Age-Related Eye Diseases in Individuals With Mild Cognitive Impairment and Alzheimer's Disease

Introduction: Alzheimer's disease (AD) and age-related eye diseases pose an increasing burden as the world's population ages. However, there is limited understanding on the association of AD/cognitive impairment, no dementia (CIND) with age-related eye diseases.

Methods: In this cross-sectional, memory clinic-based study of multiethnic Asians aged 50 and above, participants were diagnosed as AD (n = 216), cognitive impairment, no dementia (CIND) (n = 252), and no cognitive impairment (NCI) (n = 124) according to internationally accepted criteria. Retinal photographs were graded for the presence of age-related macular degeneration (AMD) and diabetic retinopathy (DR) using standard grading systems. Multivariable-adjusted logistic regression models were used to determine the associations between neurological diagnosis and odds of having eye diseases.

Results: Over half of the adults had at least one eye disease, with AMD being the most common (60.1%; n = 356), followed by DR (8.4%; n = 50). After controlling for age, sex, race, educational level, and marital status, persons with AD were more likely to have moderate DR or worse (OR = 2.95, 95% CI = 1.15–7.60) compared with NCI. In the fully adjusted model, the neurological diagnosis was not associated with AMD (OR = 0.75, 95% CI = 0.45–1.24).

Conclusion: Patients with AD have an increased odds of having moderate DR or worse, which suggests that these vulnerable individuals may benefit from specific social support and screening for eye diseases.

Introduction

The proportion of older individuals is rising rapidly, particularly in developed countries. Globally, ~2.1 billion people are estimated to be aged 60 and older in 2050 (United Nations Department of Economic Social Affairs Population Division, 2017). Aging causes a variety of changes to the brain and eye, making an older person more prone to Alzheimer's disease (AD) and visual impairment. Both AD (Wood et al., 2016) and eye diseases (Knudtson et al., 2005) decrease quality of life and worsen active aging. The major age-related eye diseases, including age-related macular degeneration (AMD) and diabetic retinopathy (DR), are the leading causes of visual impairment and blindness worldwide (Flaxman et al., 2017). In the light of the rising incidence of both AD (GBD 2016 Dementia Collaborators, 2019, 2021) and age-related eye diseases (Tham et al., 2014; Wong et al., 2014; Teo et al., 2021), knowledge on the pattern of age-related eye diseases in individuals with AD and cognitive impairment, no dementia (CIND) (Jacova et al., 2008) is critical and useful in the context of screening, early detection, and management of such ophthalmic conditions in cognitively impaired individuals.

In recent years, several studies have investigated the influence of neurological diagnosis on AMD but with inconclusive results (Baker et al., 2009; Keenan et al., 2014; Nolan et al., 2014; Williams et al., 2014; Frost et al., 2016). While Frost et al. found an increased prevalence of early AMD in patients with AD compared to cognitively normal controls (Frost et al., 2016), other researchers reported no association between AD and AMD after adjusting for potential confounders (Baker et al., 2009; Nolan et al., 2014; Williams et al., 2014). Contrary to previous studies which were cross-sectional in study design, a longitudinal study by Keenan et al. (2014) found that dementia and AD were associated with decreased incidence of AMD. However, their study was derived from patients seeking tertiary eye care services, which may represent the more severe spectrum of the disease, admission to hospital for AMD treatments, i.e., intravitreal antivascular endothelial growth factor (VEGF) therapy. Overall, past studies focused overwhelmingly on western populations, reflecting a paucity of data on other races/ethnicities. While several studies have examined the impact of having DR on cognitive impairment (Cheng et al., 2021), no studies have examined the impact of having cognitive impairment on DR. Finally, very limited data are available on the impact of CIND on eye diseases, a condition with established risk of progression to AD and other forms of dementia (Petersen, 2016).

In this study, we examined the associations of neurological diagnosis with age-related eye diseases, namely, AMD and DR, in an Asian setting. We hypothesized that prevalence of eye diseases will be higher in persons with cognitive impairment than NCI.

