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Early Age-Related Macular Degeneration, Cognitive Function, and DementiaThe Cardiovascular Health Study
Michelle L. Baker, MD;
Jie Jin Wang, MMed, PhD;
Sophie Rogers, MEpi;
Ronald Klein, MD, MPH;
Lewis H. Kuller, MD, DrPH;
Emily K. Larsen, MS;
Tien Yin Wong, MD, PhD
Arch Ophthalmol. 2009;127(5):667-673.
ABSTRACT
Objective To describe the association of cognitive function and dementia with early age-related macular degeneration (AMD) in older individuals.
Methods This population-based study included 2088 persons aged 69 to 97 years who participated in the Cardiovascular Health Study. The AMD was assessed from retinal photographs based on a modified Wisconsin AMD grading system. Cognitive function was assessed using the Digit Symbol Substitution Test (DSST) and the Modified Mini-Mental State Examination. Participants were also evaluated for dementia using detailed neuropsychological testing.
Results After controlling for age, sex, race, and study center, persons with low DSST scores (lowest quartile of scores,  30) were more likely to have early AMD (odds ratio, 1.38; 95% confidence interval, 1.03-1.85) than were persons with higher DSST scores. In analyses further controlling for education, systolic blood pressure, total cholesterol level, diabetes mellitus, smoking status, and apolipoprotein E genotype, this association was stronger (odds ratio, 2.00; 95% confidence interval, 1.29-3.10). There was no association of low Modified Mini-Mental State Examination scores, dementia, or Alzheimer disease with early AMD.
Conclusions In this older population, cognitive impairment may share common age-related pathogenesis and risk factors with early AMD.
INTRODUCTION
Age-related macular degeneration (AMD) is the leading cause of visual impairment in elderly persons in industrialized countries.1-3 Alzheimer disease and AMD have long been hypothesized to share a common pathogenesis based on several lines of evidence. First, both conditions have similar histopathologic changes.4-12 In early AMD, an accumulation of drusen containing extracellular β-amyloid, lipid, and other waste products derived from the degenerating neuroretina has been documented. These deposits may lead to subsequent retinal pigment epithelial changes, photoreceptor malfunction, and, finally, macular atrophy in late AMD.4-7 In Alzheimer disease, an accumulation of extracellular β-amyloid, axonal, and dendritic waste products from dystrophic neurons has been documented. These deposits form senile plaques and neurofibrillary tangles in the cortex and hippocampus of the brain that lead to neuronal malfunction and cell death in the later stages of Alzheimer disease.8-12 Second, clinical studies suggest that AMD13-16 and Alzheimer disease17-19 share similar vascular risk factors, such as hypertension and cigarette smoking. Both AMD and Alzheimer disease have been linked to an increased risk of stroke.20-21 Finally, there is evidence of shared genetic loci, although the effect direction conflicts, such as the association of the apolipoprotein E (APOE)  4 allele, which is positively associated with Alzheimer disease22 but has a protective effect with AMD.23-24
However, limited clinical or epidemiologic studies25-27 have directly examined the association between early AMD and cognitive function or dementia in the general population. The Atherosclerosis Risk in Communities study25 previously reported an association between cognitive impairment, defined using the Word Fluency Test, and early AMD signs (adjusted odds ratio [OR], 1.6; 95% confidence interval [CI], 1.1-2.2). However, no association was apparent for the other 2 cognitive function tests, and due to the relatively young age of the cohort (aged 45-64 years), dementia was not investigated. None of the previous studies accounted for the potential confounding effects of the APOE gene.
In view of these uncertainties and the importance of establishing a relationship, if one exists, we examined the association of cognitive function and dementia with early AMD while controlling for the APOE gene in an older population. Late AMD was not assessed owing to the infrequency of these lesions in the Cardiovascular Health Study (CHS) cohort.
