P4-354: Baseline CSF BETA-AMYLOID 42 correlates with ApoE genotype and baseline cognitive status in a phase II avagacestat predementia Alzheimer's disease study

CN156018 is an ongoing randomized, double blinded, placebo-controlled Phase II study designed to examine safety and tolerability of avagacestat in patients with predementia AD (PDAD) over a 2 year treatment period. Patients with PDAD were characterized as having objective cognitive impairment as well as low CSF Aβ42 and high tau concentrations. CSF biomarkers were utilized as an enrichment strategy to identify a subset of mild cognitively impaired patients more likely to progress to dementia of the Alzheimer's type and more likely to have increased brain amyloid burden. A multiplex immunoassay (Alzbio3) approved for research-use-only and manufactured by Innogenetics-Fujirebio was utilized to determine CSF Aβ42 and Tau eligibility concentrations for the study. Preliminary analyses with Alzbio3 data showed good correlation with baseline cognitive status and brain amyloid burden. The current study examined the performance of novel improved versions of the Mesoscale Discovery (MSD) assays for CSF Aβ42 and Tau using baseline samples from CN156018 by assessing correlations with Alzbio 3 data, ApoE and baseline cognitive status. Baseline CSF samples from randomized (153) and non-randomized (37) patients were analyzed for CSF Aβ42 and Tau levels using the MSD assays. Correlation analyses were done to compare MSD results to Alzbio3 and to determine whether MSD CSF biomarker concentrations also correlated with ApoE and baseline cognitive status. Levels of CSF Aβ42 correlated more highly between the Alzbio3 and MSD assays than did Tau levels. Preliminary analyses suggest that levels of CSF Aβ42 using both assays were lower in subjects with an ApoE4 allele that is consistent with literature reports. MSD CSF Aβ42 and Tau/Aβ42 ratio data showed statistically significant correlations with baseline ADAS-cog and Free and Cued Selective Reminding Test (FCSRT) scores. CSF Aβ42 and Tau/Aβ42 levels as measured by improved MSD assays showed good correlation with Alzbio3 data. In addition, CSF Aβ42 levels measured by both the Alzbio3 and MSD assays were lower in patients with one or more ApoE4 alleles consistent with literature reports. MSD CSF Aβ42 and Tau/Aβ42 levels correlated with baseline cognitive status in the predementia AD population.