Materials and Methods

Study Participants

We conducted a memory-clinic-based cross-sectional study, approved by the National Healthcare Group Domain-Specific Review Board (protocol number R1500/83/2017), and conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all the participants or their caregivers prior to the recruitment for this study. Individuals aged 50 and older were recruited from the National University Hospital of Singapore and St Luke's Hospital from September 2009 to September 2020, as described previously (Chua et al., 2020). Subjects with no cognitive impairment (NCI) were recruited from both memory clinics and the community. The etiological diagnoses of dementia were based on internationally accepted criteria: Alzheimer's disease (AD) was diagnosed using the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) (McKhann et al., 2011); vascular dementia (VaD) was defined using the National Institute of Neurological Disorders and Stroke and Association Internationale pour la Recherché et l'Enseignement en Neurosciences (NINDS-AIREN) criteria (Román et al., 1993). Cognitive impairment with no dementia (CIND) was determined based on the objective impairment in at least one domain of the neuropsychological assessment but did not meet the DSM-IV criteria for dementia. Mild cognitive impairment (MCI) was defined using the clinical dementia rating (CDR) scale, where scoring 0.5 on the CDR among participants with CIND will fulfill the criteria of subjective cognitive complaints (Morris, 2012). Specifically, to score 0.5 on the CDR, the participant has responded “yes” to the question “Have you had any problem with your thinking or memory?” or a caregiver has responded “yes” to the question “Does he/she have a problem with his/her memory or thinking?” Thinking problems included complaints related to executive dysfunction (e.g., poor organization, distractible, and difficulty with problem-solving) and visuospatial impairment (e.g., does not recognize familiar landmarks). Participants were classified as NCI if they had no objective impairment in any of the seven domains of the neuropsychological assessment.

Participants were excluded from this study if they had clinically relevant conditions that would significantly impede cognitive assessment and self-reported diagnosis of glaucoma due to the impending risks of acute angle-closure glaucoma with mydriatic eyedrops. All participants underwent detailed clinical and neuropsychological assessments (Gyanwali et al., 2019). Trained research psychologists administered brief cognitive tests: the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) and a formal detailed neuropsychological test battery that has been locally validated in Singapore (Hilal et al., 2021).

Demographics and Vascular Risk Factors

Information on participants' demographic, socioeconomic characteristics (e.g., age, sex, education, marital status [married, single, divorced, and widowed] (Zheng et al., 2014), and living situation [living with partner/spouse, living with children/relative/friend, living alone and other forms of arrangement]), smoking, and medical history (e.g., hyperlipidemia, hypertension, and diabetes) was collected using a standardized questionnaire and subsequently verified by medical records. Education was recorded as the highest number of years of schooling completed and was categorized into 2 groups: (1) Primary or lower (≤ 6 years, equivalent to elementary education) and (2) secondary or higher (≥7 years, equivalent to high school or college, including university education). Height was measured in centimeters using a wall-mounted measuring tape and weight in kilograms using a digital scale. Body mass index (BMI), is calculated as body weight (in kilograms) divided by body height (in meters) squared. Seated blood pressure measurements were taken using an automated oscillometric device during their clinical visits.

Definition of Eye Diseases

Ocular assessments were performed within 1 month of the cognitive assessments. Digital retinal photographs were taken using a nonmydriatic camera (Canon CR-1 Mark II, Canon, Ota, Tokyo, Japan), after pupil dilation using tropicamide 1%. For each patient, two retinal photographs (optic disc and fovea) were taken of each eye. One trained grader masked to the participant's characteristics assessed the fundus photographs for the presence of age-related macular degeneration (AMD) and diabetic retinopathy (DR) (Figure 1) (Wilkinson et al., 2003; Davis et al., 2005). If more than one-quarter of the photograph was obscured, it was considered ungradable. AMD was defined according to the Age-Related Eye Disease Study grading system, where early AMD was defined as drusen outside 2-disc diameters (2DD) of the macula center or drusen within 2DD but ≤125 μm in greatest linear diameter, intermediate AMD as numerous medium-sized drusen, 1 large drusen >125 μm in greatest linear diameter, non-central geographical atrophy, and advanced AMD as central geographical atrophy or neovascular AMD (Davis et al., 2005). Diabetic retinopathy was defined as a severity level of moderate non-proliferative diabetic retinopathy (NPDR) or worse, and/or diabetic macular edema (defined as the presence of hard exudates, microaneurysms, and hemorrhages at the posterior pole of the retinal images) using the International Classification Diabetic Retinopathy Scale (Wilkinson et al., 2003). We further categorized other types of retinal pathologies, i.e., macular hole, retinal vascular occlusives, etc.

