APOE ɛ4-TOMM40L Haplotype Increases the Risk of Mild Cognitive Impairment Conversion to Alzheimer’s Disease
Background: Mild cognitive impairment (MCI) has been considered as a pre-dementia stage, although the factors leading to Alzheimer’s disease (AD) conversion remain controversial. Objective: Evaluate whether TOMM40 poly-T (TOMM40′ 523) polymorphism is associated with the risk and conversion time from MCI to AD and secondly with AD cerebrospinal fluid (CSF) biomarkers, disentangling the APOE genotype. Methods: 147 AD patients, 102 MCI patients, and 105 cognitively normal controls were genotyped for poly-T polymorphism. MCI patients were subdivided into two groups, the group of patients that converted to AD (MCI-AD) and the group of those that remained stable (MCI-S). Results: TOMM40′ 523 L allele was significantly more frequent in the MCI-AD group and having at least one L allele significantly increased the risk of conversion from MCI to AD (OR = 8.346, p < 0.001, 95% CI: 2.830 to 24.617). However, when adjusted for the presence of APOE ɛ4 allele, both the L allele and ɛ4 allele lost significance in the model (p > 0.05). We then analyzed the APOE ɛ4-TOMM40′ 523 L haplotype and observed that patients carrying this haplotype had significantly higher risk (OR = 5.83; 95% CI = 2.30–14.83) and mean lower times of conversion to AD (p = 0.003). This haplotype was also significantly associated with a biomarker profile compatible with AD (p = 0.007). Conclusion: This study shows that the APOE ɛ4-TOMM40′ 523 L haplotype is associated with a higher risk and shorter times of conversion from MCI to AD, possibly driven by CSF biomarkers and mitochondrial dysfunction.