METHODS
STUDY POPULATION
The CHS is a population-based prospective study of coronary heart disease and stroke in adults 65 years and older. Participants were recruited from a random sample of Medicare eligibility lists from 4 US counties (Allegheny County, Pennsylvania; Forsyth County, North Carolina; Sacramento County, California; and Washington County, Maryland). Of the 11 955 participants invited, 3654 of the sampled individuals and 1547 age-eligible individuals who lived in the same household as those sampled were recruited after an extensive home visit. In 1992-1993, an additional 687 black individuals were recruited into the study from 3 sites (Forsyth County, Sacramento County, and Pittsburgh) using ethnicity-specific randomized Medicare listings. Differences between those recruited and those not recruited have been presented elsewhere.28 Informed consent was obtained from all the participants at entry into the study and at periodic intervals. Institutional review board approval was obtained at all sites collecting and analyzing data.
The study population, study design, and methods have been described previously.29 In brief, 5888 participants attended the baseline examinations between 1989 and 1993. Of the 4249 individuals who returned in 1997-1998, retinal photographs were either unavailable or could not be graded in 1872 individuals. Differences between participants with and without gradable retinal photographs have been previously described.30-31 For this analysis, we additionally excluded 7 individuals for whom cognitive function testing was invalid, 168 who were taking antipsychotic or antidepressant agents at the 1997-1998 visit, and 114 with a history of stroke before the 1997-1998 visit, which left 2088 individuals. Comparison of characteristics between participants included (n = 2088) and excluded (n = 2161) showed that those included were more likely to be younger and female and were less likely to be black or to have hypertension, coronary heart disease, diabetes mellitus, a history of cigarette smoking, or an education to the level of high school graduate (data not shown).
RETINAL PHOTOGRAPHY AND GRADING
Retinal photography was first offered to participants during the 1997-1998 visit. In brief, the photographs were evaluated for AMD using a modification of the Wisconsin AMD grading system.32 Grading was performed by the superimposition of a circular grid over the macular area of the retinal photograph, and only lesions detected in the grid area were considered for AMD diagnosis. Early AMD was defined as the presence of soft drusen alone, retinal pigment epithelial depigmentation alone, or a combination of soft drusen with increased retinal pigment or depigmentation in the absence of late AMD. Late AMD was defined as the presence of exudative AMD (subretinal hemorrhage, subretinal fibrous scar, retinal pigment epithelial detachment, or serous detachment of the sensory retina) or pure geographic atrophy. Intragrader and intergrader reliability for most early AMD signs has been assessed previously, with  values that ranged from 0.67 to 0.81 and from 0.55 to 0.92, respectively.25 Late AMD was not assessed owing to the infrequency of these lesions.
ASSESSMENT OF COGNITIVE FUNCTION AND DEMENTIA
Participants performed the Digit Symbol Substitution Test (DSST) and the Modified Mini-Mental State Examination (3MSE) during the 10 annual clinic visits between 1989 and 1998. We used the cognitive function data from the 1997-1998 visit concurrent with retinal photography. Assessment of cognitive function and dementia has been described in detail previously.33-35 Briefly, the DSST, a subtest of the Wechsler Adult Intelligence Scale,36 is a measure of psychomotor performance scored as the translation of numbers (1-9) corresponding to novel symbols in 90 seconds, with a maximum score of 93. The 3MSE is a general cognitive battery with components that cover orientation, concentration, language, praxis, and immediate and delayed memory, with a maximum score of 100.37 Low DSST and low 3MSE were defined as the lowest quartile of the distribution of scores (DSST 30; 3MSE 89).33, 37-38 We also used an alternative definition using lower than median scores (DSST 40; 3MSE 94).33
In 1998-1999, 3602 participants were also evaluated for the presence of dementia as part of an ancillary CHS Cognition Study. Dementia was defined as a progressive or static cognitive deficit of sufficient severity to affect the activities of daily living of individuals with a history of normal intellectual function before the onset of cognitive abnormalities.34 Participants were also required to have impairments in 2 cognitive domains, of which memory may have been one. This definition correlates closely to criteria used in the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition).39 Individuals who did not meet the dementia criteria but who were failing cognitively were classified as having mild cognitive impairment.34 Dementia was further classified according to subtype and Alzheimer disease using standardized criteria and magnetic resonance imaging.39-41
