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 anticipat...