Background: The APOE-ε4 allele is an established risk factor for Alzheimer's disease (AD). TOMM40 located adjacent to APOE has also been implicated in AD but reports of TOMM40 associations with AD that are independent of APOE-ε4 are at variance.
Methods: We investigated associations of AD with haplotypes defined by three TOMM40 and two APOE single nucleotide polymorphisms in 73 and 71 autopsy cases with intermediate and high likelihood of AD (defined by BRAAK stages <V and V-VI), respectively, and in 150 controls without major neurodegenerative diseases.
Results: We observed eight haplotypes with a frequency >0.02. The two haplotypes encoding APOE-E4 showed strong associations with AD that did not differ between intermediate and high likelihood AD. In contrast, a TOMM40 haplotype encoding APOE-E3 was identified as risk haplotype of high- (p = .0186), but not intermediate likelihood AD (p = .7530). Furthermore, the variant allele of rs2075650 located in intron 2 of TOMM40, increased the risk of high-, but not intermediate likelihood AD on the APOE-ε3/ε3 background (p = .0230).
Conclusion: The striking association of TOMM40 only with high likelihood AD may explain some contrasting results for TOMM40 in clinical studies and may reflect an association with more advanced disease and/or suggest a role of TOMM40 in the pathogenesis of neurofibrillary tangles.
Keywords: APOE; Alzheimer’ disease; TOMM40; beta-amyloid; genetics; haplotypes; neurofibrillary tangles.
© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.