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Nature Genetics  7, 180 - 184 (1994)

Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease

E. H. Corder1, A. M. Saunders1, N. J. Risch3, W. J. Strittmatter1, 2, D. E. Schmechel1, 2, 4, P. C. Gaskell Jr.1, J. B. Rimmler1, P. A. Locke5, P. M. Conneally6, K. E. Schmader4, 7, G. W. Small8, A. D. Roses1, 2, J. L. Haines5 & M. A. Pericak-Vance1

  1Division of Neurology, Joseph and Kathleen Bryan Alzheimer's Disease Research Center, Duke University Medical Center, Durham, North Carolina 27710, USA

  2Division of Neurobiology, Joseph and Kathleen Bryan Alzheimer's Disease Research Center, Duke University Medical Center, Durham, North Carolina 27710, USA

  3Department of Epidemiology and Public Health and Department of Genetics, Yale University, New Haven, Connecticut 06520, USA

  4GRECC Durham VA Medical Center, Durham, North Carolina 27704, USA

  5Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA

  6Department of Medical and Molecular Genetics, Indiana University Medical Center, Indianapolis, Indiana 46202, USA

  7Center for Study of Aging and Human Development, Duke University Medical Center, Durham, North Carolina 27710, USA

  8Neuropsychiatric Institute and Hospital, Center for Health Sciences, University of California, Los Angeles, California 90024, USA

Gene dosage of the apolipoprotein E (APOE) epsilon4 allele is a major risk factor for familial Alzheimer disease (AD) of late onset (after age 60). Here we studied a large series of 115 AD case subjects and 243 controls as well as 150 affected and 197 unaffected members of 66 AD families. Our data demonstrate a protective effect of the epsilon2 allele, in addition to the dose effect of the epsilon4 allele in sporadic AD. Although a substantial proportion (65%) of AD is attributable to the presence of epsilon4 alleles, risk of AD is lowest in subjects with the epsilon2/epsilon3 genotype, with an additional 23% of AD attributable to the absence of an epsilon2 allele. The opposite actions of the epsilon2 and epsilon4 alleles further support the direct involvement of APOE in the pathogenesis of AD.

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