Gene dosage of the apolipoprotein E (APOE) ε4 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 ε2 allele, in addition to the dose effect of the ε4 allele in sporadic AD. Although a substantial proportion (65%) of AD is attributable to the presence of ε4 alleles, risk of AD is lowest in subjects with the ε2/ε3 genotype, with an additional 23% of AD attributable to the absence of an ε2 allele. The opposite actions of the ε2 and ε4 alleles further support the direct involvement of APOE in the pathogenesis of AD.
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