Cross‐sectional investigation of synaptic markers Neurogranin and BACE1 in CSF from the AIBL study

Abstract

AbstractBackgroundSynaptic disfunction is a feature of Alzheimer’s disease. Recent studies show both pre‐ and post‐synaptic termini proteins change in concentration in the CSF across the A/T/N framework. Here we investigate BACE1, neurogranin (Ng) and alpha‐synuclein, along with total‐tau (t‐tau) and amyloid‐β 1‐42 (Aβ42), in relation to PET‐amyloid status.MethodParticipants (n = 105) with CSF and matching PET‐amyloid scans from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study were analysed for CSF synaptic markers BACE1, Ng and alpha‐synuclein using commercially available antibody assays (EUROIMMUN). BACE1 used ADx401 (5G7) and ADx402 (10B8) antibodies, Neurogranin trunc p75 used monoclonal ADx403 (ADxNGCI2) and ADx451 (ADxNGCT1) antibodies, and alpha‐synuclein used ADx301 and ADx302 antibodies. Total‐tau and Aβ42 were measured using the Roche Elecsys®. PET‐amyloid status was defined using a Centiloid of <25 as negative, and 25 or greater positive.ResultCross‐sectional changes in biomarker values between the PET‐amyloid negative and positive groups were seen for Ng (p<0.05), but not for BACE1 or alpha‐syn. The ratio of Ng/BACE1 improved separation between groups (p<0.001). Total‐tau displayed the greatest differentiation of a single biomarker (p = 2.7×10−10) and this separation was improved using a ratio of t‐tau/BACE1 (p = 3.2×10−12). For predicting PET‐amyloid status (adjusting for age, APOE e4 and gender), t‐tau (AUC: 0.87 [95%CI: 0.80‐0.95]) was slightly improved using the ratio of t‐tau/BACE1 (AUC: 0.90 [95%CI: 0.82‐0.97]) to the same degree as using t‐tau/Aβ42 (AUC: 0.90 [95%CI: 0.82‐0.97]), although this was not significant (p>0.05).ConclusionThis study saw within a PET‐amyloid positive subpopulation of AIBL an increase in neurogranin, a post‐synaptic marker. The presynaptic marker BACE1 alone was not changed in concentration, but when BACE1 was used in a ratio with t‐tau, a marker of neuronal degradation, the differentiation between amyloid negative and positive groups increased. The predictive ability between t‐tau/BACE1 and t‐tau/Aβ42 to estimate PET‐amyloid load is comparable and measurements incorporating BACE1 may provide an alternative to Aβ42‐based assays and the inherent variability associated with Aβ42 measurement between testing sites.