Risk of glaucoma to subsequent dementia or cognitive impairment: a systematic review and meta-analysis

Author: Wang X, Chen W, Zhao W, Miao M.

Geographical coverage: China, the United States, Sweden, Korea, the United Kingdom, France, Australia, and Denmark.

Sector: Risk factor

Sub-sector: Dementia

Equity focus: Not explicitly stated

Study population: Adult patients with glaucoma

Review type: Effectiveness review

Quantitative synthesis method: Meta-analysis

Qualitative synthesis method: Not applicable

Background

Dementia affects around 50 million people globally, with numbers expected to rise to over 131 million by 2050. Identifying modifiable risk factors is essential since there are no disease-modifying treatments. Visual impairment may indicate early dementia, as retinal ganglion cell damage could lead to cognitive decline. Glaucoma, a major cause of blindness, involves optic nerve degeneration and visual field loss. Despite the focus on intraocular pressure, its reduction doesn’t always halt glaucoma progression, hinting at other mechanisms. Glaucoma and dementia might share common pathological processes like neuronal degeneration and axonal transport dysfunction, though the link between glaucoma and cognitive impairment remains uncertain.

Objectives

To assess whether glaucoma increases the risk of dementia or cognitive impairment.

Main findings

The authors found that glaucoma increases the risk of subsequent cognitive impairment and dementia. Factors such as the type of glaucoma, gender, age, and region composition of the study population may significantly affect the relationship between glaucoma and dementia.

The review included 27 studies (20 cohort studies, 7 case-control studies) with a total of 9,061,675 participants. These studies were conducted in China (n=8), the United States (n=5), Sweden (n=5), Korea (n=3), the United Kingdom (n=2), France (n=2), Australia (n=1), and Denmark (n=1). The studies were published between 2007 and 2024, with sample sizes ranging from 509 to 2,623,130, and the mean follow-up time varied from 3 to 14 years. Twenty-four studies reported dementia, while the remaining three reported cognitive impairment. Twenty-one studies were classified as high quality, and the remaining six were classified as moderate quality.

A total of 18 studies evaluated all-cause dementia as an outcome. Of these, 11 studies showed that glaucoma was associated with an increased risk of all-cause dementia, with effect estimates (odds ratio (OR)) ranging from 1.09 (95% confidence interval (CI): 1.15 to 1.13) to 3.90 (95% CI: 1.50 to 10.14). In general, glaucoma was associated with an increased risk of all-cause dementia (OR = 1.31, 95% CI: 1.16 to 1.48, P < 0.0001). The results from 24 studies revealed a strong link between glaucoma and an increased risk of Alzheimer’s disease (OR = 1.30, 95% CI: 1.17 to 1.46, P<0.00001). Additionally, the findings from 11 studies revealed a significant link between glaucoma and the risk of vascular dementia (OR = 1.26, 95% CI: 1.07 to 1.47, P = 0.005). Furthermore, the results from three studies with a total of 1,513,047 patients revealed that glaucoma patients had twice the risk of cognitive impairment as the general population (OR = 2.00, 95% CI: 1.79 to 2.22, P<0.00001).

Subgroup analysis showed that the prevalence of dementia was 2.90 (95% CI: 1.45 to 5.77, P=0.003) in participants aged ≥65 years and 2.07 (95% CI: 1.18 to 3.62, P=0.01) in participants aged <65 years. The incidence rates in female glaucoma patients were 1.46 (95% CI: 1.06 to 2.00, P=0.02), while in male patients, the rates were 1.07 (95% CI: 0.97 to 1.19, P=0.17). Among glaucoma types, primary open-angle glaucoma was more likely to develop dementia (OR = 1.55, 95%CI: 1.21 to 2.00, P=0.0006), Alzheimer’s disease (OR = 1.29, 95% CI: 1.11 to 1.49, P=0.0006), and cognitive impairment (OR = 2.00, 95% CI: 1.79 to 2.22, P<0.0001), while angle-closure glaucoma increased the risk of vascular dementia (OR = 1.24, 95% CI: 1.01 to 1.52, P=0.04). There were also differences in regional distribution, with the highest prevalence in the Asia region, while glaucoma was not associated with dementia in Europe and North America.

Methodology

Authors included population-based, case-control or cohort studies published in English and Chinese, exploring the relationship between glaucoma and dementia or cognitive impairment and reporting risk estimates of dementia or cognitive decline as the outcome. Authors searched in PubMed, Embase, Cochrane Library, and Web of Science databases from inception to 10 March 2024. A further grey literature search was conducted using Google Scholar to identify relevant articles not found through the database search. Reference lists of the identified studies were scanned to identify additional relevant publications.

Two reviewers independently screened the potentially relevant articles against the eligibility criteria, assessed the risk of bias using the Newcastle-Ottawa Scale (Newcastle–Ottawa Scale (NOS)), and extracted data from included studies. The primary outcome indicators were the pooled odds ratios (OR) and 95% confidence interval (95% CI) with adjusted confounders. Heterogeneity was assessed using I² statistic (I2) statistics. Data was analysed using fixed-effects model meta-analysis if there was no statistical heterogeneity between studies; however, a random-effects model was used in case of clinical or statistical heterogeneity. Subgroup analyses were conducted to explore the sources of heterogeneity. Sensitivity analysis was performed to confirm the robustness of the overall results. Publication bias was assessed using a funnel plot and Egger’s test.

Applicability/external validity

The review highlighted that the findings’ external validity is affected by variability in glaucoma type, geographic regions, and assessment methods. Differences in study populations and diagnostic criteria, as well as unadjusted factors like body mass index (BMI), smoking, and alcohol use, may limit generalizability. Most studies were cohort-based, not recruiting participants at glaucoma diagnosis, which could introduce selection bias. Despite the large sample size enhancing applicability, more high-quality longitudinal studies are needed to improve understanding and external validity.

Geographic focus

Included studies were conducted in China, the United States, Sweden, Korea, the United Kingdom, France, Australia, and Denmark.

Summary of quality assessment

Overall, there is medium confidence in the conclusions about the effects of this study due to methodological concerns. The review authors included publications written in English and Chinese only, did not seek input from experts or study authors, and did not report findings based on risk of bias status.