


METHODS
Two independent research centers.


METHODS
Eighty patients with sporadic AD, 59 patients with MCI, and 69 controls.


METHODS
BACE1 levels and enzymatic activities and amyloid-beta peptide levels.


RESULTS
Increased CSF levels of BACE1 protein were associated with increased risk ratios (RRs) for patients with MCI compared with controls (RR, 2.08; 95% confidence interval [CI], 1.58-2.58) and patients with AD (RR, 1.65; 95% CI, 1.19-2.03). Similarly, patients with MCI showed increased levels of BACE1 activity compared with controls (RR, 2.17; 95% CI, 1.66-2.71) and patients with AD (RR, 3.71; 95% CI, 2.74-4.36). For total amyloid-beta peptide and tau, increased CSF levels were associated with a higher risk of MCI compared with controls. The BACE1 activity was significantly correlated with BACE1 protein level (rho = 0.23; P<.001) and amyloid-beta peptide level (rho = 0.39; P<.001), with amyloid-beta peptide correlated with BACE1 protein level (rho = 0.30; P<.001).


CONCLUSIONS
Significant elevation of BACE1 levels and activity in CSF is an indicator of MCI, which could be an early stage of AD.
Zhong
Zhenyu
Z
Haldeman Laboratory of Molecular and Cellular Neurobiology, Sun Health Research Institute, Sun City, AZ 85351, USA.
Ewers
Michael
M
Teipel
Stefan
S
Bürger
Katharina
K
Wallin
Anders
A
Blennow
Kaj
K
He
Ping
P
McAllister
Carrie
C
Hampel
Harald
H
Shen
Yong
Y
D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000175:diagnosis / Q000201:enzymology; D053829:Amyloid Precursor Protein Secretases / Q000134:cerebrospinal fluid*; D016282:Aspartic Acid Endopeptidases / Q000134:cerebrospinal fluid; D015153:Blotting, Western; D001921:Brain / Q000201:enzymology / Q000378:metabolism; D003072:Cognition Disorders / Q000134:cerebrospinal fluid* / Q000175:diagnosis / Q000201:enzymology*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D012307:Risk Factors; D012720:Severity of Illness Index; D016875:tau Proteins / Q000134:cerebrospinal fluid
D016875:tau Proteins; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human