Pre‐pivotal clinical study of β‐amyloid in the ocular lens by Sapphire II‐aftobetin eye scan: Correlation with amyloid PET imaging in mild cognitive impairment (MCI) and mild Alzheimer’s disease (AD)

Abstract Background We identified AD‐associated Aβ pathology in ocular lenses from patients with neuropathologically‐confirmed AD but not non‐AD neurodegenerative diseases or normal aging (Goldstein et al., Lancet , 2003). We reported identical early‐onset Aβ lens pathology in Down syndrome (Moncaster et al., 2010). In Framingham Eye Study participants, we found that AD phenotypes are expressed years‐to‐decade+ earlier in lens than brain and identified a new GWAS‐significant AD risk gene (CTNND2, δ‐catenin) that modulates Aβ expression in lens and brain (Jun et al., 2012). This research spurred development of a novel drug‐device eye scanner (Sapphire II‐Aftobetin system) that combines a topically‐applied Aβ‐binding fluorescent ligand (Aftobetin) with a purpose‐designed fluorescence laser eye scanner (FLES). Sapphire II detects lens Aβ with high reliability, sensitivity, specificity, and SNR. Clinical testing showed that Sapphire II distinguishes subjects with probable AD from normal controls (Kerbage et al., Front Neurol, 2013; Am J Alz Dis Dement, 2015). This study evaluated Sapphire II compared to amyloid PET scans in subjects with MCI or early AD. Method 48 participants: 28 MCI, 16 mild AD, 4 normal controls (NC); age range: 60‐85 years. MCI and AD subjects underwent cognitive testing and amyloid PET scans (Florbetapir, Amyvid). The Sapphire II system detects a highly‐specific fluorescent lifetime decay spectroscopic signature associated with bound Aftobetin‐Aβ complexes in the lens. Each scan requires <1 sec. Multiple scans can be acquired in a single sitting. Result 43 subjects have been evaluated to date. No serious adverse events have been reported. Subject correlation with amyloid PET yielded 75% specificity, 100% sensitivity, 95% accuracy, 94% PPV, and 100% NPV. To date, there has been no subject in which Sapphire II was negative and amyloid‐PET was positive. Of the 39 Sapphire II‐positive subjects, 26 were amyloid‐PET positive. Evaluation of individual PET scans and cognitive testing suggest that lens amyloid burden assessed by Sapphire II eye scan is more sensitive than amyloid PET compared to clinical criteria. Conclusion The Sapphire II‐Aftobetin drug‐device combination platform provides a safe, sensitive, and convenient screening tool for rapid non‐invasive evaluation of AD‐associated β‐amyloid (Aβ) burden in subjects with MCI and mild AD.