To Örebro University

Background: The apolipoprotein E (APOE) epsilon 4 allele is a strong risk factor for Alzheimer's disease (AD) in Caucasian and African American populations. It suggests that other genetic factors may modulate AD pathogenesis in Chinese populations, among which the frequency of this allele is reduced but the AD prevalence is maintained. The translocase of outer mitochondrial membrane 40 (TOMM40), which is located adjacent to APOE,may play an APOE-dependent role in modulating AD pathogenesis.

Aims: This work aimed to investigate whether TOMM40 polymorphisms modulate AD risk independently of, or in conjunction with APOE polymorphisms in Chinese populations.

Methods: We conducted a case-control study including 834 patients with AD recruited from the Memory Clinic and 643 cognitively normal participants recruited from the community. The Taqman SNP method was used for APOE genotyping, while TOMM40 polymorphism genotyping was conducted via a polymerase chain reaction-ligase detection reaction.

Results: TheTOMM40 rs10119 and rs71352238 alleles were associated with AD independently of the patient APO status. The rs10119 AA genotype and rs71352238 CC genotype were risk genotypes of AD. Individuals carrying a TOMM40 rs10119 GG/APOE epsilon 4+ (OR, 3.73; 95% CI 1.49-9.37;P = 0.005), TOMM40 rs10119 AG/APOE epsilon 4+ (OR, 4.16; 95% CI 3.30-5.24;P < 0.001), or TOMM40 rs10119 AA/APOE epsilon 4+ (OR, 14.78; 95% CI 8.56-25.54;P < 0.001) genotype exhibited a significantly higher AD risk. Those carrying a TOMM40 rs71352238 TT/APOE epsilon 4+ (OR, 3.82; 95% CI 2.32-6.29;P < 0.001), TOMM40 rs71352238 CT/APOE epsilon 4+ (OR, 4.40; 95% CI 3.46-5.56;P < 0.001), or TOMM40 rs71352238 CC/APOE epsilon 4+ (OR, 14.02; 95% CI 7.81-25.17;P < 0.001) genotype also exhibited a significantly increased AD risk.

Discussion and conclusions: This study provides invaluable insights into the mechanisms underlying the prevalence of AD in Chinese populations, and supports that simultaneous TOMM40 and APOE genotyping in the clinical setting may identify individuals at high risk of developing AD.