Association of Glaucoma and Cataract with Incident Dementia: A 5-Year Follow-Up in the Shanghai Aging Study

INTRODUCTION

According to the Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study 2016, 43.8 million people are living with dementia worldwide [1]. With the acceleration of aging, the number of people living with dementia is estimated to increase to more than 131 million by 2050 [2]. Without the commitment of effective treatment and preventive intervention, dementia is still bringing an enormous burden on the patients, families, and health-care systems around the world. Identification of risk factors and further mechanistic studies are imperative to dementia research.

Glaucoma is a heterogeneous disease characterized by optic nerve head cupping with retinal ganglion cells (RGC) death and visual-field damage [3, 4]. Cataract, featured by the loss of lens transparency, is the leading cause of blindness in low- and middle-income countries [5]. These two ophthalmic diseases are both commonly prevalent in the older population. The prevalence of glaucoma is 3.5% in people aged 40–80 years [3]. For cataracts, the prevalence rate varies from 3.9% in people aged 55–64 years to 92.6% in people aged ≥80 years [5]. There is evidence that patients with Alzheimer’s disease (AD) exhibit optic nerve degeneration and RGC loss and have a significantly increased risk of glaucoma occurrence [6]. It was also reported that more equatorial supranuclear cataracts were found in AD patients than controls [7]. A few population-based studies have investigated the association between glaucoma, cataract, and cognitive decline, but with inconsistent conclusions due to the different study design, sample size, disease definition, and outcome measures [8–18].

The Shanghai Aging Study (SAS) is a longitudinal cohort study with the target population of older adults residing in an urban community [19]. In this study, we intended to verify our hypothesis that glaucoma or cataract or their combination is associated with incident dementia by analyzing the data from the baseline and prospective phase of SAS.

METHODS

RESULTS

Table 1 shows the baseline demographics, lifestyle, and medical histories of 1,659 participants who were successfully followed up for averagely 5.2 years. At baseline, the prevalence rates of glaucoma and cataract were 2.5% and 37.7%, respectively. Compared to participants with glaucoma or cataract, and non-glaucoma and non-cataract, participants with both glaucoma and cataract at baseline were the oldest (mean = 77.0 years), and had the largest proportion of women (75.9%), hypertension (65.5%), diabetes mellitus (20.7%), and depression (27.6%) (p < 0.05). At follow-up, the MMSE scores were 27.1 (SD = 3.7), 26.0 (SD = 4.7), and 25.8 (SD = 4.8) (p < 0.001) in participants with two ophthalmic diseases (glaucoma and cataract), single ophthalmic disease (glaucoma or cataract), and without glaucoma and cataract, respectively. Totally, 168 cases (10.1%) of incident dementia and 124 cases (7.5%) of incident AD were identified. Significant difference of the cumulative incidence of dementia and AD was found among the three groups (Fig. 1).

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Fig.1

Cumulative incidence plots of dementia (A) and AD (B) in participants with non-glaucoma and non-cataract, glaucoma or cataract, and glaucoma and cataract.

As shown in Table 2, the incidence rates of dementia and AD in participants with glaucoma were 3.4 (95% CI 0.9–6.0)/100 person-years and 2.9 (95% CI 0.6–5.3)/100 person-years, respectively. The incidence rates of dementia and AD in participants with cataract were 2.9 (95% CI 2.4–3.5)/100 person-years and 2.1 (95% CI 1.6–2.6)/100 person-years, respectively. Glaucoma was significantly associated with a higher risk of incident dementia (HR = 2.38, 95% CI 1.08–5.23, p = 0.031) and AD (HR = 2.77, 95% CI 1.17–6.56, p = 0.021) after adjusting potential confounders. However, no significant association was found between cataract and incident dementia and AD. Besides, the incidence rates of dementia and AD in participants with both glaucoma and cataract were 4.2 (95% CI 0.8–7.6)/100 person-years and 4.2 (95% CI 0.8–7.6)/100 person-years, respectively. A higher risk for incident dementia (HR = 3.08, 95% CI 1.29–7.37, p = 0.011) and incident AD (HR = 3.72, 95% CI 1.52–9.14, p = 0.004) was found in participants with both two ophthalmic diseases, but not in those with single ophthalmic disease (glaucoma or cataract) in two multivariate models.

