Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Arch Ophthalmol. Author manuscript; available in PMC Dec 13, 2010.
Published in final edited form as:
PMCID: PMC3001290

Early Age-Related Macular Degeneration, Cognitive Function and Dementia: The Cardiovascular Health Study

Michelle L Baker, MD,1 Jie Jin Wang, MMed, PhD,1,2 Sophie Rogers Mepi,1 Ronald Klein, MD, MPH,3 Lewis H Kuller, MD, DrPH,4 Emily K Larsen, MS,5 and Tien Yin Wong, MD, PhD1,6



To describe the association of cognitive function and dementia with early age-related macular degeneration (AMD) in older individuals.


A population-based study of 2,088 persons (1769 whites and 319 blacks) aged 69 to 97 years participating in the Cardiovascular Health Study. 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 (3MSE). Participants were also evaluated for dementia with detailed neuropsychological testing.


After controlling for age, gender, race, and center, persons with low DSST scores (lowest quartile of scores, ≤30) were more likely to have early AMD (odds ratio [OR] 1.38; 95% confidence intervals [CI] 1.03, 1.85) than persons with higher DSST scores. In analyses further controlling for education, systolic blood pressure, total cholesterol, diabetes, smoking status and APOE genotype, this association was stronger (OR 2.00; 95% CI, 1.29, 3.10). There was no association with low 3MSE scores, dementia or Alzheimer’s disease with early AMD.


In this older population, cognitive impairment may share common age-related pathophysiology and risk factors with early AMD.


Age-related macular degeneration (AMD) is the leading cause of visual impairment among elderly persons in industrialized countries.13 AMD and Alzheimer’s disease have long been hypothesized to share a common pathogenesis, based on several lines of evidence. First, both conditions have similar histopathological changes.412 In early AMD, an accumulation of drusen containing extracellular β-amyloid, lipids and other waste products, derived from the degenerating neuro-retina, has been documented. These deposits may lead to subsequent RPE atrophy, photoreceptor malfunction and finally macula death in late AMD.47 In Alzheimer’s 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 which lead to neuronal malfunction and cell death in the later stages of Alzheimer’s disease.812 Second, clinical studies suggest that AMD1316 and Alzheimer’s disease1719 share similar vascular risk factors, such as hypertension and cigarette smoking. Both AMD and Alzheimer’s disease have been linked with 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 apolipoprotein E (APOE) ε4 allele, which is positively associated with Alzheimer’s disease22 but inversely with AMD.23, 24

However, there remains limited clinical or epidemiological studies that have directly examined the association between early AMD and cognitive function or dementia in the general population.2527 The Atherosclerosis Risk in Communities (ARIC) 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 intervals [CI], 1.1, 2.2). However, no association was apparent for the other two cognitive function tests and, due to the relatively young age of the cohort (aged 45 to 64 years), dementia was not investigated. Importantly, 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, dementia and early AMD, while controlling for APOE gene, in an older population. Late AMD was not assessed due to the infrequency of these lesions in the CHS cohort.


Study Population

The Cardiovascular Health Study (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 four counties (Allegheny County, Pennsylvania; Forsyth County, North Carolina; Sacramento County, California; and Washington County, Maryland). Of the 11,955 participants invited, 3,654 of the sampled individuals and 1,547 age-eligible individuals, living in the same household as those sampled were recruited after an extensive home visit. In 1992–1993, an additional 687 blacks were recruited into the study from three sites (Forsyth County, Sacramento County, and Pittsburgh) using race-specific randomized Medicare listings. Differences between those recruited and those not recruited have been presented elsewhere.28 Informed consent was obtained from all 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 from 1989–1993. 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 gradeable retinal photographs have been previously described.30, 31 For this analysis, we additionally excluded 7 individuals for whom cognitive function testing was invalid, 168 individuals taking anti-psychotics or anti-depressants at the 1997–1998 visit and 114 individuals with a history of stroke prior to the 1997–1998 visit, leaving 2088 individuals. Comparison of characteristics between participants included (n=2,088) and excluded (n=2,161) showed that those included were more likely to be younger and female and less likely to be black, have hypertension, coronary heart disease, diabetes, a history of cigarette smoking or an education to the level of high school graduate (data not shown).

