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

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.

Figure 1.. Hypothesized Associations Between Cataracts or Other Eye Conditions and Brain Regions, Leading to Dementia

With mendelian randomization, variations in genetic risk can be used to distinguish between 2 causal scenarios. A, If incipient neurodegeneration or other physiological markers cause cataracts to form, then genetic risk for Alzheimer disease (AD) should be associated with later cataracts. B, If cataracts have independent effects on processes leading to dementia (ie, cataracts are a causal risk factor for dementia), then genetic risk for AD should be independent of cataracts and that genetic risk for cataracts would be associated with dementia.

Figure 2.. Association Between Cataracts or Cataracts-Genetic Risk Scores (GRS) and Total Brain and Gray Matter Volumes

Models for cataracts include adjustment for age at visit, self-reported sex, self-reported racial and ethnic identity, index of multiple deprivation by country of origin, binary indicators for history of comorbidities (falls, broken bones, cardiovascular disease, stroke, diabetes, and problems hearing), and imaging center. Models for cataracts-GRS (primary) include adjustment for age, sex, first 10 principal components, imaging center, and intracranial volume. Error bars indicate 95% CI.