82.8% for e3, and 7.5% and 15.6% for e4. Geographic var- iation in APOE allele frequencies has been reported previ- ously, with a resultant impact on statistical power (36–38). It was not possible for us to ascertain the geographic origin of each participant individually within this study, but adjust- ment for potential confounding by study bias/location was incorporated into our analyses to assess the relation between APOE and age. Since it was not possible to genotype markers that were informative for ancestry in these samples, we cannot rule out the possibility that population stratifica- tion could have made some contribution to our findings. Adjustment for center partly addressed some of the issues raised by Lewis and Brunner (30) with respect to population stratification and variation in genotype frequencies. Further- more, individual smoking status data were available for sub- jects, although adjustment for this lifestyle risk factor failed to have any significant impact on the associations inferred.

versity Hospital Wu¨rzburg, Wu¨rzburg, Germany (Claudia N. Keilhauer); Macular Degeneration Center, Casey Eye Institute, Oregon Health and Science University, Portland, Oregon (Michael L. Klein, Peter J. Francis); Department of Epidemiology, Erasmus Medical Centre, Rotterdam, the Netherlands (Johannes R. Vingerling, Lintje Ho); Depart- ment of Ophthalmology, Erasmus Medical Centre, Rotter- dam, the Netherlands (Caroline C. Klaver); Netherlands Institute for Neuroscience, Netherlands Academy of Arts and Sciences, Amsterdam, the Netherlands (Paulus T. D. V. De Jong); Department of Ophthalmology, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands (Paulus T. D. V. De Jong); Cancer and In- flammation Program, National Cancer Institute, Frederick, Maryland (Michael Dean, Julie Sawitzke); Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, University of Melbourne, East Melbourne, Victoria, Australia (Paul N. Baird, Robyn H. Guymer); Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania (Dwight Stambolian, Anton Orlin); Department of Ophthalmology, Tufts University School of Medicine and Tufts Medical Center, Boston, Massachusetts (Johanna M. Seddon); Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York (Inga Peter); MRC Human Genetics Unit, Western General Hospi- tal, Edinburgh, United Kingdom (Alan F. Wright, Caroline Hayward); Clinical Neurosciences Division, School of Med- icine, University of Southampton, Southampton, United Kingdom (Andrew J. Lotery); Southampton Eye Unit, South- ampton General Hospital, Southampton, United Kingdom (Andrew J. Lotery); Genetic Epidemiology and Bioinfor- matics Group, Human Genetics Division, University of Southampton, Southampton, United Kingdom (Sarah Ennis); Departments of Ophthalmology and Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California (Michael B. Gorin); De- partment of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania (Daniel E. Weeks, Chia-Ling Kuo); University Centre for Clinical Pharmacology, Department of Medicine, University College London, London, United Kingdom (Aroon D. Hingorani, Reecha Sofat); Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan (Anand Swaroop, Mohammad Othman); Neurobiology-Neurodegeneration and Repair Laboratory, National Eye Institute, Bethesda, Maryland (Anand Swaroop, Atsuhiro Kanda); Center for Statistical Genetics, Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan (Wei Chen, Goncalo R. Abecasis); Department of Medical Genetics, Cambridge Institute for Medical Research, Univer- sity of Cambridge, Cambridge, United Kingdom (John R. Yates); Institute of Ophthalmology, University College Lon- don, London, United Kingdom (John R. Yates, Andrew R. Webster, Anthony T. Moore, Valentina Cipriani); Moorfields Eye Hospital, London, United Kingdom (John R. Yates, Andrew R. Webster, Anthony T. Moore, Valentina Cipriani); Eye Department, Stavanger University Hospital, University of Bergen, Stavanger, Norway (Johan H. Seland); Depart-

The statistical analyses for measuring the effects of gender and age in the current study were performed on categorized data, which were arbitrarily grouped into 5-year intervals prior to undertaking the analysis. The data from this study support a 5% reduction in the odds for the e4 allele every 5 years beyond the age of 60 years, while the associated odds for the e3 allele increased by 4% across the same time period. Narrower and broader age intervals were assessed, with little change in terms of the significance of the effect observed, as was the case when age was treated as a continuous variable.

Limitations of our study to accurately assess the role of APOE in longevity pertain to the impact associated with this gene on debilitating diseases such as coronary heart disease, atherosclerosis, or age-related disorders, such as Alzheimer’s disease and other dementias. Persons who are affected by such diseases may be less likely to participate in a case- control study. In addition, AMD was ruled out in our study subjects, which could also have had some effect, since APOE has been reported to be associated with AMD in previous studies (4, 15, 31, 32). We suspect that these effects would have been small, but ideally a prospective population-based study with a sufficient sample size and follow-up would be best placed to offer an unbiased and accurate reflection on the role of APOE in longevity.