The TearAD Study: Tear Biomarkers for Alzheimer's Disease (AD) Screening and Diagnosis

• Tear Fluid collection (Schirmer's strip) (Diagnostic test): Tear fluid will be collected non-invasively form all participants with the use of Schirmer's strips, which is a small paper strip placed in the lower eye lid for a maximum of 5 minutes.
• Retinal imaging (Diagnostic test): The retina from all participants will be visualised with the use of a standard (Clarus 700 Zeiss), ultra-wide field (Optos), and cross-sectional (Optical Coherence Tomography) retinal images.

Primary outcomes

• Capability of tear biomarkers to discriminate individuals with neurodegeneration from those without neurodegeneration and assess the change in biomarker levels over time. [Sampling done at t= 0, 1 and 2 years.]: Levels of tear biomarkers will be determined from the Schirmer's strips. The biomarker levels will be analysed to see whether they can be discriminate between people with and without neurodegeneration.

Secondary outcomes

• The difference in tear biomarker level between patients and controls, and between patient groups and how these differences change over time. [Sampling done at t= 0, 1 and 2 years.]: Additional analysis to see whether tear biomarkers can also discriminate patients from controls and differences inbetween patient groups.
• Correlation of biomarker levels in tears, blood and cerebral spinal fluid (CSF). [Baseline measurements (t=0) will be used to determine correlation.]: This analysis will be done to determine the correlation between biomarkers of different body fluids.
• Correlation between tear biomarkers and other ocular imaging biomarkers, as well as assessing the change of this correlation over time. [Imaging done at t= 0, 1 and 2 years.]: The correlation between tear biomarkers and ocular imaging biomarkers (e.g. thickness of the retinal nerve fiber layer, retinal vasculature tortuosity) will be analysed.

Sex: All, ages: 50 Years to any, accepts healthy volunteers

Inclusion Criteria (healthy controls):

* Available CSF, PET, CT or MRI data to evaluate the presence/absence of neurodegeneration (preferably within 1 year of inclusion in this study)
* Absence of cognitive complaints or treatment and did not seek help for cognitive complaints in the past
* MMSE score 26-30 at baseline
* Age > 50 years
* Available for follow-up (up to 24 months)
* Written informed consent obtained and documented

Inclusion criteria (patients):

* Available CSF, PET, CT or MRI data to evaluate the presence/absence of neurodegeneration (preferably within 1 year of inclusion in this study)
* Available for follow-up (up to 24 months)
* Written informed consent obtained and documented
* Capable of giving informed consent themselves (MMSE score > 17/30)

Exclusion Criteria (all subjects):

* Ocular conditions that could influence tear biochemical parameters (including eye infection, eye inflammation, eye surgery within the last 28 days or other acute eye conditions)
* Neurological or systemic chronic conditions known to interfere with retinal thickness (e.g., glaucoma, diabetes mellitus)
* Ocular conditions interfering with optical coherence tomography (OCT) quality/retinal thickness: e.g. severe cataract, age-related macular degeneration, and glaucoma

• Results publication: van de Sande N, Ramakers IHGB, Visser PJ, Verhey FRJ, Verbraak FD, Bouwman FH, Berendschot TTJM, Nuijts RMMA, Webers CAB, Gijs M. Tear biomarkers for Alzheimer's disease screening and diagnosis (the TearAD study): design and rationale of an observational longitudinal multicenter study. BMC Neurol. 2023 Aug 5;23(1):293. doi: 10.1186/s12883-023-03335-y. PMID 37543602

• Marlies Gijs, PhD, Principal investigator, Maastricht University Medical Center