Altered tear fluid protein expression in persons with mild cognitive impairment

Virve Kärkkäinen; Toni Saari; Minna Rusanen; Hannu Uusitalo; Ville Leinonen; Bernd Thiede; Anne M Koivisto; Kai Kaarniranta; Tor P Utheim

doi:10.1177/13872877251413291

Altered tear fluid protein expression in persons with mild cognitive impairment

J Alzheimers Dis. 2026 Jan 20:13872877251413291. doi: 10.1177/13872877251413291. Online ahead of print.

Authors

Virve Kärkkäinen^{1

2

3}, Toni Saari⁴, Minna Rusanen^{5

6}, Hannu Uusitalo⁷, Ville Leinonen^{2

3}, Bernd Thiede⁸, Anne M Koivisto^{1

9}, Kai Kaarniranta¹⁰, Tor P Utheim^{11

12

13}

Affiliations

¹ NeuroCenter, Neurology, Kuopio University Hospital, Kuopio, Finland.
² NeuroCenter, Neurosurgery, Kuopio University Hospital, Kuopio, Finland.
³ Neurosurgery, Institute of Clinical Medicine, School of Medicine, University of Eastern Finland, Kuopio, Finland.
⁴ Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
⁵ Geriatric Center, Wellbeing Services Country of North Karelia, Joensuu, Finland.
⁶ Neurology, Institute of Clinical Medicine, School of Medicine, University of Eastern Finland, Kuopio, Finland.
⁷ Eye and Vision Research, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
⁸ Department of Biosciences, University of Oslo, Oslo, Norway.
⁹ Department of Geriatrics, Helsinki University Hospital and Department of Neurosciences, University of Helsinki, Helsinki, Finland.
¹⁰ Department of Ophthalmology, Institute of Clinical Medicine, School of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
¹¹ Department of Ophthalmology, Oslo University Hospital, Oslo, Norway.
¹² Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway.
¹³ Department of Ophthalmology, Sørlandet Hospital Trust, Arendal, Norway.

PMID: 41555821
DOI: 10.1177/13872877251413291

Abstract

BackgroundTear fluid (TF) is a protein-rich fluid reported to reflect pathophysiological changes in several neurodegenerative diseases, including Alzheimer's disease. TF proteins are increasingly being considered as putative biomarker candidates to help in the diagnosis of disease. However, little information is available on TF protein changes in persons with mild cognitive impairment (MCI).ObjectiveThis study aimed to determine alterations in the expression of proteins in TF collected from persons with MCI compared with cognitively healthy controls.MethodsWe analyzed data from 54 study participants, including 34 controls (mean age, 71 years; mean Mini-Mental State Examination [MMSE] score ± standard deviation, 28.9 ± 1.4) and 20 persons with MCI (mean age, 71 years; mean MMSE score, 27.1 ± 1.9). All participants underwent cognitive, neurological, and ophthalmological examinations. TF was collected using Schirmer strips and evaluated using mass spectrometry-based proteomics and label-free quantification.ResultsThe expression of 33 TF proteins involved in oxidative stress, clearance mechanism, cytoskeleton stability, and inflammation were altered in persons with MCI compared with controls (p ≤ 0.05).ConclusionsOur findings reveal that numerous cellular stress-related biomarker candidate proteins are upregulated or downregulated in the TF of persons with MCI, a condition that may increase the risk of developing AD or other memory disorder. These data encourage TF protein studies in neurodegenerative diseases and TF provides an additive source of biomarkers for early diagnostics of memory diseases.

Keywords: Alzheimer's disease; biomarkers; inflammation; mild cognitive impairment; oxidative stress; protein function; proteomics; tear fluid.