Abstract
Objective
We aim to quantify the co-existence of age-related macular degeneration (AMD), glaucoma, or diabetic retinopathy (DR) and cognitive impairment or dementia.
Method
MEDLINE, EMBASE, PsycINFO and CINAHL were searched (to June 2020). Observational studies reporting incidence or prevalence of AMD, glaucoma, or DR in people with cognitive impairment or dementia, and of cognitive impairment or dementia among people with AMD, glaucoma, or DR were included.
Results
Fifty-six studies (57 reports) were included but marked by heterogeneities in the diagnostic criteria or definitions of the diseases, study design, and case mix. Few studies reported on the incidence. Evidence was sparse but consistent in individuals with mild cognitive impairment where 7.7% glaucoma prevalence was observed. Prevalence of AMD and DR among people with cognitive impairment ranged from 3.9% to 9.4% and from 11.4% to 70.1%, respectively. Prevalence of AMD and glaucoma among people with dementia ranged from 1.4 to 53% and from 0.2% to 25.9%, respectively. Prevalence of DR among people with dementia was 11%. Prevalence of cognitive impairment in people with AMD, glaucoma, and DR ranged from 8.4% to 52.4%, 12.3% to 90.2%, and 3.9% to 77.8%, respectively, and prevalence of dementia in people with AMD, glaucoma and DR ranged from 9.9% to 62.6%, 2.5% to 3.3% and was 12.5%, respectively.
Conclusions
Frequency of comorbid eye disease and cognitive impairment or dementia varied considerably. While more population-based estimations of the co-existence are needed, interdisciplinary collaboration might be helpful in the management of these conditions to meet healthcare needs of an ageing population.
Trial registration
PROSPERO registration: CRD42020189484.
摘要
目的: 我们旨在量化老年黄斑变性 (AMD) 、青光眼或糖尿病视网膜疾病合并认知障碍或痴呆情况。
方法: 本文检索了MEDLINE、EMBASE、PsycINFO和CINAHL (至2020年6月) 数据库。观察性研究报道了认知障碍或痴呆患者中AMD、青光眼或糖尿病视网膜病变 (DR) 的发病率或流行率, 以及AMD、青光眼或DR患者中认知障碍或痴呆的情况。
结果: 本文共纳入了56项研究 (57份报告), 这些研究在疾病的诊断标准或定义、研究设计和病例组合方面存在着异质性。很少研究报告发病率。虽然证据少, 但在轻度认知障碍者中的证据是连续的, 观察到7.7%的青光眼发病率。认知障碍者中AMD和DR的患病率分别为3.9%至9.4%和11.4%至70.1%。痴呆症患者中AMD和青光眼的患病率分别为1.4%至53%和0.2%至25.9%。痴呆症患者中DR的患病率为11%。
患有AMD、青光眼和DR的人中认知障碍的发病率分别为8.4%至52.4%、12.3%至90.2%和3.9%至77.8%, 患有AMD、青光眼和DR的人中痴呆症的发病率分别为9.9%至62.6%、2.5%至3.3%和12.5%。
结论: 眼病合并认知障碍或痴呆的频率差异性大。虽然需要更多基于人口的共病估计, 但跨学科合作可能有助于管理这些疾病以满足老龄化人口的医疗保健需求。
Similar content being viewed by others
Introduction
Dementia affects around 50 million people, and there are nearly 10 million new cases each year worldwide [1]. Among general populations (aged ≥60 years), the prevalence of dementia has been estimated as ranging from 4.6% in Central Europe to 8.7% in North Africa and the Middle East [2], and prevalence estimates are inevitably influenced by diagnostic criteria and information source (e.g., claims or pharmacy data, or survey) [3]. Mild cognitive impairment (MCI) is a diagnosis that refers to impaired cognition [4], which is not severe enough to interfere with independent daily functioning. MCI is not a static condition with some cases progressing to dementia and some reverting to normal cognitive function [4]. Furthermore, concerns about the heterogeneity in the diagnostic and operational criteria for MCI have also been raised [4], and MCI has been applied to cognitive impairment no dementia, age-associated memory impairment, MCI, and amnestic MCI [4]. Likely due to this heterogeneity and the age of the studied participants, there has been substantial disparity in the reported prevalence of MCI, ranging from 0.5 to 42% [4].
The retina, being an extension to the brain, is particularly relevant as a potential window to explore dementia, because of the retinal-brain embryological, anatomical, and physiological connections. Thinning of the retinal nerve fibre layer and ganglion cell inner plexiform layer measured through optical coherence tomography retina scans has been reported in individuals with MCI and Alzheimer’s disease (AD) [5, 6]. Retinal microvascular variations have been investigated as biomarkers for cerebral microvasculature changes [7], and sparser retinal microvascular networks, increased tortuosity in the retinal vessels, and reduced blood flow are associated with cognitive decline, MCI, and dementia [8,9,10].
Eye diseases that affect the retina including age-related macular degeneration (AMD), glaucoma and diabetic retinopathy (DR) are leading causes of blindness among adults [11,12,13]. Meta-analyses of 39 and 50 population-based studies, and of individual participant data from 35 studies conducted in the USA, Europe, Asia and Australia, estimated that globally 170 million (in 2014, pooled prevalence of 8.7%), 64 million (in 2013, 3.5% of population aged 40 to 80 years), and 93 million (in 2010, 34.6% of those with diabetes) people had AMD, glaucoma and DR, respectively [11,12,13].