ASSESSMENT OF GENETIC RISK FACTORS
Genotyping of APOE in the CHS has been previously described.33, 42 The 3 major allelic forms of the APOE gene (2, 3, and 4) were determined in the Core Molecular Genetics facility at the University of Vermont College of Medicine, Burlington, using the method of Hixson and Vernier.43 In statistical analysis, we controlled for APOE status based on 6 common genotypes of APOE.44
ASSESSMENT OF VASCULAR RISK FACTORS
Participants underwent an extensive assessment of atherosclerotic disease and its risk factors during the study.29 Hypertension was defined as a systolic blood pressure of 140 mm Hg or greater, a diastolic blood pressure of 90 mm Hg or greater, or the combination of a self-reported high blood pressure diagnosis and use of antihypertensive medications. Coronary heart disease was ascertained and classified by means of an adjudication process involving medical history, physical examination, and laboratory criteria, including an electrocardiograph.45-46 Medical history, medication use, and cigarette smoking status were ascertained from questionnaires. Anthropometry was assessed by measurement of body mass index and waist-hip ratio. Fasting glucose and lipid levels were assessed as previously described.47 All variables defined were based on the 1997-1998 visit, concurrent with retinal photography and cognitive function assessment, except for data on dementia (1998-1999), blood chemistry (1992-1993), waist-hip ratio (1992-1993), body mass index (1996-1997), and fasting glucose level (1996-1997).
STATISTICAL ANALYSES
Cognitive function and dementia were the exposure variables, and AMD was the outcome variable. Differences in characteristics between individuals with and without AMD at the 1997-1998 visit were assessed using analysis of variance, the Pearson  2 test, or the t test for unequal variance, as appropriate. Normality was assessed for all relevant variables, and appropriate nonparametric methods were applied as necessary. Given the nonnormality of the cognitive function scores, their summary statistics are presented as medians (interquartile ranges), and any trend in scores across age groups was assessed using the Cuzick nonparametric test for trend. Logistic regression models were constructed to determine the ORs, 95% CIs, and P values (<.05) for early AMD (vs no AMD) associated with low cognitive function and dementia. In the analyses, we adjusted for age, sex, race, and study center (model 1) and for education (completed high school), systolic blood pressure, total cholesterol level, diabetes, and smoking status (ever smoked) (model 2); a third model was created that included the variables in model 2 and APOE (model 3). Persons with dementia were excluded from the low cognitive function analysis. Cross-product terms were constructed to examine for possible interactions between age, race, sex, hypertension, and diabetes. All analyses were performed using Intercooled Stata 9.2 for Windows (Stata Corp, College Station, Texas).
RESULTS
Of the 2088 participants, any AMD was present in 351 (16.8%): 324 (15.5%) were classified as having early AMD and 27 (1.3%) as having late AMD. Characteristics of persons with and without AMD are given in Table 1. Persons with any AMD were significantly older, were less likely to be black, and were more likely to have a lower triglyceride level compared with those without AMD. There were no significant differences in other characteristics between the 2 groups.
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Table 1. Characteristics of Individuals With and Without Age-Related Macular Degeneration (AMD), the 1997-1998 Cardiovascular Health Study Examination
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Mean DSST and 3MSE scores decreased with age in persons with and without early AMD (data not shown). Table 2 shows that participants (1760 white, 320 black, and 8 other) with early AMD had lower median DSST and 3MSE scores than did those without AMD; although the difference for the DSST was small (median score of 41 in those without AMD and 39 in those with early AMD), the trend was significant (P < .001). Associations were generally similar for specific early AMD lesions between white and black participants, although they were statistically significant only in whites (data not shown).
