TOMM40 rs10524523 polymorphism's role in late-onset Alzheimer's disease and in longevity

Recently, it has been reported that TOMM40 variable-length poly-T sequence polymorphism (rs10524523) in combination with APOE alleles (E2, E3, E4) significantly influences late-onset Alzheimer's disease (LOAD) age of onset. In a group of 414 LOAD patients, 173 centenarians and 305 neurologically healthy individuals, we investigated the impact of TOMM40 poly-T tracts on LOAD incidence, age of onset, and longevity. TOMM40 allelic variants were classified into four categories: short (S; 14-16T), long a (La; 20-22T), long b (Lb; 26-30T), and very long (VL; 31-39T). Our results demonstrate that La and Lb share similar characteristics in affecting LOAD risk, thus for some analyses they were combined into L category. We observed significantly lower frequency of VL allele (p < 0.0001) and significantly higher frequency of L alleles in the LOAD patients compared to the control individuals (p < 0.0001). S/S, S/VL, and VL/VL genotypes and VL-E2, S-E3, VL-E3 haplotypes are significantly associated with lower LOAD risk. VL-E3 haplotype carriers significantly more frequently developed LOAD when they were ≥79 years old. Additionally, S/L genotype is associated with a significantly increased LOAD risk (p < 0.0001). We conclude that in the carriers of TOMM40-APOE haplotypes comprising E4 allele, the TOMM40 rs10524523 allele does not play substantial role in establishing LOAD risk. Nevertheless, TOMM40 L allele increases the risk when E4 is absent. Finally, L allele, as well as genotypes (S/L, V/L) and haplotypes (L-E3, L-E4) comprising L significantly reduce the likelihood of living up to 100 years.