There are commonalities between AMD, glaucoma, or DR, and cognitive impairment or dementia. Clinically, they are all chronic and progressive, with strong family history connections and increasing incidence with age [14,15,16]. Pathophysiologically, common characteristics for AMD and AD include the presence of amyloid β in the drusen of AMD patients [14]. Amyloid β has been suggested as a target for glaucoma treatment [17] and other shared characteristics between glaucoma and dementia include common gene coding OPTINEURIN [18], neuroinflammation [19], and elevated levels of tumour necrosis factor α [20]. Common risk factors for DR, brain amyloid burden, and cognitive impairment include hyperglycaemia and insulin resistance [21].
To our knowledge, there is no existing systematic review evidence on the frequency of these eye diseases in people with cognitive impairment or dementia, or the frequency of cognitive impairment or dementia in people with these eye diseases. Knowledge of these relationships can help promote timely referral and inter-disciplinary communications between healthcare professionals, e.g., optometrists, ophthalmologists, diabetologists, geriatricians and neurologists, involved in the management of such co-morbidities.
Methods
The protocol was registered in PROSPERO (CRD42020189484). Reporting of the review was followed the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guideline and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist.
Inclusion and exclusion criteria
The population of interest included studies reporting on participants (aged ≥18 years) with any types and stages of AMD, glaucoma, DR, cognitive impairment, or dementia. Studies specifically on people with comorbid AMD, glaucoma or DR and cognitive impairment or dementia in the context of other diseases were excluded, except for those on comorbid DR and cognitive impairment or dementia in people with diabetes since DR is a complication of diabetes.
Published observational studies with consecutive, random, or convenience sampling were eligible. Studies with selective sampling were excluded. Observational study designs were accepted except for case-reports, case series, and studies of fewer than 50 participants. Outcomes were incidence and prevalence of AMD, glaucoma, or DR, in people with cognitive impairment or dementia, and/or incidence and prevalence of cognitive impairment or dementia in people with AMD, glaucoma or DR.
Search strategy and screening
Four databases were searched: MEDLINE, EMBASE, PsycINFO and CINAHL (from inception to 1 June 2020, eTable 1). The following search terms were used as free text or controlled vocabulary as appropriate for the corresponding database: macular degeneration, geographic atrophy or dystrophy, macular oedema, vitelliform macular dystrophy, retina degeneration, drusen, glaucoma, ocular or eye hypertension, diabetic retinopathy AND Alzheimer(s), dementia, cognitive dysfunction.
No language or publication date restriction was applied. All identified titles and abstracts were screened by at least one of three reviewers, and 20% of the titles and abstracts were screened independently by two of the three reviewers. Full texts of relevant documents were obtained and independently assessed for relevance by two reviewers. All differences were resolved by discussion with the lead reviewer until the final set was agreed. Reference lists or citation trails of the included studies were checked to identify additional studies.
Statistical analyses
To estimate frequencies, within study variances were calculated as square root of (p × (1 − p)/n), where p is the cumulative incidence or prevalence, and n is the sample size. The cumulative incidence and prevalence rates were sorted from lowest to highest rates and plotted with 95% confidence intervals (CIs). Population-based studies were listed first in forest plots, easing visual comparisons to the other studies. Statistical heterogeneity and consistency were assessed using the standard I2 and Q statistic, with p < 0.05 indicating heterogeneity and I2 > 75% indicating high inconsistency. Rates were synthesized using a random effect inverse variance approach for weighting. We also conducted meta-analyses to provide summary estimates of the associations between each eye disease and cognitive impairment or dementia, based on multivariable adjusted odds ratios (ORs), relative risks (RRs), or hazard ratios (HRs). All analyses were conducted using Stata 13.
Data extraction and risk of bias assessment
Data extraction was completed by two reviewers independently and compared and compiled by the lead reviewer. Risk of bias was assessed using the risk of bias tool for prevalence studies developed by Hoy et al (Appendix A) [22]. There were 9 items, and each item was judged as “low” versus “high risk of bias”.
Results
The search results and selection process are summarised in a PRISMA flowchart (eFig. 1). After removing duplicates, a total of 5496 titles and abstracts were screened, including 1098 (20%) screened independently by two reviewers. Discrepancies occurred on 21 (1.9%) records of titles and abstracts, and were solved through discussion. Seventy-four full text reports were retrieved and assessed for inclusion/exclusion. Twenty-nine reports were excluded with reasons (Appendix B) and a total of 56 studies (57 reports, two reports on the same study [23, 24], Appendix C) were considered eligible for inclusion.
Twenty-four studies (25 reports) reported AMD, glaucoma or DR among people with cognitive impairment or dementia [23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47], and 34 studies reported cognitive impairment or dementia among people with AMD, glaucoma or DR [41, 43, 48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79]. These included two longitudinal studies [41, 43] reporting on both directions of the association: (1) cumulative incidence of AMD among people with dementia and cumulative incidence of dementia among AMD [41]; and (2) cumulative incidence of POAG among people with dementia and cumulative incidence of dementia among POAG [43]. Studies used four methodologies for eye diseases (Appendix D): retinal photograph grading, clinical examination, diagnostic coding, and histopathological assessments. For cognition, studies used standard diagnostic criteria for MCI or cut-offs on cognitive screening tools. Dementia was mainly assessed according to diagnostic criteria or diagnostic coding.
Eye diseases among people with cognitive impairment or dementia
Studies were conducted in Australia [25, 26], Canada [27], China [28], France [29], Germany [30, 47], Greece [31], Italy [32], Japan [33, 34], the Philippines [35], Poland [23, 24], Singapore [36], Spain [37], Taiwan [38,39,40], the UK [41,42,43,44] and the USA [45, 46], and published between 1986 and 2020 (eTable 2). Twenty studies (83.3% of the studies, 21 reports) were published in the decade since 2011. There were nine population-based [25, 36, 38,39,40,41, 43,44,45], three community-based [29, 37, 47], 11 (12 reports) hospital-based [23, 24, 26,27,28, 31,32,33,34,35, 42, 46], and one nursing home based [30] studies. Sixteen studies (17 reports) were cross-sectional, and eight studies were longitudinal with varied follow up times reported as a mean and standard deviation of 7.6 ± 1 [25] and 2 ± 0.4 years [30] of follow-up, at least one year of follow-up [41, 43, 47], or reporting that AMD or glaucoma was diagnosed before the diagnosis of dementia (length of follow-up not reported) [38,39,40].
