Abstract
INTRODUCTION: Despite advances, understanding the protective role of the apolipoprotein E (APOE) ε2 allele in Alzheimer's disease (AD) remains elusive. METHODS: We examined associations of variants comprised of the TOMM40 rs8106922 and APOE rs405509, rs440446, and ε2-encoding rs7412 polymorphisms with AD in a sample of 2862 AD-affected and 169,516 AD-unaffected non-carriers of the ε4 allele. RESULTS: Association of the ε2/ε3 heterozygote of men with AD is 38% (P = 1.65 × 10(-2) ) more beneficial when it is accompanied by rs8106922 major allele homozygote and rs405509 and rs440446 heterozygotes than by rs8106922 heterozygote and rs405509 and rs440446 major allele homozygotes. No difference in the beneficial associations of these two most common ε2/ε3-bearing variants with AD was identified in women. The role of ε2/ε3 heterozygote may be affected by different immunomodulation functions of rs8106922, rs405509, and rs440446 variants in a sex-specific manner. DISCUSSION: Combination of TOMM40 and APOE variants defines a more homogeneous AD-protective ε2/ε3-bearing profile in men.