Abeta oligomers as a pharmacodynamic biomarker of secretase therapy in Alzheimer's disease?

Alzheimer's disease (AD) is the most common neurodegenerative dementia, with the Aβ peptides continuing as a top target for therapeutic intervention, either by reducing Aβ accumulation (secretase inhibition) or facilitating Aβ clearance/neutralization (immunotherapy). Oligomers have emerged as the most toxic Aβ species. Using our Aβ oligomer-specific CSF assay (J. Neurosci. 2014, 34(8):2884-97), we recently demonstrated a potential diagnostic ability of Aβ oligomers in early AD (MCI), with a robust 3-5-fold increase in oligomers in AD (N=63) vs. healthy controls (N=54). Herein, we further decipher the role of Aβ oligomers in AD, and suggest their novel use as a marker in evaluating drug/oligomer pharmacodynamics in preclinical and clinical models of APP processing. To expand our study of Aβ oligomers as a pharmacodynamic biomarker in response to secretase inhibition, we treated cisterna magna-ported Rhesus monkeys (N=6, 7-12 years old) with a Merck BACE inhibitor (BACEi: MBI-5; 30 or 125 mpk), gamma secretase inhibitor (GSi: MK-0752; 240 mpk) or vehicle in a four-way crossover design. CSF draws were taken up to 96 hrs post-treatment. We observed Aβ oligomers in vehicle-treated Rhesus’ CSF at concentrations similar to the healthy human CSF (∼1 pg/mL). Treatment with secretase inhibitors resulted in a significant (∼5-fold) reduction in oligomers in Rhesus CSF in a time- and dose-dependent fashion, with greatest inhibition between 9 and 31 hrs post-treatment. The kinetics and magnitude of response of oligomers differed compared with Aβ monomers and sAPPα/sAPPβ, enabling a revised model of Rhesus central nervous system APP processing that includes a role for Aβ oligomers. Together, these findings demonstrate potential utility of Aβ oligomers as not only a diagnostic and prognostic tool for human AD but, importantly, as a novel marker of pharmacodynamic response to secretase inhibitor therapy. Further, the novel oligomer-specific assay is sensitive enough to quantify/monitor Aβ oligomer levels in Rhesus CSF before and after secretase inhibitor therapy, suggesting it can also be used in human clinical trials of BACE inhibitors for the treatment of AD. Future studies will explore the correlation of CSF oligomers with cognitive decline in novel cross-sectional/longitudinal AD and healthy control cohorts.