DISCUSSION

In this study, we found that participants with glaucoma had a higher risk of all-cause dementia and AD in a 5-year follow-up period after controlling for potential confounders. There was no significant association between cataract and incident dementia/AD. Participants with both glaucoma and cataract were at a higher risk for incident dementia and AD comparing to those without these two ophthalmic diseases. To our knowledge, this is one of a few prospective community-based studies exploring the relationship between ophthalmic disorders and the risk of incident dementia and AD in the non-western population. Consensus diagnoses of dementia and AD were reached by a panel of professionals based on neuropsychological results and detailed clinical data to make the outcome measure more reliable. Furthermore, variables of demographic and lifestyle characteristics and medical histories collected at the baseline can be used to adjust potential confounders in multivariate models.

Several population-based studies were conducted to examine the relationship between ophthalmic disorders and cognitive dysfunction, and the results were inconsistent. Two studies were conducted by the cross-sectional design. In the Beijing Eye Study, comprehensive ophthalmologic examinations were conducted in 3,127 older adults. They found that better cognition function was significantly associated with lower prevalence of primary angle-closure glaucoma (PACG) (β= –0.07) [15]. The Newcastle 85+ Cohort study from UK pointed out that glaucoma was associated with lower standardized MMSE (sMMSE) (odds ratio [OR] = 1.76), but not with MMSE-blind (OR = 1.17), suggesting that the association was driven by poor vision. They also found that treated cataract was related to better cognitive performance in both sMMSE and MMSE-blind [10]. In both studies, cognitive function was measured only based on MMSE scores rather than a clinical diagnosis based on neuropsychological and neurological assessments. Some prospective studies provided the association of ophthalmic disorders with the risk of incident AD and dementia. The Adult Change in Thought (ACT) cohort followed 3,877 participants with total 31,142 person-years. It demonstrated that people with ≤5 years glaucoma diagnosis had an increased risk of AD (HR = 1.46) and all-cause dementia, but not for participants with >5 years diagnosis [14]. However, the association was not found in the cataract diagnosis, which is consistent with our study. Another 3-year study prospectively followed 812 older adults found that participants with open angle glaucoma (OAG) were four times more likely to develop dementia (OR = 3.9). Although they used MMSE and other comprehensive domain-specific neuropsychological tests similar to ours, only suspected participants were assessed by a neurologist [9]. Studies using the Taiwan National Health Insurance Research Database found that the HR of dementia for glaucoma patients was 1.13 [16]; people with POAG had a significantly higher risk of AD (HR = 1.40) [17] and dementia (HR = 1.21) [16]; and people with normal tension glaucoma (NTG) had a higher risk of AD (HR = 1.52) [18]. However, Ou et al. analyzed the Medicare claims data (n = 63,235) and concluded that individuals with OAG had a decreased rate of AD or other dementia, comparing to those without OAG [8]. In addition, Curt Ekström et al. did not find an increased risk of AD in OAG patients during a 30-year follow-up [13]. In summary, previous studies did not obtain the consistent results of POAG/PACG/OAG with an increased risk of dementia/AD. Besides study design, genetic or cultural factors of the target population may also induce the diversity of results from different studies. Evidence of the association between ophthalmic disorders and the risk of incident cognitive impairment in the Chinese population has only been reported in Taiwan. Our study provided a unique opportunity to examine this longitudinal association in older community-dwellings living in mainland China.

Some studies demonstrated that vision impairment is a risk factor of dementia or cognitive impairment [28–34]. The Health ABC Study revealed that visual acuity, contrast sensitivity, and stereo acuity impairments were all associated with more annual score declining of the Modified MMSE for 9 years [28]. Zheng et al. found distant visual acuity was related to a declining MMSE score both cross-sectionally and longitudinally over time [29]. The 3C study concluded that moderate to severe near visual impairment was associated with an increased risk of dementia over 0–2 years (HR = 2.0) and 2–4 years (HR = 1.8), and self-reported distance visual function loss was associated with increased dementia risk beyond 4 years (HR = 1.5) [33]. Although glaucoma and cataract are all sight-threatening ophthalmic diseases, we only found a significant association of glaucoma, not cataract, with incident dementia. Our results provide evidence that vision impairment may not be regarded as a confounding factor for the development of dementia.