Retinal Photography and Grading

Retinal photographs were 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 superimposing a circular grid over the macular area of the retinal photograph and only lesions detected within the grid area were considered for AMD diagnosis. Early AMD was defined as the presence of either soft drusen alone, RPE depigmentation alone, or a combination of soft drusen with increased retinal pigment and/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 epithelium detachment, and/or serous detachment of the sensory retina) or pure geographic atrophy. Intra- and inter-grader reliability for most early AMD signs has been assessed previously with Kappa values that ranged from 0.67 to 0.81 and 0.55 to 0.92, respectively.25 Late AMD was not assessed due 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) annually during the 10 annual clinic visits from 1989–1998. 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.3335 Briefly, the DSST, a subtest of the Wechsler Adult Intelligence Scales,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 covering orientation, concentration, language, praxis and immediate and delayed memory, with a maximum score of 100.37 Low DSST and low 3MSE was 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 subjects’ activities of daily living and a history of normal intellectual function before the onset of cognitive abnormalities.34 Participants were also required to have impairments in two cognitive domains of which memory may have been one. This definition correlates very closely to criteria used in Diagnostic and Statistical Manual of Mental Disorders.39 Individuals who did not meet the dementia criteria, but who were failing cognitively, were classified with mild cognitive impairment.34 Dementia was further classified according to the subtype, and Alzheimer’s disease, using standardized criteria and the MRI.3941

Assessment of Genetic Risk Factors

Genotyping of APOE in the CHS has been previously described.33, 42 The three major allelic forms of the APOE gene (ε2, ε3, and ε4) were determined in the Core Molecular Genetic facility at the University of Vermont College of Medicine by the method of Hixson and Vernier.43 In statistical analysis, we controlled for APOE status based on six common genotypes of APOE.44

Assessment of Vascular Risk Factors

Participants underwent an extensive assessment of atherosclerotic diseases and its risk factors during the course of the study.29 Hypertension was defined as systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg, or the combination of a self-reported high blood pressure diagnosis and use of anti-hypertensive medications. Coronary heart disease was ascertained and classified by an adjudication process involving previous medical history, physical examination and laboratory criteria, including an electrocardiograph.45,46 Past medical history, medication use and cigarette smoking status were ascertained from questionnaires. Anthropometry was assessed by measurement of body mass index (BMI) and waist-hip ratio. Fasting glucose and lipids were assessed, as previously described.47 All variables defined were based on the1997–1998 visit, concurrent with retinal photography and cognitive function assessment, except data on dementia (1998–1999), blood chemistry (1992–1993), waist-hip ratio (1992–1993), BMI (1996–1997) and fasting glucose (1996–1997).

Statistical Methods

Cognitive function and dementia were the exposure variables and AMD was the outcome variable. Differences in characteristics between those with and without AMD at the 1997–1998 visit were assessed, using analysis of variance, Pearson’s chi-squared test, or t-test for unequal variance, as appropriate. Normality was assessed for all relevant variables and appropriate nonparametric methods were applied as necessary. Given the non-normality of the cognitive function scores, their summary statistics were presented as medians (interquartile range) 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 odds ratios [OR], 95% confidence intervals [CI] and p-values (<0.05) for early AMD (versus no AMD) associated with low cognitive function and dementia. In the analyses, we adjusted for age, gender, race and center (Model 1) and for education (completed high school), systolic blood pressure, total cholesterol, diabetes and smoking status (ever smoked) (Model 2) and finally a third model was created which 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, gender, hypertension, and diabetes. All analyses were performed using Intercooled Stata 9.2 for Windows (Stata Corp., College Station, TX).


Of the 2,088 participants, any AMD was present in 351 persons (16.8%); 324 (15.5%) were classified as early and 27 (1.3%) were late AMD. Characteristics between persons with and without AMD are shown in Table 1. Persons with any AMD were significantly older, less likely to be black, and more likely to have a lower triglyceride level, compared to those without AMD. There were no significant differences in other characteristics between the two groups.

Table 1
Characteristics of Individuals with and without Age-related Macular Degeneration (AMD), the 1997–98 Cardiovascular Health Study Examination

Average 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; 8 other) with early AMD had lower median DSST and 3MSE scores than those without AMD, although the difference for DSST was small (median DSST = 41 in those without AMD and 39 in those with early AMD), the trend was statistically significant (p<0.001). Associations were generally similar for specific early AMD lesions between whites and black, although only statistically significant in whites (data not shown).

