SEXUAL DIMORPHISM IN PLASMA BETA-SECRETASE 1 CONCENTRATIONS IN COGNITIVELY NORMAL INDIVIDUALS AT RISK FOR AD: CROSS-SECTIONAL AND LONGITUDINAL STUDIES

Abstract

The development of effective disease-modifying treatments for early Alzheimer's disease (AD) and targeting β-site amyloid precursor protein cleaving enzyme 1 (BACE1)-targeted requires biomarker-drug co-development strategies, including the validation and qualification of accessible and non-invasive biological markers for different contexts of use. Cross-sectional and longitudinal studies demonstrated that plasma and cerebrospinal fluid (CSF) concentrations of BACE1 closely correlate with each other. We conducted both cross-sectional and longitudinal explorative studies in a cohort of individuals with subjective memory complaint (SMC), a condition at risk for AD, to investigate whether key biological factors such as sex, APOE ε4allele, and age affect plasma BACE1 concentrations. SMC individuals were recruited from the “INveStIGation of AlzHeimer's PredicTors in Subjective Memory Complainers” (INSIGHT-preAD) study, a university-based cohort which is part of the Alzheimer Precision Medicine Initiative (APMI) and its Cohort Program (APMI-CP). In the cross-sectional analysis, we found that baseline plasma BACE1 concentrations were highly significantly increased in females compared to males (p<0.001). Women showed a highly significantly increased plasma BACE1 concentrations compared to men, at all the three investigated time intervals (p<0.001). No difference regarding the longitudinal trajectories of plasma BACE1 concentrations was found between women and men. There was no significant effect of age and APOE ε4carrier status neither on overall BACE1 concentrations nor on BACE1 concentrations evolution. There was a highly significant decrease in plasma BACE1 concentrations in the whole sample of SMC individuals over time (p<0.001). We did not find any significant impact of two-way interactions between age and sex, age and APOE ε4 allele, sex and APOE ε4 allele on BACE1 plasma concentrations either at baseline or longitudinally. Thus, we demonstrate that the impact of a sexual-dimorphism on plasma BACE1 concentrations is irrespective of age and time. Evidence of the potential impact of a sexual dimorphism on the concentration and activity of BACE1 may be a relevant missing design component contributing to the failure of negative clinical BACE1 inhibitor therapy trial outcomes. Our results indicate that the impact of a sexual dimorphism on plasma BACE1 should be considered in further biomarker validation and qualification studies and in clinical BACE1 trials.