BACE inhibition causes rapid, regional, and non-progressive volume reduction in Alzheimer’s disease brain

Abstract

In the phase 3 EPOCH trial (Clinicaltrials.gov; NCT01739348), treatment with the BACE inhibitor verubecestat failed to improve cognition in patients with mild-to-moderate Alzheimer’s disease, but was associated with reduced hippocampal volume after 78 weeks as assessed by MRI. The aims of the present exploratory analyses were to: (i) characterize the effect of verubecestat on brain volume by evaluating the time course of volumetric MRI changes for a variety of brain regions; and (ii) understand the mechanism through which verubecestat might cause hippocampal (and other brain region) volume loss by assessing its relationship to measures of amyloid, neurodegeneration, and cognition. Participants were aged 55–85 years with probable Alzheimer’s disease dementia and a Mini Mental State Examination score ≥15 and ≤26. MRIs were obtained at baseline and at Weeks 13, 26, 52 and 78 of treatment. MRIs were segmented using Freesurfer and analysed using a tensor-based morphometry method. PET amyloid data were obtained with 18F-flutemetamol (Vizamyl®) at baseline and Week 78. Standardized uptake value ratios were generated with subcortical white matter as a reference region. Neurofilament light chain in the CSF was assessed as a biomarker of neurodegeneration. Compared with placebo, verubecestat showed increased MRI brain volume loss at Week 13 with no evidence of additional loss through Week 78. The verubecestat-related volumetric MRI loss occurred predominantly in amyloid-rich brain regions. Correlations between amyloid burden at baseline and verubecestat-related volumetric MRI reductions were not significant (r = 0.05 to 0.26, P-values > 0.27). There were no significant differences between verubecestat and placebo in changes from baseline in CSF levels of neurofilament light chain at Week 78 (increases of 7.2 and 14.6 pg/ml for verubecestat versus 19.7 pg/ml for placebo, P-values ≥ 0.1). There was a moderate correlation between volumetric MRI changes and cognitive decline in all groups including placebo at Week 78 (e.g. r = −0.45 to −0.55, P < 0.001 for whole brain), but the correlations were smaller at Week 13 and significant only for the verubecestat groups (e.g. r = −0.15 and −0.11, P < 0.04 for whole brain). Our results suggest that the verubecestat-associated MRI brain volume loss is not due to generalized, progressive neurodegeneration, but may be mediated by specific effects on BACE-related amyloid processes.

A multisite analysis of the concordance between visual image interpretation and quantitative analysis of [18F]flutemetamol amyloid PET images

“…Declarations Data described in this report was compiled post hoc (by MB) from the clinical cohorts described in references [17][18][19][20][21][22][23][26][27][28]. Each of the studies reported was conducted with the principles of the Declaration of Helsinki, the Good Clinical Practise: Consolidated Guideline approved by the International Conference on Harmonisation and applicable national and local laws and regulations.…”

“…Each of the studies reported was conducted with the principles of the Declaration of Helsinki, the Good Clinical Practise: Consolidated Guideline approved by the International Conference on Harmonisation and applicable national and local laws and regulations. The Ethical boards for the specific studies are listed: GE: statement of ethics compliance (and committees) in Wolk et al 2018 [48]; KAROLINSKA: Ethical approval was obtained from the Regional Human Ethical Committee of Stockholm (2016-120-32); MCK: statement of ethics compliance in Sur et al 2020 [19] Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material.…”

The Use, Standardization, and Interpretation of Brain Imaging Data in Clinical Trials of Neurodegenerative Disorders

“…For example, a change in the local tissue microenvironment associated with amyloid plaques or tau tangles-associated elicited by an Alzheimer's disease therapeutic candidate targeting one of those pathologies could result in effects on brain atrophy that reflect the underlying distribution of that pathology. Preferentially increased brain volume loss in regions with high amyloid load was recently reported for a phase 3 trial of the BACE inhibitor verubecestat in mild-to-moderate Alzheimer's disease [187]. The increasing availability of PET tracers for other pathological targets (tau for Alzheimer's disease, with more under development for other pathologies) will enable such effects, if present, to be revealed across different therapeutic approaches and neurological disorders.…”

“…Fig 6. Schematic illustrating the interpretive value of intermediate scans, similar to data observed in[187]. (a) A transient increased volume loss relative to placebo immediately after treatment initiation, with no long-term change in the rate of atrophy, can be detected and…”

“…First, results from trials in multiple sclerosis with compounds having an anti-inflammatory action suggest that accelerated brain tissue loss is strongest in the first year after treatment initiation but becomes less apparent at later time points [181,182]. Second, frequent vMRI scans during trials with the BACE inhibitor verubecestat in Alzheimer's disease revealed a transient decrease in hippocampal volume loss relative to placebo immediately following treatment initiation (0-3 months) but subsequently no difference from placebo over the remaining trial period (3-18 months) [187].…”