Among people with cognitive impairment
There were no studies reporting on the incidence. Prevalence of AMD ranged from 3.9% [37] to 9.4% [36] (three studies, Fig. 1). There was no evidence of heterogeneity or high inconsistency between the two studies on prevalence of glaucoma (p = 0.18, I2 = 44.1%) [32, 37], and the pooled prevalence was 7.7% (95% CI 4.8% to 10.6%). Among people with diabetes and cognitive impairment, prevalence of DR ranged from 20% [25] to 70.1% [23, 24] (eight studies/nine reports). The lowest prevalence of DR (11.4%) was reported in a study where diabetes was not an inclusion criterion [32].
Among people with dementia
During follow-ups of “1 year or more”, cumulative incidence of AMD and glaucoma was 0.01% [41] and 0.09% [43], respectively (Fig. 2). Prevalence of AMD and glaucoma ranged from 1.4% [38] to 53% [46] (five studies), and from 0.2% [45] to 25.9% [30] (11 studies), respectively. One study, in which diabetes was not an inclusion criterion, reported prevalence of DR (11%) [32].
Cognitive impairment or dementia among people with eye diseases
Studies were conducted in Australia [48], Canada [49], China [50], Denmark [51, 52], Japan [53], Malaysia [54], the Netherlands [55], Norway [56], Singapore [57, 58], South Korea [59,60,61], Taiwan [62,63,64,65,66,67,68,69], Turkey [70,71,72], the UK [41, 43, 73] and the USA [74,75,76,77,78,79], and published between 1999 and 2020 (eTable 3). Twenty-eight studies (82.4%) were published in the most recent decade since 2011 [41, 43, 49, 50, 52,53,54, 57,58,59,60,61, 63,64,65,66,67,68,69,70,71,72,73, 75,76,77,78,79]. There were 21 population-based [41, 43, 48, 51, 55, 57, 58, 60,61,62,63,64,65,66,67,68,69, 74, 76,77,78], one community-based [73], and 12 hospital-based studies [49, 50, 52,53,54, 56, 59, 70,71,72, 75, 79]. Other than the frequency, a single study reported on risk factors in univariate analyses, in which higher levels of HbA1c and neuron-specific enolase, and a lower education level increased the risk of cognitive impairment among people with DR [50].
Among people with AMD
Cumulative incidence of dementia ranged from 0.3% [41] to 9.9% [55] during various follow-up periods (Fig. 3, four studies). Prevalence of cognitive impairment and dementia ranged from 8.4% [48] to 52.4% [59] (six studies) and from 9.9% [74] to 62.6% [79] (three studies), respectively.
Among people with glaucoma
Incidence of dementia was reported in three studies: 2.85 per 1000 person-years among people with POAG [63], and 9.22 [65] and 11.63 [69] per 1000 person-years among people with POAG or PACG. Cumulative incidence of dementia ranged from 1.4% [63] to 32% [76] during various follow-up periods (Fig. 4, 10 studies). Prevalence of cognitive impairment and dementia ranged from 12.3% [49] to 90.2% [53] (four studies) and from 2.5% [62] to 3.3% [68] (four studies), respectively.
Among people with DR
Cumulative incidence of cognitive impairment was 8.5% (Fig. 5) [58]. Incidence rate of dementia was reported in one study, 32.87 per 1000 person-years [77]. Cumulative incidence of dementia was 5.5% [78] and 19.2% [77] within mean follow-ups of up to 7 years [77, 78]. There were 3.9% [73] to 77.8% [72] of people with DR having cognitive impairment (three studies), and 12.5% [73] of individuals with DR had dementia.
Associations between eye diseases and cognitive impairment or dementia
One study reported that people with dementia were more likely to have prior neovascular AMD than controls, adjusted OR 1.37 (95% CI 1.14 to 1.65) [38]. Conversely, the associations between AMD, glaucoma, or DR, and cognitive impairment or dementia have been reported in multivariable adjusted models in nine, 10, and three studies, respectively (eFigs. 2–4). In three, eight, and two longitudinal studies, pooled RRs/HRs were 1.46 (95% CI 1.31, 1.61), 1.20 (1.02 to 1.42) and 1.29 (95% CI 1.15, 1.45) for AMD, glaucoma, and DR, respectively.
Risk of bias
In 48 out of the 56 studies (86%), the target population was considered not representative of the national population with AMD, glaucoma, DR, cognitive impairment or dementia, due to the use of specific inclusion and exclusion criteria (eTable 4a–n), e.g. exclusion of people with a history of cerebrovascular events [27, 64, 72, 73], hearing impairment [26, 28, 75], or not living independently [26, 29]. Among the 16 studies reporting incidence [41, 43, 51, 52, 55, 58, 60, 61, 63,64,65, 67, 69, 76,77,78], only four reported all three of the relevant components, i.e., number of incident cases, person-years of follow-up, and incidence rate [63, 65, 69, 77]. Only 21 (22 reports) out of 40 studies reporting on the prevalence reported on all three of the relevant components, i.e., numerator, denominator and prevalence rate [23, 24, 26,27,28, 30, 31, 33, 34, 37,38,39,40, 48, 57, 62, 66, 70,71,72,73, 79].
