Can we identify people with Alzheimer’s disease from examination of the eye? A bidirectional Mendelian randomization (MR) study - 02/07/26

Doi : 10.1016/j.tjpad.2026.100635

Humayun Kiser ^1,², Ashley Budu-Aggrey ^3,⁴, Jessica N. Cooke Bailey ^5,^12,¹³, Ana Villaplana-Velasco ⁶, Miguel O. Bernabeu ^7,⁸, Xiaofan Jiang ^9,¹⁰, Christopher G. Owen ¹¹, Jonathan L. Haines ^12,¹³, Louis R. Pasquale ¹⁴, Stuart MacGregor ¹⁵, Xiaoyi Raymond Gao ¹⁶, Janey L. Wiggs ¹⁷, Chen Jiang ¹⁸, Hélène Choquet ^18,¹⁹, George Davey Smith ^b,^c, Patrick G. Kehoe ^a, Neil M. Davies ^20,^21,²², Aimee L. Hanson ^b,^c, Emma L. Anderson ^b,²², Denize Atan ^23,^24,^⁎

NEIGHBORHOOD consortium, International Glaucoma Genetics Consortium, UK Biobank Eye and Vision Consortium ^a

¹ Bristol Medical School, Translational Health Sciences, University of Bristol, Bristol, UK

² Department of Statistics, Comilla University, Bangladesh

³ Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, UK

⁴ Bristol Medical School, Population Health Sciences, University of Bristol, Bristol, UK

⁵ Center for Health Disparities, Department of Pharmacology & Toxicology, Brody School of Medicine, East Carolina University, USA

⁶ Baillie Gifford Pandemic Science Hub, Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK

⁷ Centre for Medical Informatics, Usher Institute, The University of Edinburgh, Edinburgh, Scotland, UK

⁸ The Bayes Centre, The University of Edinburgh, Edinburgh, Scotland, UK

⁹ UCL Institute of Ophthalmology, London. UK

¹⁰ UCL Great Ormond Street Institute of Child Health, University College London, UK

¹¹ Population Health Research Institute, City St. George’s, University of London, London, UK

¹² Department of Population and Quantitative Health Sciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA

¹³ Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, Ohio, USA

¹⁴ Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, NY USA

¹⁵ QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia

¹⁶ Departments of Ophthalmology and Visual Science and Biomedical Informatics, Division of Human Genetics, The Ohio State University, Columbus, OH 43212, USA

¹⁷ Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA

¹⁸ Division of Research, Kaiser Permanente Northern California, Pleasanton, CA, USA

¹⁹ Department of Health Systems Science Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, CA, USA

²⁰ Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Norway

²¹ Department of Statistical Science, University College London, UK

²² Division of Psychiatry, University College London, UK

²³ School of Neuroscience and Psychology, University of Bristol, UK

²⁴ Bristol Eye Hospital, University Hospitals Bristol & Weston NHS Foundation Trust, UK

^a Bristol Medical School, Translational Health Sciences, University of Bristol, Bristol, UK.

^b Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, UK.

^c Bristol Medical School, Population Health Sciences, University of Bristol, Bristol, UK.

^⁎ Corresponding author: Dr Denize Atan, Bristol Eye Hospital, Lower Maudlin Street, Bristol, BS1 2LX, +44 1174552762 Bristol Eye Hospital Lower Maudlin Street Bristol BS1 2LX

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Highlights

•	Genetic risk of Alzheimer’s disease (AD) causes increased retinal arteriolar tortuosity.
•	AD may also cause inner retinal degeneration, but the evidence is weak.
•	Odds of AD reduced by 24% for each standard deviation increase in optic disc area.
•	The relationship between AD and optic disc area was mediated by refractive error.

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STRUCTURED ABSTRACT

Background

Neurodegeneration in Alzheimer’s disease (AD) is thought to be driven by amyloid-beta and tau deposition in the cerebral vasculature and brain. As the eye is an extension of the central nervous system, this study aimed to determine which neurovascular and neuroretinal changes in the eye are caused by AD rather than associations of the disease.

Methods

Bidirectional two-sample univariable and multivariable Mendelian randomization (MR) methods were applied. Instrumental variables were derived from genome-wide association studies (GWAS) of AD and the following ocular features: thickness measurements of central macula (MT), retinal nerve fibre layer (mRNFL), ganglion cell-inner plexiform layer (mGCIPL), outer nuclear layer (ONL), inner segment layer (IS), and outer segment (OS) from macular region OCT scans; arteriolar tortuosity (AT), venular tortuosity (VT), venular width (VW), fractal dimension (FD), vertical cup-to-disc ratio (VCDR), optic cup area (OCA), and optic disc area (ODA) derived from other imaging methods.

Results

There was strong evidence that genetic liability to AD affected the retinal vasculature by specifically increasing AT (β=0.007;95%CI=0.002,0.011;p-value=0.005) in UK Biobank participants (n=52,798). AD may influence the mRNFL (β=-0.047,95%CI=-0.119,0.023,p-value=0.18) and mGCIPL (β=-0.061;95%CI=-0.14,0.025,p-value=0.16) of the inner retina and OS layer (β=0.044;95%CI=-0.0001,0.08;p-value=0.05) but the evidence was weak. Multivariable MR analysis showed that a causal relationship between optic disc area and AD (OR=0.76;95%CI=0.62,0.93,p-value=0.009) was probably mediated by refractive error.

Conclusion

Early cerebrovascular signs of AD may be detected by examination of the eye. Further investigation is required to determine the clinical utility of eye screening for dementia.

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