Research Project
10300246
Project Summary/Abstract Alzheimer?s disease (AD) is a gradually progressive neurodegenerative disorder, ultimately resulting in total cognitive and functional loss. To date, disease-modifying therapeutics and secondary prevention efforts to combat this significant public health burden have proven ineffective. The proposed project will address the critical need for the development of non-invasive, cost-efficient, scalable, and accessible AD risk screening biomarkers, that are capable of detecting AD in the earliest pathologic stages (preclinical AD), before clinical symptoms are evident. We will target biomarkers in the human retina, an extension of the central nervous system (CNS) that can be visualized non-invasively using standard ophthalmologic techniques. Autosomal dominant Alzheimer?s disease (ADAD) is a particularly useful population for retinal risk biomarker development in AD, as it allows for the study of asymptomatic individuals decades prior to the emergence of clinical symptoms. The objective of this study is to examine retinal neuronal layer morphology and beta-amyloid (Aß) differences between ADAD mutation carriers and non-carriers and to determine the utility of retinal biomarkers in the prediction of cerebral Aß burden in the earliest pathophysiologic stages of ADAD. Our central hypothesis is that ADAD mutation carriers and non-carriers will demonstrate differences in both the morphology of retinal neuronal layers and the presence of Aß, and that retinal Aß will predict cerebral Aß as measured by Aß positron emission tomography (PET) and/or cerebrospinal fluid (CSF) assay. Guided by strong preliminary data, this study will pursue two specific aims: 1) identify retinal biomarker differences between ADAD mutation carriers and non-carriers; and 2) determine whether retinal biomarker alterations predict cerebral biomarker status in ADAD. To accomplish these aims, we will leverage the infrastructure of a rigorously-designed global cohort, Dominantly Inherited Alzheimer?s Network ? Observational (DIAN-Obs), consistent of participants with ADAD mutations and a built-in control group of mutation non-carriers. DIAN-Obs follows adult children of individuals in a pedigree with a known ADAD mutation from age 18, with regular, bi-annual study visits that include AD biomarker testing (Ab PET, CSF), allowing the comparison of retinal biomarker alterations against validated AD risk biomarkers. Work will be carried out at three participating DIAN-Obs clinical performance sites. The proposed work is the first to characterize retinal biomarker changes in ADAD. Significantly, it will provide foundational data for the development of a longitudinal retinal biomarker study in DIAN-Obs, to study within subjects? alterations in retinal pathology and determine which retinal biomarkers are sensitive and specific at each stage of the AD pathophysiologic cascade. Findings have important translational applications, as screening for AD risk by point- of-care clinicians at routine eye exams has the potential to transform AD risk assessment and identify those ideal for secondary prevention therapeutics.