Discussion
Our work comprehensively reviewed the frequency of coexistent eye disease and cognitive impairment or dementia. The included studies were conducted in 21 countries or regions in Asia (23 studies), Australia (3 studies), Europe (19 studies/20 reports), and North America (11 studies). Most of the studies were conducted in high income countries, with only 13% in upper (6 studies) or lower middle (1 study) income countries. We found heterogeneity across studies with varied frequencies, which was likely due to case mix, e.g., country and ethnicity, various diagnostic criteria or definitions for eye disease and cognitive impairment or dementia, and cross-sectional versus longitudinal study design with various length of follow-up.
Potential mechanisms influencing the coexistence of eye disease and cognitive impairment
There are several potential mechanisms which have been put forward to explain relationships between eye disease and cognitive function. Whilst a full review of these mechanisms is beyond our systematic summary of the reported levels of co-existence, within the field, we highlight some of the most prominent theories. One such theory is the “use it or lose it” hypothesis in cognitive aging, i.e., a lack of, or reduction in, cognitive, physical, and social activities due to visual impairment has negative consequences for future cognitive function.
Alongside this there may also be common mechanisms operating in eye and cognitive outcomes, e.g., accumulation of similar molecules (for example amyloid β) and pathophysiology, related to both retinal changes and endothelial dysfunction in retinal and cerebral micro-vessels. Besides amyloid β, other molecules that have been found in both drusen and AD plaques include tau protein, proteoglycan, and complement component 3, etc [14]. Chronic inflammation including complement activation, oxidative stress, increased vascular endothelial growth factor in the retinal pigment epithelium and in the cerebrospinal fluid, and decreased clearance of amyloid β have also been suggested as common drivers for AMD and AD [14]. Further, similar retinal changes have been observed in glaucoma and dementia, e.g., decreased retinal thickness, protein deposits, microglial activation, neurodegeneration, and apoptosis [19, 30]. Potential mechanisms also link diabetes and cognitive impairment including a role of the insulin-degrading enzyme (IDE), degrading amyloid β such that amyloid β aggregates in patients with diabetes and hyperinsulinemia as result of lower availability of the IDE [21]. Additionally, in the retina of people with diabetes, micro-vessels are impaired through endothelial dysfunction caused by glycation, oxidative stress, and increased polyol pathway activity, while endothelial dysfunction in the brain affects the development and progression of cerebral small vessel disease associated with the risk of cognitive impairment [21].
Why knowledge of the co-existence is important
In the current systematic review, population-based data on prevalence were sparse, and estimations were close to, if not lower than, those reported in general populations [2, 4, 11,12,13]. Thus our summary of the current data does not support population-based based screening of eye diseases in people with cognitive impairment or dementia, or screening of cognitive impairment or dementia in people with AMD, glaucoma, or DR. Indeed, we acknowledge the variations in prevalence estimates for each disease in general populations due to disparities in diagnostic criteria, information sources, and assessment years, etc. For instance, around 11%, 3.2%, and 1.7% Australians aged 55 years and over were affected by AMD, glaucoma, DR, respectively [80], and 8.3% of Australians aged 65 and over had dementia [81], which are slightly different to other estimations [2, 4, 11,12,13]. Thus, comparisons to rates in general populations should be interpreted with caution.
We did observe that co-existence tended to be more frequent in hospital- or nursing-home based settings potentially because hospital- or nursing-home based populations may be those with more co-morbidities and severe disease, or those who are more likely to seek medical advice from specialists [82]. It is important that clinicians remain alert to the potential need for an eye or cognitive assessment for their older patients. Furthermore, individuals with an eye disease, cognitive impairment, or dementia may be disadvantaged, potentially due to the challenges faced by people who rely on carers and additional help to schedule and attend optometrist appointments (for example, individuals with diabetes who had dementia were 15% less likely to receive an annual eye examination than those without dementia [83]). Therefore, preventative eye checks (or cognitive screening) might be recommended when people with cognitive impairment or dementia (or people with an eye disease) attend their check-ups.
Measures of the association
Two recent systematic reviews and meta-analyses examined whether AMD, glaucoma and/or DR increase the risk of cognitive decline and/or dementia, and vice versa [84, 85], but the presented evidence is both sparse and mixed. A meta-analysis in 2021 found no evidence for the associations between AMD or glaucoma and risk of dementia [84], but an increased risk of dementia associated with DR, HR 1.34 (95% CI 1.11 to 1.61, pooled estimation of four studies with heterogeneity, p = 0.002) [84]. Another meta-analysis in 2019 found that individuals with dementia were at risk of AMD, pooled adjusted OR 1.24 (95% CI 1.04 to 1.47) based on four cross-sectional or case-control studies [85]. Conversely, AMD was also associated with increased risk of cognitive impairment, pooled adjusted OR 2.42 (95% CI 1.06 to 5.56) based on two cross-sectional studies [85]. However, when combining two longitudinal cohort studies with heterogeneity (p = 0.01), the association for AMD as a risk factor for AD did not exist, pooled adjusted risk ratio 1.27 (95% CI 0.53 to 3.04) [85]. The current study added to the literature regarding the associations between eye diseases and cognitive impairment or dementia. Longitudinal research is still needed to clarify the causative relationships between eye and cognitive conditions.
Limitations
Firstly, the validity of the AMD, glaucoma, and DR diagnosis in patients with cognitive impairment or dementia may be questionable, as ocular structural and functional results may be confounded by the presence of comorbidity, such as the likely affected patient cooperation during imaging or visual field testing. Conversely, AMD, glaucoma and DR driven visual impairments may also interfere with cognitive tests, especially when studies adopted cognitive assessment scales containing vision-dependent items to define cognitive impairment. Validated adapted versions of scales, e.g., MMSE [86] and MoCA [87], could be advocated when participants or part of them were visually impaired. However, out of the nine included studies defining cognitive impairment using cut-offs on MMSE or MoCA, an adapted version had been used in only a couple [48, 49].
