Relationships of visual impairment and eye conditions with imaging markers, cognition, and diagnoses of dementia: a bi-directional Mendelian randomization study

Objective. To evaluate the causal relationships between visual acuity, eye conditions (focusing on cataracts and myopia), and Alzheimer disease (AD) and related dementias. Design. Cohort and two sample bi-directional mendelian randomization (MR) study. Setting. UK Biobank participants and summary statistics from previously published genome-wide association studies on cataract, myopia, and AD. Participants. UK Biobank participants (n=304,953) aged 55-70 without dementia at baseline, underwent genotyping, reported on eye conditions, and a subset completed visual acuity exams (n=113,756) or brain imaging (n=36,855) Main outcome measures. All-cause dementia, AD, and vascular dementia (VaD) identified from electronic medical records. Results. The sample averaged 62.1 years (SD=4.1) of age at baseline, 4.7% had cataracts, and 3.9% had worse than 20/40 vision. History of cataracts (HR=1.18, 95% CI: 1.07 to 1.29) and 20/40 vision (HR=1.35, 95% CI: 1.06 to 1.70) were associated with higher hazard of all-cause dementia. In MR analyses to estimate causal effects, cataracts increased risk of VaD inverse-variance weighted (OR=1.92, 95% CI: 1.26-2.92) borderline increased all-cause dementia (OR =1.21, 95% CI: 0.98 to 1.50) but not AD (OR=1.01, 95% CI: 0.97-1.06). There was no significant association between observed or genetic risk for myopia and dementia. In MR for reverse causality using genetic risk for AD, AD was not significantly associated with cataracts (inverse-variance weighted OR=0.99, 95% CI: 0.96 to 1.01). Genetic risk for cataracts were associated with smaller total brain (β= -597.4 mm3, 95% CI: -1077.9 to -117.0) and grey matter volumes (β= -375.2 mm3, 95% CI: -680.1 to -70.2), but not other brain regions or cognition. Conclusions. Our findings suggest cataracts increase risk of dementia and may reduce brain volume. This lends further support to the hypothesis that cataract extraction may reduce risk for dementia. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by National Institutes of Health/National Institute on Aging grants T32AG049663-06A1 (ELF, MT) and K01AG062722 (WDB). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. SJA is supported by K99/R00 AG070109l. KY is supported by R35 AG071916. MMG is supported by R01AG057869. HC is supported by the National Eye Institute (NEI) grant R01 EY033010. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics approval for data collection was obtained from the National Health Service National Research Ethics Service, and all participants provided written informed consent. This research was conducted under UK Biobank project #78748. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Researchers can apply to access the data used in this study from UK Biobank (http://www.ukbiobank.ac.uk/).