FIGURE 1

Figure 1. (Left panel) Color fundus photograph of the left eye without any eye diseases. (Middle panel) Color fundus photograph of the left eye with signs of intermediate age-related macular degeneration (AMD). Notably, features include large soft drusen at the macular region (white arrows), (Right panel) Color fundus photograph of the right eye with signs of severe non-proliferative diabetic retinopathy (DR). Notably, features include microaneurysms and hemorrhages (yellow arrows).

Statistical Analyses

The primary outcome of the study was eye disease. The Shapiro–Wilk test was used to assess the normality of the distribution of the continuous variables. To compare the characteristics of participants among groups, independent t-test or one-way analysis of variance (ANOVA) was performed for continuous variables, and chi-square or Fisher's exact tests were performed for categorical variables. Age-, sex-, and ethnicity-adjusted and multivariable-adjusted logistic regression models were used to determine the odds ratios (ORs) and 95% confidence intervals (CIs) for associations between neurological diagnosis (exposure) and age-related eye diseases (outcome). The potential confounders we considered were age, sex, ethnicity, education attainment, marital status, living situation, hypertension, and systolic blood pressure. Statistically significant confounders were determined using manual backward elimination procedures with a criterion of p < 0.10 for elimination. A p < 0.05 was considered statistically significant. Statistical analyses were performed using SPSS Statistics version 26 (IBM) and STATA, version 16; StataCorp LP.

Results

A total of 656 participants were recruited between September 2009 to September 2020, 592 (90.2%) of whom had gradable fundus photographs. A comparison of characteristics between persons with and without gradable fundus photographs is shown in Supplementary Table 1. Persons who had ungradable photographs were more likely to be older and have AD and diabetes (p ≤ 0.034). A total of 124 NCI participants, 252 CIND participants, and 216 AD participants with gradable fundus images were available for analysis.

Table 1 presents the characteristics of the participants with gradable fundus photographs by their neurological diagnosis. The mean ± standard deviation (SD) of age was 68.3 ± 7.7 years for NCI, 72.8 ± 7.7 years for CIND, and 74.7 ± 7.4 years for AD. AD participants were likely to be older and of Malay ethnicity, had lower educational level, more likely to be divorced and widowed, more likely to be living with children, relatives, or friends, higher prevalence of hypertension and diabetes, and higher systolic blood pressure (p ≤ 0.007). There was no significant difference in sex, smoking status, hyperlipidemia, BMI, and diastolic blood pressure among the groups.

TABLE 1

Table 1. Characteristics of participants stratified by neurological diagnosis.

Of the 592 participants with gradable photographs, 396 (66.9%) had at least one eye disease, with AMD being the most common (60.1%; n = 356), followed by DR (8.4%; n = 50). Table 2 shows the associations of neurological diagnosis with any eye diseases, AMD, and DR. Only AD participants were more likely to have higher odds of having DR (OR = 2.95, 95% CI = 1.15–7.60) in the multivariable model. However, this association was no longer significant after further adjusting for the presence of diabetes (OR = 1.83, 95% CI = 0.66–5.04). We next analyzed the association of DR in AD in persons with vascular dementia and report a stronger association between DR and AD (OR = 5.22, 95%CI = 1.74–15.67; Table 2). Neurological diagnosis was not significantly associated with an increased odds of having any AMD (OR = 0.75, 95%CI = 0.45–1.24; Table 2). Figure 2 further demonstrates that the presence of AMD was similar across the neurological groups whereas DR status was significantly higher in AD participants. We performed a separate analysis and report that both CIND without MCI (OR = 1.07, 95% CI = 0.29–3.97) and CIND with MCI (OR = 0.99, 95% CI = 0.35–2.82) were not independently associated with having DR (Supplementary Table 2). We also performed a subgroup analysis and report that both CIND and AD were not independently associated with either early AMD (OR = 0.83, 95% CI = 0.44–1.58) or intermediate AMD or worse (OR = 0.68, 95% CI = 0.38–1.22; Supplementary Table 3).

TABLE 2

Table 2. Association between neurological diagnosis and eye diseases.

FIGURE 2

Figure 2. Types of eye diseases by neurological diagnosis. Diabetic retinopathy (DR) status was significantly higher in patients with Alzheimer's disease whereas the presence of age-related macular degeneration (AMD) was similar across the neurological groups.

