Retinal Optical Coherence Tomography Metrics Are Unchanged in Verubecestat Alzheimer’s Disease Clinical Trial but Correlate with Baseline Regional Brain Atrophy

Abstract

Background: We performed exploratory analyses of retinal thickness data from a clinical trial of the AβPP cleaving enzyme (BACE) inhibitor verubecestat in patients with Alzheimer’s disease (AD). Objective: To evaluate: 1) possible retinal thickness changes following BACE inhibition; and 2) possible association between retinal thickness and brain atrophy. Methods: Retinal thickness was measured using spectral-domain optical coherence tomography in a 78-week randomized placebo-controlled trial of verubecestat in 1,785 patients with mild-to-moderate AD. Changes from baseline in retinal pigment epithelium, macular grid retinal nerve fiber layer, central subfield retinal thickness, and macular grid volume were evaluated for verubecestat versus placebo. Correlation analyses were performed to investigate the potential association between macular grid retinal nerve fiber layer and central subfield retinal thickness with brain volumetric magnetic resonance imaging (vMRI) data at baseline, as well as correlations for changes from baseline at Week 78 in patients receiving placebo. Results: Verubecestat did not significantly alter retinal thickness during the trial compared with placebo. At baseline, mean macular grid retinal nerve fiber layer and central subfield retinal thickness were weakly but significantly correlated (Pearson’s r values≤0.23, p-values < 0.01) with vMRI of several brain regions including whole brain, hippocampus, and thalamus. At Week 78, correlations between retinal thickness and brain vMRI changes from baseline in the placebo group were small and mostly not statistically significant. Conclusion: BACE inhibition by verubecestat was not associated with adverse effects on retinal thickness in patients with mild-to-moderate AD. Correlations between retinal thickness and brain volume were observed at baseline. Trial registration: Clinicaltrials.gov NCT01739348 (registered December 3, 2012; https://clinicaltrials.gov/ct2/show/NCT01739348).

Retinal Alterations as Potential Biomarkers of Structural Brain Changes in Alzheimer’s Disease Spectrum Patients

“…Instead, we focused on the association between retinal measures and hippocampal subfields. We found that thicker RNFL in the special sector showed significantly increased subiculum, presubiculum, GC-ML-DG and molecular_layer_HP volumes, which is consistent with previous studies [ 35 , 36 , 37 ].…”

“…One study found an inverse correlation between macular thickness and cerebral cortical atrophy, especially parietal cortical atrophy in AD patients [ 30 ]. Others revealed a significant positive correlation between RNFL thickness and hippocampal volume, with this association being more pronounced in the m-RNFL in people without dementia [ 35 , 36 , 37 ]. However, these studies were focused on the relationship between retinal structure and a relatively large area of the brain (i.e., temporal lobe, whole hippocampus) [ 35 , 36 , 37 , 63 ].…”

“…Others revealed a significant positive correlation between RNFL thickness and hippocampal volume, with this association being more pronounced in the m-RNFL in people without dementia [ 35 , 36 , 37 ]. However, these studies were focused on the relationship between retinal structure and a relatively large area of the brain (i.e., temporal lobe, whole hippocampus) [ 35 , 36 , 37 , 63 ]. Instead, we focused on the association between retinal measures and hippocampal subfields.…”

“…In an OCTA study, the authors found that reductions in retinal vessel density (VD) were significantly associated with inferolateral ventricle (ILV) enlargement in MCI and AD. However, most of these studies focused on the hippocampus in large scale measures despite its heterogeneous composition consisting of distinct subfields with varying anatomical, functional and electrophysiological properties, including the dentate gyrus, subiculum, parasubiculum and presubiculum [ 32 , 35 , 36 , 37 , 38 ]. Multiple studies had reported that atrophy in the CA1, subiculum and presubiculum represent the earliest sites for AD pathologic changes (i.e., amyloid deposits, tau aggregation) [ 39 , 40 , 41 ].…”

The correlation of retinal neurodegeneration and brain degeneration in patients with Alzheimer’s disease using optical coherence tomography angiography and MRI

“…RNFL thickness may also reflect cingulate cortex atrophy in individuals without dementia ( Shi et al, 2019a ). Other studies have reported a correlation between retinal thickness and brain structure in patients with AD, but these findings are inconsistent ( Yoon et al, 2019 ; Zhao et al, 2020 ; Sergott et al, 2021 ).…”