The Landmark Beaver Dam Eye Study Ushered in Modern Epidemiologic Research in Age-Related Macular Degeneration

The landmark Beaver Dam Eye Study (BDES) of 5000 participants 43 years of age or older residing in Beaver Dam, Wisconsin, provided seminal information on age-related macular degeneration (AMD).¹ The chief architects, Barbara and Ron Klein, had the foresight to initiate this population-based study that included comprehensive eye examinations and centrally graded fundus photographs (see page S122). The BDES began in 1987, when AMD research focused mainly on the treatment of the neovascular form of the disease. In fact, the first clinical trial, the Macular Photocoagulation Study was called a study of “senile” macular degeneration, and the BDES investigators labelled it “age-related maculopathy.”² The objectionable modifier of “senile” was soon replaced by the current name, age-related macular degeneration. With the BDES, the modem era of epidemiologic studies of AMD and its natural history began. The data from this landmark study provided us with the basic information for the subsequent studies in AMD, including the Age-Related Eye Disease Study (AREDS) and AREDS 2.

The purpose of the BDES was to collect information on the prevalence, incidence, and potential causes or risk factors associated with AMD. The BDES demonstrated the association of increased AMD prevalence rates with age. By 75 years of age, the prevalence of large drusen (125 μm or more in diameter), exudative macular degeneration, and geographic atrophy were 24.0%, 5.2%, and 2.0%, respectively. The investigators concluded that signs of AMD were common in those 75 years of age or older and that this posed a “substantial public health problem.” We know now that AMD is the leading cause of visual impairment in the United States.³

The presence of large drusen and pigmentary changes of the retinal pigment epithelium were known to be important predictors of progression to late AMD in multiple studies. The BDES established these key features as risk predictors for the development of late AMD, and they were incorporated into the classification of AMD severity such as the 12-step AREDS classification of AMD severity.⁴ Drusen and pigmentary changes also were key components in the development of the AREDS AMD simplified scale.⁵ Both eyes were evaluated for the presence of large drusen (considered also as soft drusen in the BDES), and pigmentary changes of the retinal pigment epithelium, or both in each eye. The sum of these factors in both eyes in the AREDS simplified scale resulted in 5 levels, with risk scores ranging from 0 (no drusen or pigmentary changes in either eye) to 4 (both drusen and pigmentary changes in both eyes). Those participants with a risk score of 0 for the AREDS simplified scale showed a 0.3% progression rate to late AMD in 5 years. However, for those with risk score of 4, which also may include the presence of late AMD in 1 eye, the 5-year progression rate to late AMD was 50%. This scale was validated with the data from AREDS 2 that show similar rates of progression.⁶

In the BDES, small or so-called indistinct drusen (less than 63 μm in diameter) were observed in the macula in at least 1 subfield in 94% of the cohort. The frequency of these small drusen did not increase in frequency with age. The investigators confirmed findings from previous clinical and histopathologic studies that suggested that the presence of these small drusen is frequent and, again, not related to age. In the clinical classification that was proposed later by the Beckman Initiative for Macular Research Classification Committee, small drusen were termed drupelets to convey the concept that these lesions do not carry the same poor prognosis as those with larger drusen.⁷ Again, this clinical classification noted the importance of large drusen and pigmentary changes in the development of the AMD scale.

The enormous amount of data from this seminal study resulted in more than 360 publications on AMD and many additional reports in other ocular diseases.⁸ The BDES provided strong evidence of genetic association in AMD through sibling studies, leading the way for further molecular genetic analyses.⁹ The BDES provided strong evidence of the association of AMD with cigarette smoking¹⁰ and cardiovascular risk.¹¹ This study set the bar high for quality research in the leading cause of visual impairment in the United States. Each of the contributions have provided the bases for other investigators to expand this knowledge. We continue to benefit from the creativity, productivity, and the tenacity of the Kleins and their team, whose work has resulted in a great legacy for other investigators, and the data from this landmark study surely have propelled AMD research.