Discussion

In a multiethnic Asian population, our data showed that the odds are three times higher that an patient with AD will get moderate DR or worse compared to a participant with NCI whereas neurological diagnosis was not associated with AMD, after controlling for age, sex, race, educational level, and marital status. There is less available data comparing the odds of DR between cognitive groups. Further statistical adjustment for the presence of diabetes demonstrates that the association between DR and AD is due to higher numbers of diabetic individuals in the AD cohort compared with the CIND and NCI cohorts. A meta-analysis pooled a total of 17 studies involving 1,746,777 individuals reported that participants with diabetes had significant higher incidence of AD than those without diabetes (Zhang et al., 2017).

To our knowledge, this is the first study investigating the risk of DR in subjects with clinically diagnosed CIND or AD (Table 3). Previous studies investigating the association between DR and cognitive function all focused on DR as the independent factor, i.e., as a potential marker for present or incident CIND/AD. To this end, they found that patients with DR had increased prevalence (Ong et al., 2012; Liao et al., 2017) and incidence (Gupta et al., 2019) of CIND, as well as increased incidence of AD (Chen et al., 2016; Lee et al., 2019; Pedersen et al., 2022). A recent systematic review and meta-analysis support these results by concluding that having moderate DR or worse was strongly associated with cognitive impairment (Cheng et al., 2021). Considered in tandem with the findings of our study, this suggests that the association between DR and cognitive impairment may be bidirectional. Although there is consistent evidence of shared risk factors between retinal and cerebral neurodegeneration (Jindal, 2015; Ong et al., 2015), including microvasculature-specific associations (Chua et al., 2020), the contribution of AD in the pathogenesis of DR has not been elucidated. In particular, it has been suggested that vascular lesions in eyes with DR may mirror similar pathological processes in the cerebral microcirculation (Cheung and Wong, 2008). Our finding of increased odds of DR in vascular dementia supports this proposition. Future longitudinal studies will need to be performed to determine the risk of DR in pre-diabetic AD and CIND cases.

TABLE 3

Table 3. Summary of studies investigating the association between Alzheimer's disease (AD) and eye diseases.

There is currently no published guideline on the prevalence, management, and outcomes of DR in patients with AD, although there is a national diabetic retinal photograph screening for individuals with diabetes in Singapore (Goh et al., 2014). The reasons underpinning higher odds of DR in patients with AD are multifactorial. Apart from the higher prevalence of diabetes as pointed out earlier, individuals with AD may be less likely to attend annual DR screening program since they might be more reliant on caregivers to attend primary eyecare appointments and less likely to notice or report visual symptoms. Previous research reported that a high proportion of individuals with dementia are living with undiagnosed age-related eye diseases (Wong et al., 2015). A persistent lack of referral of moderate DR or worse can lead to worsening of retinopathy, visual impairment, or blindness, whereas timely delivery of sight-saving treatments can decrease the risk of blindness (Ting et al., 2017).

The finding that AD was not associated with AMD is in concordance with most studies on older White populations (Table 3) (Baker et al., 2009; Nolan et al., 2014; Williams et al., 2014). While an Australian study found increased prevalence of early AMD in subjects with AD (Frost et al., 2016), they did not find a significant association of AD diagnosis with intermediate and advanced AMD. It most likely indicates that AMD is associated with higher risks of cognitive dysfunction or AD, as consistently demonstrated in cross-sectional (Wong et al., 2002; Seden et al., 2015) and cohort (Klaver et al., 1999; Tsai et al., 2015; Chen et al., 2016; Lee et al., 2019; Choi et al., 2020) studies, but not vice versa. Another potential reason for the lack of association may have been consequent to the limited sample size and thus the lack of power in statistical analysis; to date, the odds of AMD in persons CIND or AD have not been investigated in a large-scale cohort study.

Notably, high prevalence of AMD (59.3%) was observed in adults aged 50 and older in this study. A previous population-based cross-sectional study of a multiethnic Asian cohort residing in Singapore found the prevalence of AMD (early and late AMD combined) in persons aged 80 and above to be 26.3% (Cheung et al., 2014). This difference may be accounted for partly by the different grading criteria used. The aforementioned population-based study used the modification Wisconsin Age-Related Maculopathy Grading System, which defines AMD as either soft indistinct or reticular drusen or both soft, distinct drusen plus retinal pigment epithelium abnormalities which is stricter than our study. Moreover, the AMD prevalence in our study of 59.3% is comparable to the 41.5% reported by Williams et al. (2014), similarly a clinic-based study in which disease prevalence would tend to be higher than population-based studies.

