Protective association of the ε2/ε3 heterozygote with Alzheimer's disease is strengthened by TOMM40-APOE variants in men

Introduction Despite advances, understanding the protective role of the apolipoprotein E (APOE) epsilon 2 allele in Alzheimer's disease (AD) remains elusive. Methods We examined associations of variants comprised of the TOMM40 rs8106922 and APOE rs405509, rs440446, and epsilon 2-encoding rs7412 polymorphisms with AD in a sample of 2862 AD-affected and 169,516 AD-unaffected non-carriers of the epsilon 4 allele. Results Association of the epsilon 2/epsilon 3 heterozygote of men with AD is 38% (P = 1.65 x 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 epsilon 2/epsilon 3-bearing variants with AD was identified in women. The role of epsilon 2/epsilon 3 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 epsilon 2/epsilon 3-bearing profile in men.