INHIBITION OF AMYLOID OLIGOMER FORMATION BY ENDOGENOUS METABOLITE OF ALZ-801/TRAMIPROSATE IN THE HUMAN BRAIN: DISCOVERY AND CHARACTERIZATION OF 3-SPA IN NORMAL SUBJECTS AND ALZHEIMER’S DISEASE PATIENTS

Abstract

Background: In a recent Phase-3 trial (APECS) verubecestat was associated with poorer clinical outcomes compared with placebo in prodromal AD subjects. The subjects were screened using amyloid PET imaging and a subgroup of patients participated in a tau PET substudy. Here we report on the characteristics of neurofibrillary tangle (NFT) distribution in these prodromal AD subjects. Methods: Participants 50-85 years of age with prodromal AD/amnestic mild cognitive impairment due to AD were randomized in a double-blind, 24-month, placebo-controlled trial of verubecestat (12mg and 40mg). Subjects had a MMSE score between 24-30 and a positive Ab imaging PET scan at screening. After 1 year in the trial, thirteen participants (3 females and 10 males) participated in a tau PET imaging substudy. Participants underwent 30 min (80 – 110min post-tracer injection) brain PET scans with [F]MK-6240. PET scans were obtained at multiple sites, but centrally collected and quality controlled by Bioclinica. The image processing including motion correction, spatial coregistration to 3D T1 MRI, normalization and smoothing were performed consistently across subjects. Cortical and subcortical SUVRs were calculated with cerebellar gray matter as reference. Results: At the time of scanning 4 subjects were on placebo, 3 and 6 subjects had received 12 mg or 40 mg verubecestat for 12 months, respectively. Subjects age ranged between 55-87 year old and MMSE score between 23-29. There was no significant difference in cortical gray matter, parahippocampal and ambient gyri SUVRs between treatment groups. A positive [F]MK-6240 signal was observed in hippocampal and limbic regions of all patients with SUVR ranging from 1 to > 3. Different patterns of NFT cortical distribution were observed, with 6 subjects showing levels consistent with Braak V-VI in typical brain regions known for NFT accumulation while the other subjects showed less NFT. In this limited sample size, both higher global and regional SUVRs tended to correlate with worse cognitive scores. Conclusions: In the APECS trial, prodromal amyloid positive subjects exhibited positive [F]MK-6240 PET scan indicating the presence of NFT pathology. The diversity of brain NFT distribution pattern suggests that these prodromal subjects were at different stages on the AD pathological continuum.