Secondly, the current data is limited with less than half of the studies being population-based, and only half being longitudinal. Although many studies reported on incident cases did have cumulative incidence data available, incidence rates were available in only four studies. Further, evidence on the risk factors of the comorbidity is sparse, and thus we cannot comment on among those with one condition who are vulnerable to have another. Finally, based on the “use it or lose it” theory and biological associations between eye diseases and cognition, it can be assumed that co-existence would be more pronounced among individuals with severe disease compared to those with mild disease. Also, such coexistence is likely to increase with age, because of the increased prevalence of AMD, POAG, DR, and cognitive impairment or dementia with ageing [2, 4, 11,12,13]. However, current data are insufficient to explore these further.
Conclusions and implications
Our review of the co-existence of eye disease and cognitive impairment or dementia provides an important in-depth addition to the evidence base on the frequencies and confirmed the concurrence. We advocate the need for awareness of the comorbid conditions, which deserves appropriate collaborative care across disciplines. Further studies are warranted to collect data on the population-based prevalence and incidence of coexistent eye disease and cognitive impairment or dementia. Our study supports consideration of regular eye examinations or cognitive screening in clinical practice guidelines among older adults with one of these conditions.
Summary
What is known about this topic
-
There may be relationships between age-related macular degeneration (AMD), glaucoma or diabetic retinopathy (DR) and cognitive impairment or dementia.
What this study adds
-
56 studies were synthesized.
-
Frequencies of co-morbid AMD, glaucoma or DR and cognitive impairment or dementia were quantified.
-
More research is required to support or oppose regular eye examinations and cognitive screening among older adults with one of these conditions.
Data availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
References
Global action plan on the public health response to dementia 2017–2025. World Health Organization, 2017.
World Alzheimer report 2015, the global impact of dementia, an analysis of prevalence, incidence, cost and trends 2015. Available from: https://www.alzint.org/u/WorldAlzheimerReport2015.pdf.
Lin PJ, Kaufer DI, Maciejewski ML, Ganguly R, Paul JE, Biddle AK. An examination of Alzheimer’s disease case definitions using medicare claims and survey data. Alzheimers Dement. 2010;6:334–41.
Ward A, Arrighi HM, Michels S, Cedarbaum JM. Mild cognitive impairment: disparity of incidence and prevalence estimates. Alzheimers Dement. 2012;8:14–21.
Santos CY, Johnson LN, Sinoff SE, Festa EK, Heindel WC, Snyder PJ. Change in retinal structural anatomy during the preclinical stage of Alzheimer’s disease. Alzheimers Dement (Amst). 2018;10:196–209.
Chan VTT, Sun Z, Tang S, Chen LJ, Wong A, Tham CC, et al. Spectral-domain OCT measurements in Alzheimer’s disease: a systematic review and meta-analysis. Ophthalmology. 2019;126:497–510.
Kwa VI, van der Sande JJ, Stam J, Tijmes N, Vrooland JL. Retinal arterial changes correlate with cerebral small-vessel disease. Neurology. 2002;59:1536–40.
Feke GT, Hyman BT, Stern RA, Pasquale LR. Retinal blood flow in mild cognitive impairment and Alzheimer’s disease. Alzheimers Dement (Amst). 2015;1:144–51.
Cheung CYL, Ong YT, Ikram MK, Ong SY, Li X, Hilal S, et al. Microvascular network alterations in the retina of patients with Alzheimer’s disease. Alzheimers Dement (Amst). 2014;10:135–42.
Deal JA, Richey Sharrett A, Rawlings AM, Gottesman RF, Bandeen-Roche K, Albert M, et al. Retinal signs and 20-year cognitive decline in the Atherosclerosis Risk in Communities Study. Neurology. 2018;90:e1158–e66.
Yau JWY, Rogers SL, Kawasaki R, Lamoureux EL, Kowalski JW, Bek T, et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care. 2012;35:556–64.
Tham YC, Li X, Wong TY, Quigley HA, Aung T, Cheng CY. Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-analysis. Ophthalmology. 2014;121:2081–90.
Wong WL, Su X, Li X, Cheung CM, Klein R, Cheng CY, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Global Health. 2014;2:e106–16.
Ohno-Matsui K. Parallel findings in age-related macular degeneration and Alzheimer’s disease. Prog Retin Eye Res. 2011;30:217–38.
Crosby-Nwaobi R, Sivaprasad S, Forbes A. A systematic review of the association of diabetic retinopathy and cognitive impairment in people with Type 2 diabetes. Diabetes Res Clin Pract. 2012;96:101–10.
Ghiso JA, Doudevski I, Ritch R, Rostagno AA. Alzheimer’s disease and glaucoma: mechanistic similarities and differences. J Glaucoma. 2013;22:S36–8.
Guo L, Salt TE, Luong V, Wood N, Cheung W, Maass A, et al. Targeting amyloid-beta in glaucoma treatment. Proc Natl Acad Sci USA 2007;104:13444–9.
Liu YH, Tian T. Hypothesis of optineurin as a new common risk factor in normal-tension glaucoma and Alzheimer’s disease. Med Hypotheses. 2011;77:591–2.
Ramirez AI, de Hoz R, Salobrar-Garcia E, Salazar JJ, Rojas B, Ajoy D, et al. The role of microglia in retinal neurodegeneration: Alzheimer’s disease, Parkinson, and glaucoma. Front Aging Neurosci. 2017;9:214.
