JAMA Netw Open. 2024 Jul 30;7(7):e2424539. doi: 10.1001/jamanetworkopen.2024.24539

Visual Impairment, Eye Conditions, and Diagnoses of Neurodegeneration and Dementia

Erin L Ferguson 1,✉, Mary Thoma 1, Peter T Buto 1,2, Jingxuan Wang 1, M Maria Glymour 2, Thomas J Hoffmann 1, Hélène Choquet 3, Shea J Andrews 4, Kristine Yaffe 1,4,5, Kaitlin Casaletto 5, Willa D Brenowitz 1,6

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PMCID: PMC11289698  PMID: 39078629

See commentary "Visual Deficit Related to Cataracts-A Potential Modifiable Risk Factor for Vascular Dementia." on page e2424518.

Key Points

Question

Are eye conditions and visual acuity risk factors for Alzheimer disease (AD) and related dementias?

Findings

In this cohort study of 304 953 UK Biobank participants, cataracts were associated with lower total gray matter volume, white matter hyperintensities, and increased risk of dementia, especially vascular dementia. Mendelian randomization analyses estimated that cataracts were associated with a 92% increase in the odds of vascular dementia risk; although poor visual acuity was associated with an increased risk of dementia, myopia was not associated with dementia in genetic analyses.

Meaning

These results suggest that cataracts increase the risk of dementia through vascular and non-AD mechanisms; treating or preventing cataracts may reduce dementia risk.

Abstract

Importance

Vision and eye conditions are associated with increased risk for Alzheimer disease and related dementias (ADRDs), but the nature of the association and the underlying biological pathways remain unclear. If causal, vision would be an important modifiable risk factor with viable population-level interventions.

Objective

To evaluate potentially causal associations between visual acuity, eye conditions (specifically cataracts and myopia), neuroimaging outcomes, and ADRDs.

Design, Setting, and Participants

A cohort and 2-sample bidirectional mendelian randomization (MR) study was conducted using UK Biobank participants and summary statistics from previously published genome-wide association studies on cataract, myopia, and AD. The participants included in the analysis were aged 55 to 70 years without dementia at baseline (calendar years 2006 to 2010), underwent genotyping, and reported on eye conditions; a subset completed visual acuity examinations (n = 69 852-71 429) or brain imaging (n = 36 591-36 855). Data were analyzed from August 15, 2022, through November 28, 2023.

Exposure

Self-reported cataracts, visual acuity, and myopia measured by refraction error.

Main Outcomes and Measures

ADRD, AD, and vascular dementia were identified from electronic medical records. Total and regional brain volumes were determined using magnetic resonance imaging.

Results

The sample included 304 953 participants (mean [SD] age, 62.1 (4.1) years; 163 825 women [53.72%]); 14 295 (4.69%) had cataracts and 2754 (3.86%) had worse than 20/40 vision. Cataracts (hazard ratio [HR], 1.18; 95% CI, 1.07-1.29) and myopia (HR, 1.35; 95% CI, 1.06-1.70) were associated with a higher hazard of ADRD. In MR analyses to estimate potential causal effects, cataracts were associated with increased risk of vascular dementia (inverse variance-weighted odds ratio [OR], 1.92; 95% CI, 1.26-2.92) but were not associated with increased dementia (OR, 1.21; 95% CI, 0.98-1.50). There were no associations between myopia and dementia. In MR for potential reverse causality, AD was not associated with cataracts (inverse variance–weighted OR, 0.99; 95% CI, 0.96-1.01). Genetic risk for cataracts was associated with smaller total brain (β = −597.43 mm3; 95% CI, −1077.87 to −117.00 mm3) and gray matter (β = −375.17 mm3; 95% CI, −680.10 to −70.24 mm3) volumes, but not other brain regions.

Conclusions and Relevance

In this cohort and MR study of UK Biobank participants, cataracts were associated with increased risk of dementia, especially vascular dementia, and reduced total brain volumes. These findings lend further support to the hypothesis that cataract extraction may reduce the risk for dementia.

This cohort study examines visual acuity and eye conditions in individuals with genetic risk for Alzheimer disease and related dementias.

Introduction

Visual impairment and ocular disease are emerging as potential modifiable risk factors for Alzheimer disease (AD) and related dementias (ADRDs).1 Self-reported vision impairment,2,3 eye conditions such as cataracts,4,5 and poor visual acuity6,7,8 are associated with an increased risk of dementia. If causal, this association would be clinically meaningful; some vision impairments can be reversed or corrected. For example, observational studies have reported that cataract surgery is associated with a decreased risk of dementia.4,9

Establishing the causality of this association is methodologically difficult. Both vision impairment and ADRDs can develop slowly over decades, they share risk factors,10,11 and early ADRDs could affect visual processing (reverse causation).12 Additionally, previous studies are observational and may be affected by unmeasured confounding by social or other health factors13,14,15 or confounding by indication.16 Alternative approaches are needed to inform whether vision care could delay the onset of ADRD.

Genetic variants associated with eye conditions or AD17,18,19 can be leveraged to estimate causal associations, because genetic variants are likely independent of key confounders. Mendelian randomization (MR) uses genetic variants, single-nucleotide variants (SNVs), as instruments, allowing for an unbiased estimate of causal effect, provided certain assumptions are met.20,21 Few studies have used MR methods to evaluate associations between vision impairments and dementia. One study reported null findings for the association between cataracts and AD; however, this study did not examine vision impairments or dementia more broadly.22 Furthermore, previous studies have not investigated related indicators of ADRD, such as neuroimaging markers, which would provide convergent evidence and elucidate biological pathways.

We evaluated the possible associations between visual impairment, cataracts, and ADRD in the UK Biobank (UKB). With recent interest in visual acuity23 and cataracts9 as dementia risk factors, we focused our genetic analyses on cataracts and myopia. With MR, we first used genetic risk for AD to evaluate whether shared genetics or incipient AD increases the risk of later vision impairment or eye conditions (Figure 1A). Second, we used genetic risk for eye conditions (cataracts and myopia) to evaluate whether incipient eye conditions increase the risk of ADRD, vascular dementia (VaD), or AD (Figure 1B). Third, to explore biological pathways, we evaluated eye conditions and brain magnetic resonance imaging (MRI) outcomes.