Association between glaucoma and the risk of Alzheimer's disease: A systematic review of observational studies

Abstract

To address inconsistency as well as investigate the relationship between glaucoma and the risk of Alzheimer's disease (AD). We systematically conducted this meta‐analysis based on observational studies published up to 15 January 2018, identified from PubMed and Web of Science. Two team members independently extracted the data and assessed the quality of each included study. Summary relative risk (RR) and 95% confidence intervals (CIs) were calculated using a random‐effects model. Eight observational studies with 6870 AD cases were included. The majority of these studies (n = 6) were graded as low risk according to the Newcastle‐Ottawa Quality Assessment Scale. Individuals diagnosed with glaucoma, compared to those who were not, had an increased risk of AD (RR = 1.52; 95% CI: 1.41–1.63; I2 = 97%, p < 0.001). A significant finding was also observed for primary open‐angle glaucoma (RR = 1.52; 95% CI: 1.41–1.63; I2 = 97%, p < 0.001). However, when stratified by study design, only the case–control studies (RR = 1.08; 95% CI: 0.89–1.31; I2 = 37.3%, p = 0.207) yielded significant results, while the cohort studies did not (RR = 1.08; 95% CI: 0.89–1.31; I2 = 97.7%, p < 0.001). Of note, our meta‐regression analysis suggested that study design might be a source of heterogeneity (p = 0.009). Additionally, a significantly positive association was observed when the analyses were restricted to Asia (RR = 2.03; 95% CI: 1.02–4.07). There was no significant publication bias in these analyses. Recent evidence suggests that glaucoma may increase the risk of AD. Additional cohort studies are needed to confirm these findings and to have improved knowledge on the true nature of this association.

Altered coupling of cerebral blood flow and functional connectivity strength in visual and higher order cognitive cortices in primary open angle glaucoma

“…3–6 In addition, close links between POAG and Alzheimer’s disease (AD) have been observed. 7 Studies have established deposition of amyloid β (Aβ) and tau in the retina and vitreous of glaucoma patients, consistent with the pattern found in the cerebral spinal fluid of patients with AD. 8,9 Impaired neurovascular coupling has been suggested as the earliest pathological event in AD, which might serve as an early biomarker of cerebral pathology.…”

Diffusional Kurtosis Imaging of White Matter Degeneration in Glaucoma

“…In this context, while the association between glaucoma and risk to develop Alzheimer’s disease remains a controversial issue, a more focused approach to study the link between cognitive performance over and above visual deficit (e.g., via auditory-based tasks), glaucoma, and changes in the grey and white matter (via different neuroimaging techniques) have the potential to improve our knowledge regarding the true nature of the associations between glaucoma and AD that have been reported in past epidemiological research [ 4 , 63 , 74 , 75 , 76 ].…”

Cerebral Modifications in Glaucoma and Macular Degeneration: Analysis of Current Evidence in Literature and Their Implications on Therapeutic Perspectives

“…The hypothesis of a possible link between the two diseases arose from the observation of some shared characteristics: both diseases are age-related; 117 , 118 they present progressive neurodegeneration; 118 , 119 the deposits of tau protein and β-amyloid (major pathological features of AD, accumulating in the brain) have been detected in the retina of both AD subjects and glaucoma subjects; 118 , 119 APOE polymorphisms, strongly associated with AD, have also been suspected to be involved in optic nerve damage and visual field defect in glaucoma, although the latter is a point still under discussion. 118 The most recent systematic reviews and meta-analyses 117 , 120 ) conducted on the studies in literature, however, did not allow to reach a conclusive result, as many questions emerged: although a first analysis found a statistically significant increase of the risk of developing AD in glaucomatous patients, the results of the analysed studies appeared to be often contradictory and the studies were sometimes inadequately designed and poorly conducted. 120 The high heterogeneity of study design and study population was suspected to be a source of bias so that, after stratifying by study type, the association between AD and glaucoma persisted only in the subgroup of case-control studies (more susceptible to selection bias and recall bias) while it disappeared in cohort studies.…”

“… 120 The high heterogeneity of study design and study population was suspected to be a source of bias so that, after stratifying by study type, the association between AD and glaucoma persisted only in the subgroup of case-control studies (more susceptible to selection bias and recall bias) while it disappeared in cohort studies. 117 Even the great genetic heterogeneity of the two diseases under investigation (65 genes suspected to be involved in glaucoma, 31 in AD 117 ) has been accused of being a source of bias if not adequately controlled; the same applies to other potential confounders (comorbidities, alcohol drinking, smoking), which were not always adequately controlled in the considered studies, and to the different diagnostic criteria used to define the diseases. The results of these systematic reviews, therefore, have been described as “hypothesis generating” and should be interpreted with caution.…”