Yuan J, Amin P, Ofengeim D. Necroptosis and RIPK1-mediated neuroinflammation in CNS diseases. Nat Rev Neurosci. 2019;20:19–33.
Kawamura T, Umemura T, Hotta N. Curious relationship between cognitive impairment and diabetic retinopathy. J Diabetes Investig. 2015;6:21–3.
Hoy D, Brooks P, Woolf A, Blyth F, March L, Bain C, et al. Assessing risk of bias in prevalence studies: modification of an existing tool and evidence of interrater agreement. J Clin Epidemiol. 2012;65:934–9.
Gorska-Ciebiada M, Saryusz-Wolska M, Ciebiada M, Loba J. Mild cognitive impairment and depressive symptoms in elderly patients with diabetes: prevalence, risk factors, and comorbidity. J Diabetes Res. 2014:179648. https://doi.org/10.1155/2014/179648.
Gorska-Ciebiada M, Saryusz-Wolska M, Borkowska A, Ciebiada M, Loba J. Adiponectin, leptin and IL-1 beta in elderly diabetic patients with mild cognitive impairment. Metab Brain Dis. 2016;31:257–66.
Bruce DG, Davis WA, Casey GP, Starkstein SE, Clarnette RM, Foster JK, et al. Predictors of cognitive impairment and dementia in older people with diabetes. Diabetologia. 2008;51:241–8.
Finger RP, Fenwick E, Cheung CY, Ikram MK, Wong TY, Lamoureux EL. Near vision impairment is associated with cognitive impairment in type 2 diabetes. Asia Pac. J Ophthalmol (Phila). 2014;3:17–22.
Pelletier AA, Theoret ME, Boutin T, Kergoat MJ, Massoud F, Latour J, et al. Prevalence of glaucoma in hospitalized older adults with Alzheimer’s disease. Can J Neurol Sci. 2014;41:206–9.
Xia SS, Xia WL, Huang JJ, Zou HJ, Tao J, Yang Y. The factors contributing to cognitive dysfunction in type 2 diabetic patients. Ann Transl Med. 2020;8:104.
Verny C, Doucet J, Bauduceau B, Constans T, Mondon K, Le Floch JP, et al. Prevalence of cognitive decline and associated factors in elderly type 2 diabetic patients at inclusion in the GERODIAB cohort. Eur Geriatr Med. 2015;6:36–40.
Bayer AU, Ferrari F, Erb C. High occurrence rate of glaucoma among patients with Alzheimer’s disease. Eur Neurol. 2002;47:165–8.
Tsolaki F, Kountouras J, Topouzis F, Tsolaki M. Helicobacter pylori infection, dementia and primary open-angle glaucoma: are they connected? BMC Ophthalmol. 2015;15:24.
Mandas A, Mereu RM, Catte O, Saba A, Serchisu L, Costaggiu D, et al. Cognitive impairment and age-related vision disorders: their possible relationship and the evaluation of the use of aspirin and statins in a 65 years-and-over Sardinian population. Front Aging Neurosci. 2014;6:309.
Tamura H, Kawakami H, Kanamoto T, Kato T, Yokoyama T, Sasaki K, et al. High frequency of open-angle glaucoma in Japanese patients with Alzheimer’s disease. J Neurol Sci. 2006;246:79–83.
Sanke H, Mita T, Yoshii H, Yokota A, Yamashiro K, Ingaki N, et al. Relationship between olfactory dysfunction and cognitive impairment in elderly patients with type 2 diabetes mellitus. Diabetes Res Clin Pract. 2014;106:465–73.
Blanquisco LR, Abejero JE, Buno B, Trajano-Acampado L, Cenina A, Santiago D. Factors associated with mild cognitive impairment among elderly Filipinos with type 2 diabetes mellitus. J ASEAN Fed Endocr Soc. 2017;32:145–50.
Ong S-Y, Ikram MK, Haaland BA, Cheng C-Y, Saw S-M, Wong TY, et al. Myopia and cognitive dysfunction: the Singapore Malay Eye Study. Invest Ophthalmol Vis Sci. 2013;54:799.
Marquié M, Castilla-Martí M, Valero S, Martínez J, Sánchez D, Hernández I, et al. Visual impairment in aging and cognitive decline: experience in a Memory Clinic. Sci Rep. 2019;9:8698.
Chung SD, Lee CZ, Kao LT, Lin HC, Tsai MC, Sheu JJ. Association between neovascular age-related macular degeneration and dementia: a population-based case-control study in Taiwan. PLoS One. 2015;10:e0120003.
Chung SD, Ho JD, Chen CH, Lin HC, Tsai MC, Sheu JJ. Dementia is associated with open-angle glaucoma: a population-based study. Eye. 2015;29:1340–6.
Lai SW, Lin CL, Liao KF. Glaucoma may be a non-memory manifestation of Alzheimer’s disease in older people. Int Psychogeriatr. 2017;29:1535–41.
Keenan TDL, Goldacre R, Goldacre MJ. Associations between age-related macular degeneration, Alzheimer disease, and dementia: record linkage study of hospital admissions. JAMA Ophthalmol. 2014;132:63–8.
Williams MA, Silvestri V, Craig D, Passmore AP, Silvestri G. The prevalence of age-related macular degeneration in Alzheimer’s disease. J Alzheimers Dis. 2014;42:909–14.
Keenan TD, Goldacre R, Goldacre MJ. Associations between primary open angle glaucoma, Alzheimer’s disease and vascular dementia: record linkage study. Br J Ophthalmol. 2015;99:524–7.
Naidu VV, Ismail K, Amiel S, Kohli R, Crosby-Nwaobi R, Sivaprasad S, et al. Associations between retinal markers of microvascular disease and cognitive impairment in newly diagnosed type 2 diabetes mellitus: a case control study. PLoS One. 2016;11:e0147160.