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Table 2. Cognitive Function Scores by Early Age-Related Macular Degeneration (AMD)
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After adjustment for age, sex, ethnicity, and study center, persons with low DSST scores (30) were more likely to have early AMD (OR, 1.38; 95% CI, 1.03-1.85) than were those with higher scores (Table 3, model 1). This association remained significant after adjustment for the variables in model 1 plus education (completed high school), systolic blood pressure, total cholesterol level, diabetes mellitus, and smoking status (Table 3, model 2) and the APOE genotype (Table 3, model 3). Persons with low 3MSE scores (89) were also more likely to have early AMD (OR, 1.21, 95% CI, 0.91-1.62), although this association was not statistically significant (Table 3). Using alternative definitions, in persons with low DSST scores defined using a median DSST score of 40 or less, the findings were similar. A further analysis investigating a 5-point decrease in cognitive function in a 5-year period (measures at the 1992-1993 visit compared with those at the 1997-1998 visit) as a predictor of early AMD in 1997-1998 showed that declines in DSST scores across time, but not in 3MSE scores, were significantly associated with early AMD (Table 4).
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Table 3. Relationships Among Early Age-Related Macular Degeneration (AMD), Low Cognitive Function, Dementia, and Alzheimer Disease
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Table 4. Relationship Between 5-Year Change in Cognitive Function (1992-1993 to 1997-1998) and Early Age-Related Macular Degeneration (AMD)
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Of the 2088 participants, 1672 were evaluated for dementia. Of these, 135 were diagnosed as having dementia, and 86 were classified as having pure Alzheimer disease. There were no statistically significant associations of dementia or Alzheimer disease with early AMD (Table 3). Finally, analyses excluding people with dementia (included n = 1156) showed that the association of DSST score with early AMD persisted (adjusted OR, 2.00; 95% CI, 1.29-3.10; model 3).
COMMENT
In this population-based study in an older population, we document the cross-sectional association between low cognitive function and early AMD. After controlling for age, sex, ethnicity, and study center, persons with low DSST scores were more likely to have early AMD. These associations were largely unchanged after further adjustment for education, vascular risk factors, and APOE status. Participants with cognitive test scores in the lowest quartile of the DSST were 2 times more likely to have early AMD signs. While controlling for the same risk factors, a similar pattern of association was seen for 3MSE scores, although these associations were of borderline nonsignificance. There was no association between dementia and Alzheimer disease, measured by means of detailed neuropsychological testing in the CHS, and early AMD in this population. There were insufficient numbers to assess the associations with late AMD.
Few studies have evaluated the relationship of AMD to cognitive impairment25-26 or dementia27 for comparison with the present results. In the Atherosclerosis Risk in Communities25 population (aged 45-64 years, n = 9286), in which an identical protocol to assess AMD signs was used, an association between cognitive impairment, defined as Word Fluency Test scores in the lowest 10% of the population, with early AMD was reported. However, the Atherosclerosis Risk in Communities study found no association between DSST (or Delayed Word Recall) scores and early AMD. The DSST is a sensitive and reliable48-49 indicator of neurologic brain damage (although not the location of the abnormality) that is relatively independent of intellectual ability, memory, or learning.36 The association with early AMD and low DSST scores found only in the older CHS population suggests a likely shared pathogenesis of AMD and possibly neurologic diseases with increasing age.
The Blue Mountains Eye Study26 (3509 participants aged 49-97 years) found an association between cognitive impairment (defined as a Mini-Mental State Examination [MMSE] score <24) and late AMD (OR, 3.7; 95% CI, 1.3-10.6). This association persisted after modifying the MMSE to exclude vision-related items and while adjusting for age, sex, visual impairment, education, and vascular risk factors (OR, 2.2; 95% CI, 1.0-5.0). However, no association was observed between MMSE and early AMD in the Blue Mountains Eye Study. We found a borderline nonsignificant association between low scores on the 3MSE and early AMD.
In the Rotterdam study27 (1438 participants aged  75 years), the presence of late AMD was associated with a 2-year incidence of Alzheimer disease (age- and sex-adjusted relative risk, 2.1; 95% CI, 1.1-4.3), although this association was attenuated after adjusting for smoking and atherosclerosis (relative risk, 1.5; 95% CI, 0.6-3.5). For early AMD, no association was observed in this study. Consistent with this study, we did not find any association between early AMD and Alzheimer disease. However, we did not have any persons who had both late AMD and dementia or Alzheimer disease for analysis.
