Use of novel fluorescent tracers to develop a comprehensive retinal biomarker database that maps the heterogeneity of Alzheimer's pathogenesis

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Project Summary Alzheimer’s disease (AD), the most common form of dementia, has traditionally been defined by the accumulation of amyloid beta (Aβ) in neuritic plaques and hyperphosphorylated tau in neurofibrillary tangles. However, recent evidence indicates that AD is better viewed as a continuum of disease with a broader degree of mechanistic and pathological heterogeneity. For example, ~15% of AD patients are negative for Aβ and most AD patients have “mixed pathology”, with large subsets exhibiting accumulation of additional neurodegenerative biomarkers such as α-synuclein (α-syn) and the TDP-43. Hippocampal and amygdalar deposits of TDP-43 have recently been characterized as defining a disease state that overlaps heavily with AD: Limbic-predominant, Age- related TDP-43 Encephalopathy (LATE). At present, AD diagnosis relies on clinical evaluation of symptoms and PET imaging of Aβ and Tau load. However, this is costly, involves exposure to radiation, and does not have the ability to detect broader dimensions of AD heterogeneity, such as the presence of pathological α-syn and TDP- 43 deposits that define large subsets of the AD continuum. There is an unmet medical need for an antemortem diagnostic that can reliably identify mechanistic heterogeneity in individual AD patients, ideally one that can detect multiple disease-related biomarkers simultaneously and non-invasively in CNS tissue. Amydis is leveraging the retina as a “window to the brain” to address this unmet need by developing an ocular contrast agent – i.e. a “retinal tracer – that can be used to fluorescently label α-syn, TDP-43, and Aβ in patients suspected of having AD. The retinal tracer, AMDX-2011P, currently in human clinical trials, has these remarkable capabilities and is designed to have fluorescent properties amenable for use with standard retinal imaging equipment found in the eye care office, making this technology widely accessible. In this proposal, Amydis will take the first clinical steps towards developing transformative new diagnostic technology in AD focusing on the biomarker Aβ in AD patient retinas. The specific aims of the project are: (1) to develop a lyophilized product of AMDX-2011P for i.v. delivery; (2) to complete a Phase 1B clinical trial of AMDX-2011P in patients with a clinical diagnosis of FAD (known FAD mutation and dementia) who have a positive Aβ PET scan (N=12), subjects with known FAD mutation but without clinical evidence of dementia (N=12) and healthy subjects (N=8) to determine if the tracer reliably reports on Aβ status; and, (3) to begin constructing a database of AD and normal retinal images for use in developing automated, AI-assisted retinal biomarker analytics tools for physicians and researchers. Completion of these aims will advance the development of our in vivo ocular diagnostic test, getting us one step closer to our mission of providing an antemortem, simple, and affordable diagnostic to parse the heterogeneity of AD. Future studies will integrate knowledge obtained from ongoing clinical studies of AMDX- 2011P as a marker of a-syn and TDP-43 and assess whether the tracer can report on the co-occurrence and variability of these critical biomarkers in individual patients.