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 enzyme1 [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<.001) and amyloid-β peptide level (ρ=0.39; P<.001), with amyloid-β peptide correlated with BACE1 protein level (ρ=0.30; P<.001). Conclusion: Significant elevation of BACE1 levels and activity in CSF is an indicator of MCI, which could be an early stage of AD.