Several explanations and potential mechanisms support the association between glaucoma and dementia, especially AD. First, some AD-related pathological proteins were found in glaucoma patients. Yoneda et al. reported that a notable decrease of Aβ₄₂ level and a significant increase of tau level was found in vitreous samples of glaucoma patients [35]. Decreased normal tau protein and significantly increased abnormal hyperphosphorylated tau protein (AT8) were also found in the retina of glaucomatous eyes [36]. Second, the theory about cerebrospinal fluid (CSF) and intra cranial pressure (ICP) was raised to explain the relationship between glaucoma and AD. It was reported that both POAG and NTG patients had lower CSF pressure or ICP [37, 38]. Some AD patients also presented with low CSF pressure [39]. Considering low CSF pressure may lead to an abnormally high trans-lamina cribrosa pressure, which could induce glaucomatous optic nerve damage [37, 41], glaucoma may be a kind of ocular manifestation of AD. Third, a common mechanism based on glymphatic system was proposed recently [42]. Some evidence has shown that AD patients had a deficient clearance of Aβ due to the failure of the glymphatic system. Intriguingly, a similar glymphatic system is also present in the retina [43]. Increasing trans-lamina cribrosa pressure mentioned above may also suppress the glymphatic transport, leading to a deficient clearance of Aβ protein and subsequent glaucoma optic neuropathy [44]. Fourth, Helicobacter pylori (Hp) infection was raised as another hypothesis of the linkage between AD and glaucoma [45]. According to this theory, Hp may influence the pathophysiology of glaucoma and AD by promoting platelet and platelet-leucocyte aggregation [45]. Fifth, genetic studies indicated that OPTINEURIN (OPTN) gene was a contributory gene not only in adult-onset POAG, but also in neurofibrillary tangles and dystrophic neurites in AD [46]. The coding protein ‘optineurin’ may be a new common role involved in both glaucoma and AD. Finally, autophagy may play a crucial role in both AD and glaucoma. Jaeger et al. found that autophagy participated in the transport and metabolism of amyloid-β protein precursor (AβPP). The alteration of autophagy could result in AβPP and Aβ accumulation, which would lead to neuronal cell death [47]. It has also been confirmed that autophagy occurs constitutively in RGC, and an increase of intraocular pressure can disrupt the retinal autophagic mechanism through a low expression of two specific autophagy markers [48].

The controversial evidence had been presented for the association between cataract and AD in recent years [7, 49–51]. Goldstein et al. firstly found that Aβ would accumulate in lenses from AD patients. They also saw equatorial supranuclear cataracts in lenses from 9 AD individuals but not in 8 controls [7]. Moncaster et al. found protein aggregation, amyloid formation when synthetic Aβ was incubated with human lens protein [49]. However, Michael et al. draw the opposite conclusion. They did not find detectable Aβ deposition in the lens of AD patients, and concluded that cortical lens opacities have no relationship with the pathology of AD [50, 51]. From their point of view, cataract could not be a predictor of AD, which is consistent with our population-based result.

The current study has some limitations. We excluded individuals with severe vision impairment at the recruitment according to our exclusion criteria. Therefore, our study may have a selection bias because participants with severe glaucoma and cataract could not be recruited to our study. This selection bias could induce an underestimated intensity of the association of glaucoma and cataract to the risk of dementia. Additionally, we collected the history of ophthalmic diseases based on self-reports with confirmation from the medical records instead of ophthalmological examinations by ophthalmologists. Misdiagnoses of glaucoma/cataract was inevitable because mild symptoms of glaucoma/cataract may not be aware by some participants. Lacking ophthalmic examinations obstructed the classification of glaucoma and cataract subtypes, which may relate to different pathophysiological mechanisms. The self-report information may also induce a quite rough “exposure time” which was used for the time-to-event statistical model. Furthermore, in the statistical models, we have adjusted all the potential confounders collected in our study. However, we still might not exclude the possible influence of uncollected confounders, which could be the unique characteristics of participants with glaucoma or cataract, and could also affect cognitive function. Finally, our findings may not be generalized to other areas in China or other countries, since the participants in our study were all Han Chinese living in an urban community in a well-developed metropolis in China.