Clinical Implications

Older people with AD are “vulnerable patients.” General physicians should highlight the importance of having regular diabetic eye screening to the patients and their caregivers. If this vulnerable group of people is not accessing screening appointments, this could lead to irreversible loss of vision (Cheung et al., 2010). Also, there is the question of what happens to patients with AD who have unsuccessful screening, either because of difficulties with retinal photography or because of a positive screen. In this study, we found that AD persons were more likely to have ungradable retinal photographs than their counterparts. Future studies need to evaluate the prevalence, management, and outcomes of DR screening services in AD individuals.

Strengths and Limitations

Strengths of this study include the use of internationally recognized criteria for the clinical assessment of neurological status, objective grading of age-related eye diseases using fundus photographs, and the standardized assessment of other systemic and ocular factors. This study also has limitations. First, although the observed associations were statistically significant, the CIs were quite wide. Therefore, the clinical application of our findings needs to be further validated in future studies. Second, the cross-sectional nature of this study limits causal inferences. Further robust longitudinal studies are required to investigate this association. Third, although our study population comprises Asians, the cultural, health, and living conditions in Singapore are different from other Asian countries. Thus, our findings may not be entirely inferred to other Asian countries with the same ethnicity group. Moreover, as most study subjects were Chinese, we were not able to determine whether similar findings are seen in the Singaporean Malays or Indians. Fourth, we did not assess the association of neurological diagnosis on having glaucoma which is one of the common age-related eye diseases. Patients with glaucoma were excluded from the study as the use of pharmacological dilation drops may induce an episode of angle-closure glaucoma in susceptible elderly individuals. Furthermore, we recruited study participants from specialized memory disorder clinics and not from the population which may be subjected to bias and not as generalizable. Finally, in our study, AD individuals tended to have ungradable photographs as compared to CIND or NCI individuals, and this might have resulted in potential underestimation of the observed effects of neurological diagnosis on eye disease prevalence.

Conclusion

This cross-sectional study of older adults from a multiethnic Asian population demonstrated that having AD was associated with DR, for which there was limited prior data. These data suggest that AD with diabetes should be followed up more actively by their physicians, with interventions as appropriate, to prevent visual impairments. Potential barriers to care for these vulnerable individuals need to be investigated and addressed in future studies.

Data Availability Statement

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Ethics Statement

The studies involving human participants were reviewed and approved by National Healthcare Group Domain-Specific Review Board protocol number R1500/83/2017. The patients/participants provided their written informed consent to participate in this study.

Author Contributions

JC, ZZ, CChen, and LS conceived and designed the study. JC, ZZ, DW, BiT, BK, CS, SH, NV, BoT, CCheu, GG, AP-C, TW, CChen, and LS analyzed and interpreted the data. JC, ZZ, and LS wrote the main manuscript text. All authors reviewed the manuscript.

Funding

This study was supported by the National Medical Research Council (CG/C010A/2017_SERI, OFIRG/0048/2017, OFLCG/004c/2018, TA/MOH-000249-00/2018, MOH-OFIRG20nov-0014, and NMRC/CG2/004b/2022-SERI), National Research Foundation Singapore (NRF2019-THE002-0006 and NRF-CRP24-2020-0001), A^*STAR (A20H4b0141), the Singapore Eye Research Institute and Nanyang Technological University [SERI-NTU Advanced Ocular Engineering (STANCE) Program], the Duke-NUS Medical School [Duke-NUS-KP(Coll)/2018/0009A], and the SERI-Lee Foundation (LF1019-1) Singapore. The sponsor or funding organization had no role in the design or conduct of this research.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary Material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fnagi.2022.933853/full#supplementary-material

Abbreviations

2DD, 2-disc diameters; 3MSE, Modified Mini-Mental State Examination; AD, Alzheimer's disease; AMD, age-related macular degeneration; ANOVA, one-way analysis of variance; BMI, body mass index; CI, confidence interval; CIND, cognitive impairment no dementia; DR, diabetic retinopathy; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders; DSST, Digit Symbol Substitution Test; ETDRS, Early Treatment Diabetic Retinopathy Study; MCI, mild cognitive impairment; MMSE, Mini-Mental State Examination; MoCA, Montreal Cognitive Assessment; NCI, no cognitive impairment; NINCDS-ADRDA, National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association; NPDR, non-proliferative diabetic retinopathy; OR, odds ratio; SD, standard deviation; VaD, vascular dementia; VEGF, vascular endothelial growth factor.

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