Association of tear fluid glutathione synthetase and glutathione levels with amyloid positivity

Tear fluid is a promising source of biomarkers for Alzheimer's disease (AD). This study characterized the tear fluid proteome across AD and dementia stages. Tear fluid was collected from 60 participants, cognitively normal (CN) individuals (n = 32), patients with mild cognitive impairment (n = 14), and dementia (n = 14). Of these, 27 were amyloid PET-negative and 33 PET-positive. The proteome was analyzed using label-free mass spectrometry, followed by targeted validation immunoassays of key findings. In total, 703 proteins were reliably identified. A notable upregulated protein in dementia compared with CN was glutathione synthetase (GSS) (1.7-fold, p = 0.02). Validation revealed elevated GSS (2-fold) and its enzymatic product glutathione (1.7-fold) in tear fluid of amyloid PET-positive participants. Incorporating GSS and glutathione as pre-screeners could reduce the need for PET scans by up to 75%. Tear fluid shows promise as a non-invasive source for AD biomarkers, offering novel disease insights, and potential utility for pre-screening prior to PET imaging.