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

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.

Keywords: Alzheimer's disease; apolipoprotein E polymorphism; haplotypes; linkage disequilibrium.

Figure 1.. Sex-specific associations of two common ε2-bearing compound genotypes with Alzheimer’s disease (AD).

The APOE ε3ε3 genotype was used as a reference. Compound genotypes 0111 and 1001 were encoded using symbols 0 and 1, which indicate the major allele homozygote and heterozygote, respectively, of SNPs ordered as rs8106922 (A/g), rs405509 (G/t), rs440446 (G/c), and rs7412 (C/t). Upper/lower case denotes here major/minor allele. Variants 0111 and 1001 denote AAGtGcCt and AgGGGGCt compound genotypes, respectively. With no carriers of the ε4 allele, the rs7412 Ct heterozygote encodes the ε2ε3 genotype. The x-axis shows effect size beta. “Pooled” shows the estimates for the pooled sample of PCB, LOADFS, ADGC, and ADSP, excluding a biased sample of the ADGC AD-unaffected subjects. UKB denotes UK Biobank data. “Mega” indicates a sample with data merged from the Pooled and UK Biobank datasets. Horizontal lines show standard errors (SE). Other details are given in Supplementary Table S1.