Table 2
Median Cognitive Function Scores by Early Age-related Macular Degeneration (AMD)

After adjustment for age, gender, race and study center, persons with low DSST score (≤30) were more likely to have early AMD (OR 1.38; 95% CI, 1.03, 1.85) than 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, diabetes 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, persons with low DSST scores, defined using median DSST score ≤40, the findings were similar. A further analysis investigating a 5-point decrease in cognitive function over a 5-year period (measures at the 1993–1993 visit compared to those at the 1997–1998 visit) as a predictor of early AMD in 1997–1998 showed that decline in DSST over time, but not 3MSE, were significantly associated with early AMD (Table 4).

Table 3
Relationship Between Early Age-Related Macular Degeneration (AMD), Low Cognitive Function, Dementia and Alzheimer’s Disease
Table 4
Relationship Between 5-Year Change in Cognitive Function (1992–3 to 1997–98) and Early Age-Related Macular Degeneration (AMD)

Of the 2088 participants, 1672 participants were evaluated for dementia. Of these, 135 were diagnosed with dementia, and 86 participants were classified as pure Alzheimer’s disease. There were no statistically significant associations between dementia or Alzheimer’s disease with early AMD (Table 3). Finally, analyses excluding people with dementia (included n=1156) showed the association of DSST with early AMD persisted (adjusted OR 2.00, 95% CI, 1.29, 3.10, Model 3).


In this population-based study among an older population, we document the cross-sectional association between low cognitive function with early AMD. After controlling for age, gender, race and centre, 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 two 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 non-significance. There was no association between dementia and Alzheimer’s disease, measured by detailed neuropsychological testing in the CHS, and early AMD in this population. There were insufficient numbers to assess the associations with late AMD.

There are few studies that have evaluated the relation of AMD to cognitive impairment25, 26 or dementia27 for comparison with our results. In the ARIC25 population (aged 45 to 64 years, n=9286), where 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 ARIC study found no association between DSST (or Delayed Word Recall) with early AMD. The DSST is a sensitive and reliable48, 49 indicator of neurologic brain damage (although not location of the site of pathology) which 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 likely shared pathophysiology of AMD and possibly neurological diseases with increasing age.

The Blue Mountains Eye Study26 (aged 49 to 97 years, n=3509) 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, gender, 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 non-significant association of low scores on the modified MMSE (3MSE) with early AMD.

In the Rotterdam study27 (aged 75 years and older, n=1438) the presence of late AMD was associated with a 2-year incidence of Alzheimer’s disease (age and gender adjusted relative risk [RR]: 2.1; 95% CI, 1.1, 4.3), although this association was attenuated after adjusting for smoking and atherosclerosis (RR: 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 with early AMD and Alzheimer’s disease. However, we did not have any persons who had both late AMD and dementia or Alzheimer’s disease for analysis.

Strengths of our 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 a number of study limitations. First, selection bias, including survival bias, may have affected our observed associations. For example, among the 707 participants evaluated to have dementia in the CHS, only 145 (21%) of these 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 prior to the CHS Cognition Study, which was one year after retinal photography was performed. Furthermore, retinal photography was performed in only one eye in the CHS, which would likely have led to an under-detection of AMD.25, 50 Second, misclassification may have occurred as visual acuity data were not available. The DSST is vision dependent and the 3MSE contains four visual-spatial sub-tests. 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 than that of 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 even though the words to remember were modified over 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 for low cognitive function (DSST ≤30; 3MSE ≤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) over 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 a deterioration in 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 two 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’s disease with early AMD. Our data, along with others, provide further support that AMD and cognitive impairment may share similar complex pathophysiology and risk factors.


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 contribution from the National Institute of Neurological Disorders and Stroke. A full list of participating CHS investigators and institutions can be found at http://www.chs-nhlbi.org. Additional support was provided by NHBLI grant R21-HL077166, and the National Heart Foundation (TYW). 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. Full access to all the data in the study was available and full responsibility has been taken for the integrity of the data and the accuracy of the data analysis (SR).


Justification for >6 authors: Contributions of authors: study design and conduct (MB, RK, TW); data collection (TW, RK), analysis and interpretation (MB, EL, SR, TW), critical revision (all).


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