Chandra V, Bharucha NE, Schoenberg BS. Conditions associated with Alzheimer’s disease at death: case-control study. Neurology. 1986;36:209–11.
Smilnak GJ, Deans JR, Doraiswamy PM, Stinnett S, Whitson HE, Lad EM. Comorbidity of age-related macular degeneration with Alzheimer’s disease: a histopathologic case-control study. PLoS One. 2019;14:e0223199.
Michalowsky B, Hoffmann W, Kostev K Association between hearing and vision impairment and risk of dementia: results of a case-control study based on secondary data. Front Aging Neurosci. 2019;11.
Pham TQ, Kifley A, Mitchell P, Wang JJ. Relation of age-related macular degeneration and cognitive impairment in an older population. Gerontology. 2006;52:353–8.
Harrabi H, Kergoat MJ, Rousseau J, Boisjoly H, Schmaltz H, Moghadaszadeh S, et al. Age-related eye disease and cognitive function. Invest Ophthalmol Vis Sci. 2015;56:1217–21.
Yu ZW, Liu R, Li X, Wang Y, Fu YH, Li HY, et al. High serum neuron-specific enolase level is associated with mild cognitive impairment in patients with diabetic retinopathy. Diabetes Metab Syndr Obes. 2020;13:1359–65.
Kessing LV, Lopez AG, Andersen PK, Kessing SV. No increased risk of developing Alzheimer disease in patients with glaucoma. J Glaucoma. 2007;16:47–51.
Bach-Holm D, Kessing SV, Mogensen U, Forman JL, Andersen PK, Kessing LV. Normal tension glaucoma and Alzheimer disease: comorbidity? Acta Opthalmologica. 2012;90:683–5.
Honjo M, Numaga J, Hara T, Asaoka R. The association between structure-function relationships and cognitive impairment in elderly glaucoma patients. Sci Rep. 2017;7:7095.
Raman P, Khy Ching Y, Sivagurunathan PD, Ramli N, Mohd Khalid KH. The association between visual field reliability indices and cognitive impairment in glaucoma patients. J Glaucoma. 2019;28:685–90.
Klaver CC, Ott A, Hofman A, Assink JJ, Breteler MM, de Jong PT. Is age-related maculopathy associated with Alzheimer’s Disease? The Rotterdam Study. Am J Epidemiol. 1999;150:963–8.
Ritland JS, Egge K, Lydersen S, Juul R, Semb SO. Exfoliative glaucoma and primary open-angle glaucoma: associations with death causes and comorbidity. Acta Ophthalmol Scand. 2004;82:401–4.
Ong SY, Cheung CY, Li X, Lamoureux EL, Ikram MK, Ding J, et al. Visual impairment, age-related eye diseases, and cognitive function: the Singapore Malay Eye Study. Arch Ophthalmol. 2012;130:895–900.
Gupta P, Gan ATL, Man REK, Fenwick EK, Sabanayagam C, Mitchell P, et al. Association between diabetic retinopathy and incident cognitive impairment. Br J Ophthalmol. 2019;103:1605–9.
Woo SJ, Park KH, Ahn J, Choe JY, Jeong H, Han JW, et al. Cognitive impairment in age-related macular degeneration and geographic atrophy. Ophthalmology. 2012;119:2094–101.
Moon JY, Kim HJ, Park YH, Park TK, Park EC, Kim CY, et al. Association between open-angle glaucoma and the risks of Alzheimer’s and Parkinson’s Diseases in South Korea: a 10-year nationwide cohort study. Sci Rep. 2018;8:11161.
Choi S, Jahng WJ, Park SM, Jee D. Association of age-related macular degeneration on Alzheimer or Parkinson Disease: a retrospective cohort study. Am J Ophthalmol. 2020;210:41–7.
Lin HC, Chien CW, Hu CC, Ho JD. Comparison of comorbid conditions between open-angle glaucoma patients and a control cohort: a case-control study. Ophthalmology. 2010;117:2088–95.
Lin IC, Wang YH, Wang TJ, Wang IJ, Shen YD, Chi NF, et al. Glaucoma, Alzheimer’s disease, and Parkinson’s disease: an 8-year population-based follow-up study. PLoS One. 2014;9:e108938.
Tsai DC, Chen SJ, Huang CC, Yuan MK, Leu HB. Age-related macular degeneration and risk of degenerative dementia among the elderly in Taiwan a population-based cohort study. Ophthalmology. 2015;122:2327–35.e2.
Su CW, Lin CC, Kao CH, Chen HY. Association between glaucoma and the risk of dementia. Medicine. 2016;95:e2833.
Lai SW, Lin CL, Liao KF. Glaucoma correlates with increased risk of Parkinson’s disease in the elderly: a national-based cohort study in Taiwan. Curr Med Res Opin. 2017;33:1511–6.
Chen YY, Lai YJ, Yen YF, Shen YC, Wang CY, Liang CY, et al. Association between normal tension glaucoma and the risk of Alzheimer’s disease: a nationwide population-based cohort study in Taiwan. BMJ Open. 2018;8:e022987.
Chen H-Y, Lin C-L. Comparison of medical comorbidity between patients with primary angle-closure glaucoma and a control cohort: a population-based study from Taiwan. BMJ Open. 2019;9:e024209.
Kuo FH, Chung JF, Hsu MY, Lee CY, Huang JY, Hsieh MJ, et al. Impact of the severities of glaucoma on the incidence of subsequent dementia: a population-based cohort study. Int J Environ Res Public Health. 2020;17:2426.
Dag E, Ornek N, Ornek K, Gunay F, Turkel Y. Mini mental state exam versus Montreal cognitive assessment in patients with age-related macular degeneration. Eur Rev Med Pharmacol Sci. 2014;18:3025–8.
