Rationale and design of the BeyeOMARKER study: prospective evaluation of blood- and eye-based biomarkers for early detection of Alzheimer's disease pathology in the eye clinic.

Background: Alzheimer's disease (AD) is a common, complex and multifactorial disease that may require screening across multiple routes of referral to enable early detection and subsequent future implementation of tailored interventions. Blood- and eye-based biomarkers show promise as low-cost, scalable and patient-friendly tools for early AD detection given their ability to provide information on AD pathophysiological changes and manifestations in the retina, respectively. Eye clinics provide an intriguing real-world proof-of-concept setting to evaluate the performance of these potential AD screening tools given the intricate connections between the eye and brain, presumed enrichment for AD pathology in the aging population with eye disorders, and the potential for an accelerated diagnostic pathway for under-recognized patient groups.

Methods: The BeyeOMARKER study is a prospective, observational, longitudinal cohort study aiming to include individuals visiting an eye-clinic. Inclusion criteria entail being ≥ 50 years old and having no prior dementia diagnosis. Excluded eye-conditions include traumatic insults, superficial inflammation, and conditions in surrounding structures of the eye that are not engaged in vision. The BeyeOMARKER cohort (n = 700) will undergo blood collection to assess plasma p-tau217 levels and a brief cognitive screening at the eye clinic. All participants will subsequently be invited for annual longitudinal follow-up including remotely administered cognitive screening and questionnaires. The BeyeOMARKER + cohort (n = 150), consisting of 100 plasma p-tau217 positive participants and 50 matched negative controls selected from the BeyeOMARKER cohort, will additionally undergo Aβ-PET and tau-PET, MRI, retinal imaging including hyperspectral imaging (primary), widefield imaging, optical coherence tomography (OCT) and OCT-Angiography (secondary), and cognitive and cortical vision assessments.

Results: We aim to implement the current protocol between April 2024 until March 2027. Primary outcomes include the performance of plasma p-tau217 and hyperspectral retinal imaging to detect AD pathology (using Aβ- and tau-PET visual read as reference standard) and to detect cognitive decline. Initial follow-up is ~ 2 years but may be extended with additional funding.

Conclusions: We envision that the BeyeOMARKER study will demonstrate the feasibility of early AD detection based on blood- and eye-based biomarkers in alternative screening settings, and will improve our understanding of the eye-brain connection.

Trial registration: The BeyeOMARKER study (Eudamed CIV ID: CIV-NL-23-09-044086; registration date: 19th of March 2024) is approved by the ethical review board of the Amsterdam UMC.