The strengths of this study include its large, ethnically diverse, population-based sample; use of standardized and validated methods in assessing cognitive function and AMD; and adjustment for confounders and APOE status. There are several study limitations. First, selection bias, including survival bias, may have affected the observed associations. For example, of the 707 participants evaluated as having dementia in the CHS, only 145 (20.5%) had a gradable retinal photograph and could be assessed for AMD. Moderate to severe dementia generally hampers the performance of clinical investigations such as retinal photography. If persons with AMD were more likely excluded, observed associations would be falsely attenuated, and the results would tend to be biased toward the null. In addition, individuals with AMD and dementia may have died before the CHS Cognition Study, which was 1 year after retinal photography was performed. Furthermore, retinal photography was performed in only 1 eye in the CHS, a factor that would likely have led to an underdetection of AMD.25, 50 Second, misclassification may have occurred because visual acuity data were not available. The DSST is vision dependent, and the 3MSE contains 4 visuospatial subtests. Participants who could not optimally perform the cognitive function tests might have had visual impairment. This may explain the stronger prospective association of AMD with low DSST scores vs AMD with 3MSE scores, as participants with AMD may have had more difficultly completing the DSST, although vision may not be affected substantially in persons with early AMD. Moreover, the 3MSE was conducted annually, although the words to remember were modified across time. No relationship between AMD and dementia could be explained by the fact that the CHS Cognition Study adjudication committee took into consideration the effects of poor visual acuity in the participants' cognitive performance. Third, the definitions of low cognitive function (DSST score 30; 3MSE score 89)33, 37-38 may not necessarily be interpreted clinically as overt cognitive dysfunction. However, in the CHS Cognition Study, slightly lower scores on the 3MSE (especially <90) in a short period (1992-1993, 1998-1999) were a predictor of dementia.51 Finally, this study was cross-sectional. Without temporal information, it is impossible to ascertain whether deterioration of cognitive function occurred before or after AMD.
In conclusion, we found an association between low cognitive function and early AMD in this older population. Persons with cognitive test scores in the lowest quartile on the DSST scale were 2 times more likely to have early AMD signs, independent of vascular risk factors and APOE status. We did not find an association of dementia and Alzheimer disease with early AMD. These data, along with others, provide further support that AMD and cognitive impairment may share similar complex pathogenesis and risk factors.
AUTHOR INFORMATION
Correspondence: Tien Yin Wong, MD, PhD, Centre for Eye Research Australia, University of Melbourne, 32 Gisborne St, East Melbourne, Victoria 3002 Australia (twong{at}unimelb.edu.au).
Submitted for Publication: February 27, 2008; final revision received September 24, 2008; accepted September 28, 2008.
Author Contributions: Ms Rogers had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Financial Disclosure: None reported.
Funding/Support: The research reported in this article was supported by contracts N01-HC-35129, N01-HC-45133, N01-HC-75150, N01-HC-85079 through N01-HC-85086, N01 HC-15103, N01 HC-55222, and U01 HL080295 from the National Heart, Lung, and Blood Institute, with additional contributions from the National Institute of Neurological Disorders and Stroke. Additional support was provided by grant R21-HL077166 from the National Heart, Lung, and Blood Institute and by the National Heart Foundation (Dr Wong).
Role of the Sponsors: The funders did not have any input in the design and conduct of the study; the collection, analysis, and interpretation of the data; or the preparation of the manuscript.
A full list of participating CHS investigators and institutions can be found at http://www.chs-nhlbi.org.
Author Affiliations: Centre for Eye Research Australia, University of Melbourne, Victoria (Drs Baker, Wang, and Wong and Ms Rogers); Centre for Vision Research, University of Sydney, Sydney, New South Wales, Australia (Dr Wang); Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison (Dr Klein); Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania (Dr Kuller); Department of Biostatistics, University of Washington, Seattle (Ms Larsen); and Singapore Eye Research Institute, Yong Loo Lin School of Medicine, National University of Singapore (Dr Wong).
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