Seden D, Alime G, Kadir D, Serpil D, Levent T, Ozlem T. Is Alzheimer disease related to age-related macular degeneration? Turkish J Med Sci. 2015;45:1115–21.
Ogurel T, Oğurel R, Özer M, Türkel Y, Dağ E, Örnek K. Mini-mental state exam versus montreal cognitive assessment in patients with diabetic retinopathy. Niger J Clin Pract. 2015;18:786.
Crosby-Nwaobi RR, Sivaprasad S, Amiel S, Forbes A. The relationship between diabetic retinopathy and cognitive impairment. Diabetes Care. 2013;36:3177–86.
Baker ML, Wang JJ, Rogers S, Klein R, Kuller LH, Larsen EK, et al. Early age-related macular degeneration, cognitive function, and dementia: the Cardiovascular Health Study. Arch Ophthalmol. 2009;127:667–73.
Whitson HE, Ansah D, Sanders LL, Whitaker D, Potter GG, Cousins SW, et al. Comorbid cognitive impairment and functional trajectories in low vision rehabilitation for macular disease. Aging Clin Exp Res. 2011;23:343–50.
Ou Y, Grossman DS, Lee PP, Sloan FA. Glaucoma, Alzheimer disease and other dementia: a longitudinal analysis. Ophthalmic Epidemiol. 2012;19:285–92.
Exalto LG, Biessels GJ, Karter AJ, Huang ES, Quesenberry CP Jr., Whitmer RA. Severe diabetic retinal disease and dementia risk in type 2 diabetes. J Alzheimers Dis. 2014;42:S109–17.
Rodill LG, Exalto LG, Gilsanz P, Biessels GJ, Quesenberry CP Jr., Whitmer RA. Diabetic retinopathy and dementia in type 1 diabetes. Alzheimer Dis Assoc Disord. 2018;32:125–30.
Schwaber EJ, Thompson AC, Smilnak G, Stinnett SS, Whitson HE, Lad EM. Co-prevalence of Alzheimer’s disease and age-related macular degeneration established by histopathologic diagnosis. J Alzheimer’s Dis: JAD. 2020;76:207–15.
AIHW 2005. Vision problems among older Australianss. Bulletin no. 27. AIHW cat. No. AUS 60 Canberra: AIHW. Available from: https://www.aihw.gov.au/reports/eye-health/vision-problems-in-older-australians/summary.
AIHW. Dementia in Australia 2022. Available from: https://www.aihw.gov.au/reports/dementia/dementia-in-aus/contents/summary.
Brion M-JA. Essential Epidemiology: an Introduction for students and health professionals. Penny Webb, Chris Bain, Sandy Pirozzo. Cambridge: Cambridge University Press, 2005. £24.99. ISBN 0521546613. Int J Epidemiol. 2006;35:503–4.
Thorpe CT, Thorpe JM, Kind AJH, Bartels CM, Everett CM, Smith MA. Receipt of monitoring of diabetes mellitus in older adults with comorbid dementia. J Am Geriatr Soc. 2012;60:644–51.
Kuźma E, Littlejohns TJ, Khawaja AP, Llewellyn DJ, Ukoumunne OC, Thiem U. Visual impairment, eye diseases, and dementia risk: a systematic review and meta-analysis. J Alzheimers Dis. 2021;83:1073–87.
Rong SS, Lee BY, Kuk AK, Yu XT, Li SS, Li J, et al. Comorbidity of dementia and age-related macular degeneration calls for clinical awareness: a meta-analysis. Br J Ophthalmol. 2019;103:1777–83.
Busse A, Sonntag A, Bischkopf J, Matschinger H, Angermeyer MC. Adaptation of dementia screening for vision-impaired older persons administration of the Mini-Mental State Examination (MMSE). J Clin Epidemiol. 2002;55:909–15.
Wittich W, Phillips N, Nasreddine ZS, Chertkow H. Sensitivity and specificity of the montreal cognitive assessment modified for individuals who are visually impaired. J Visual Impair Blindness. 2010;104:360–8.
Funding
This study was funded and supported by University of New South Wales Ageing Futures Institute seed grants 2020. The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Open Access funding enabled and organized by CAUL and its Member Institutions.
Author information
Authors and Affiliations
Contributions
YX has full access to all the study level data and takes responsibility for the integrity of the data and the accuracy of the data analysis and has responsibility for the decision to submit for publication. Concept and design: YX, LK, CSA, KJA, RP. Acquisition, analysis, or interpretation of data: all authors. Drafting of the manuscript: YX. Critical revision of the manuscript for important intellectual content: all authors. Statistical analysis: YX. Obtained funding: YX, JPhu, LK, CSA, KJA, RP. Supervision: RP. All authors approved the final version and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity the work are appropriately investigated and resolved.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Xu, Y., Phu, J., Aung, H.L. et al. Frequency of coexistent eye diseases and cognitive impairment or dementia: a systematic review and meta-analysis. Eye 37, 3128–3136 (2023). https://doi.org/10.1038/s41433-023-02481-4
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41433-023-02481-4
- Springer Nature Limited
This article is cited by
-
Hallmarks of aging in age-related macular degeneration and age-related neurological disorders: novel insights into common mechanisms and clinical relevance
Eye (2024)
-
Risk of glaucoma to subsequent dementia or cognitive impairment: a systematic review and meta-analysis
Aging Clinical and Experimental Research (2024)
-
Rationale and design of the BeyeOMARKER study: prospective evaluation of blood- and eye-based biomarkers for early detection of Alzheimer’s disease pathology in the eye clinic
Alzheimer's Research & Therapy (2024)