BACE1 Dynamics Upon Inhibition with a BACE Inhibitor and Correlation to Downstream Alzheimer's Disease Markers in Elderly Healthy Participants

Abstract

The β-site amyloid-β protein precursor (AβPP) cleaving enzyme-1 (BACE1) is the rate limiting enzyme in the generation of amyloid-β peptide (Aβ) from AβPP, one of the major pathways in Alzheimer's disease (AD) pathology. Increased BACE1 levels and activity have been reported in the brain of patients with sporadic AD. Therefore, changes of BACE1 levels in the cerebrospinal fluid (CSF) have also been investigated as a possible biomarker of the disease. We analyzed BACE1 levels in CSF of elderly healthy participants before and after chronic treatment with a BACE inhibitor (BACEi) and evaluated the correlation between BACE1 levels and downstream AD markers. Overall, BACE1 CSF levels showed strong correlations to all downstream AD markers investigated. This is the first reported finding that shows BACE1 levels in CSF were well correlated to its end product Aβ1 - 42. As previously described, BACE1 levels were strongly correlated to total-tau and phosphorylated tau levels in CSF. Generally, chronic BACE inhibition did not influence BACE1 CSF protein levels. Follow-up studies including early-stage AD pathophysiology and prodromal AD patients will help to understand the importance of measuring BACE1 routinely in daily clinical practice and AD clinical trials.

Keywords: AD markers; Alzheimer’s disease; BACE-1; JNJ-54861911; β-secretase enzyme.

Fig.1

Correlation of β-site AβPP-cleaving enzyme-1 (BACE1) protein levels in CSF with age in healthy elderly participants. A Pearson correlation coefficient was calculated to evaluate the possible correlation between BACE1 and age. Regression line R² = 0.1114; statistical significant level was set at 0.05. n = 38; rho = 0.33; p = 0.0406.

Fig.2

Correlation of β-site AβPP-cleaving enzyme-1 (BACE1) protein levels with Aβ species (Aβ_1 - 42, Aβ_1 - 40, Aβ_1 - 38, Aβ_1 - 37) at baseline in CSF of healthy elderly for all participants (A, D, G, J), for APOE ɛ4 allele carriers (B, E, H, K), and for APOE ɛ4 non-carriers (C, F, I, L) measured by MSD4-plex assay system. A Pearson correlation coefficient was calculated to evaluate the possible correlation between BACE1 and Aβ_1 - 42 (A-C); between BACE1 and Aβ_1 - 40 (D-F); between BACE1 and Aβ_1 - 38 (G-I); and between BACE1 and Aβ_1 - 37 (K-L) for all, APOE ɛ4 carrier and non-carriers, respectively. Number of participants for whom samples could be analyzed and for which levels were above LOQ are indicated below each panel. p < 0.05 was set as a statistically significant level.

Fig.3

Correlation of β-site AβPP-cleaving enzyme-1 (BACE1) protein levels with sAβPP total (A-C), sAβPPα (D-F), and sAβPPβ (G-I) at baseline in CSF of healthy elderly for all participants (A, D, G), for apolipoprotein (APOE) ɛ4 allele carriers (B, E, H), and for APOE ɛ4 non-carriers (C, F, I). A Pearson correlation coefficient was calculated to evaluate the possible correlation between BACE1 and sAβPP total (A-C); between BACE1 and sAβPPα (D-F); and between BACE1 and sAβPPβ (G-I) for all APOE ɛ4 carriers and non-carrier participants, respectively. Number of participants for whom samples could be analyzed and for which levels were above LOQ are indicated below each panel. p < 0.05 was set as a statistically significant level.

Fig.4

Correlation of β-site AβPP-cleaving enzyme-1 (BACE1) protein levels with Aβ_1 - 42 (A-C), phosphorylated tau (p-tau_181p, D-F), and total tau (t-tau, G-I) at baseline in CSF of healthy elderly for all participants (A, D, G), for apolipoprotein (APOE) ɛ4 allele carriers (B, E, H),and for APOE ɛ4 non-carriers (C, F, I) measured by the ALZBio3 (xMAP) assay. A Pearson correlation coefficient was calculated to evaluate the possible correlation between BACE1 and Aβ_1 - 42 (A-C); between BACE1 and p-tau_181p (D-F); and between BACE1 and t-tau (G-I) for all, APOE ɛ4 carriers and non-carriers, respectively. Number of participants for whom samples could be analyzed and for which levels were above LOQ are indicated below each panel. p < 0.05 was set as a statistically significant level.

Fig.5

Percent change in BACE1 levels from Day 1 baseline to Day 14 for those with > 20% change of BACE1 protein levels from baseline following repeated once daily dosing with JNJ-54861911 at 5, 25, 30, 50, and 90 mg or placebo for 14 days. Data are represented as individual and mean percent change (n = 8/38) in BACE1 from Day 1 baseline to Day 14 (24-h post dose).