Levels of β-Secretase (BACE1) in Cerebrospinal Fluid as a Predictor of Risk in Mild Cognitive Impairment

Context Elevated β-secretase (β-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. Design We evaluated CSF BACE1 levels using 2 sandwich enzyme-linked immunosorbent assays, BACE1 enzymatic activities by means of synthetic fluorescence substrate, and total amyloid-β peptide levels using a sandwich enzyme-linked immunosorbent assay. Setting Two independent research centers. Participants Eighty patients with sporadic AD, 59 patients with MCI, and 69 controls. Main Outcome Measures BACE1 levels and enzymatic activities and amyloid-β 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-β 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 (ρ = 0.23; P P P Conclusion Significant elevation of BACE1 levels and activity in CSF is an indicator of MCI, which could be an early stage of AD.

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