Recent research advances have led to detailed understanding of the pathogenesis of Alzheimer’s disease (AD)
and development of new and emerging disease-modifying therapies. Yet effective treatment remains elusive.
Consensus in the field has focused attention on early-stage disease (preclinical AD) that begins with clinically
silent accumulation of β-amyloid (Aβ) in the brain long before onset of cognitive symptoms. Early detection of
preclinical AD is now recognized as a critical prerequisite for effective and enduring AD treatment. Aβ is an
accepted “gold standard” AD biomarker. Currently available methods to assess Aβ burden rely on positron
emission tomography (PET) brain scans or cerebrospinal fluid (CSF) analysis. These methods are expensive,
invasive, cumbersome, not widely available, and difficult to scale. The NIA has prioritized development of new,
safe, sensitive, cost-efficient, noninvasive technology for point-of-care early AD detection. This project addresses
this unmet need by accelerating testing of an innovative FDA Breakthrough Device-designated combination
drug-device eye scanner (Aftobetin-Sapphire II) that detects AD-related Aβ in the lens. This novel approach is
based on our discovery of AD-specific Aβ lens pathology in patients with pathologically-confirmed AD, but not
other non-AD neurodegenerative diseases or normal aging. Moreover, we found that AD-related pathologies and
phenotypes are expressed much earlier in lens than brain. These findings spurred development of the Sapphire
II system lens Aβ scanner that combines a topically-applied fluorescent Aβ-binding tracer ligand (Aftobetin) and
a purpose-designed eye scanner with integrated fluorescent lifetime decay spectroscopy analyzer that reliably
measures Aβ in the lens with high specificity, sensitivity, and signal-to-noise ratio. Our preliminary data shows
that lens Aβ differentiates mild cognitive impairment (MCI) and clinical AD from normal controls with comparable
or greater sensitivity and specificity than amyloid-PET brain scans. This project leverages the longitudinal Clinical
Core cohort, NIA-funded Boston University Alzheimer’s Disease Research Center (BUADRC; P30AG-072978)
BUADRC Clinical Core cohort participants undergo annual NACC-compliant comprehensive examinations. This
project proposes to add lens Aβ measurements using the Sapphire II-Aftobetin system for early AD detection
and longitudinal monitoring. In Aim 1, we will evaluate cross-sectional associations between lens Aβ burden, AD
clinical outcomes, and established ATN biomarkers (Aβ, tau, neurodegeneration; ATN framework). In Aim 2, we
will evaluate longitudinal associations between lens Aβ burden, AD clinical outcomes, and the same ATN
biomarkers (as in Aim 1). In Aim 3, we will conduct comparative clinicopathological correlation analysis of ex vivo
Aβ burden and amyloid ultrastructural pathology in postmortem brain and lens from BUADRC participants,
including those scanned during life. We anticipate that project results will identify lens Aβ diagnostic cut-points
and accelerate introduction of the Sapphire II-Aftobetin system to evaluate AD risk, detect preclinical AD, and
assess early AD and progression in individual patients.
