Longitudinal validation of retinal biomarkers against cerebral imaging in preclinical Alzheimer's disease

Project Summary/Abstract
Alzheimer’s disease (AD) is a gradually progressive neurodegenerative disorder that results in total cognitive
and functional loss. To date, disease-modifying therapeutics and secondary prevention efforts have proven
ineffective in combating this public health burden, which impacts over 5.8 million individuals, and is the 6th
leading cause of death in the United States. The proposed study addresses the critical need for minimally
invasive, cost-efficient, scalable, and accessible AD risk screening biomarkers capable of detecting AD in the
earliest pathologic stages (preclinical AD) before clinical symptoms are evident. We target biomarkers in the
human retina, a part of the central nervous system (CNS), as they can be visualized non-invasively using
standard ophthalmologic techniques and show promise for early AD risk detection and disease monitoring. The
Atlas of Retinal Imaging in Alzheimer’s Study (ARIAS) is a longitudinal, observational cohort study to identify
sensitive and specific retinal biomarkers of preclinical AD and define their context of use. The objective of the
proposed project is to leverage the existing ARIAS infrastructure, adding reference standard brain imaging
biomarkers (3T MRI, Ab PET) and novel plasma biomarkers (ptau231, ptau181) to test the central hypothesis
that retinal biomarker alterations will predict cerebral biomarker changes and mirror longitudinal cerebral
biomarker changes in preclinical AD. Four specific aims will be pursued: (1) identify retinal biomarker differences
between preclinical AD participants and cognitively unimpaired (CU) older adults; (2) validate candidate retinal
biomarkers cross-sectionally against cerebral biomarkers using Ab PET as a measure of cerebral amyloidosis
and MRI as a measure of neurodegeneration; (3) determine the longitudinal relationship between retinal and
brain imaging biomarkers, and the ability of baseline retinal biomarkers to predict cognitive and/or brain imaging
biomarker changes over 3-year follow-up; and (4) (exploratory) assess the combined sensitivity and specificity
of candidate retinal biomarkers with emergent plasma biomarkers in AD risk prediction. Work will be carried out
at one existing ARIAS site and two high performing AD research sites. CU participants will complete 5 study
visits: screening, baseline, year (Y) 1, Y2, and Y3 follow-up. Brain imaging (MRI and Ab PET) and plasma
analysis will occur at baseline and Y3 follow-up. Retinal imaging and cognitive evaluation will occur at baseline
and Y1, Y2, and Y3 follow-up. Brain imaging, retinal imaging, cognitive evaluation, and plasma analysis will be
supported by four respective cores. Validating retinal biomarkers in preclinical AD is expected to shift focus in
AD retinal biomarker development towards systemic, quantitative characterization of retinal risk biomarkers
scalable for population-based AD risk screening. Combining plasma biomarkers with sensitive and specific
retinal biomarkers could transform AD risk assessment, allowing identification of AD-related changes decades
before clinical onset, which may offer the best chance of therapeutic success. Clinical applications include
population-based screening for ideal candidates for emerging secondary prevention therapeutics.

Grant Number: 5R01AG079241-04
NIH Institute/Center: NIH
Principal Investigator: Jessica Alber