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In this study, we investigated whether variable-length poly-T sequence polymorphism (rs10524523) in the gene encoding translocase of the outer mitochondrial membrane 40 homolog (TOMM40) may contribute to mild cognitive impairment (MCI) and Alzheimer's disease (AD) pathology, and whether it poses as a risk factor for disease progression. Methods: We enrolled 267 MCI patients and 141 AD patients from the Alzheimer's Disease Neuroimaging Initiative database. Participants were homozygous for APOE 3 and stratified according to poly-T length into homozygous for short (S/S, n=46), homozygous for long (L/L, n=51), homozygous for very long (VL/VL, n=44) and heterozygous (S/L, n=82; S/VL, n=100; L/VL, n=85) groups. We compared clinical symptoms, cerebrospinal fluid (CSF) biomarkers and magnetic resonance (MR) imaging variables amongst these groups and carried out a Cox proportional hazard regression analysis to determine the predictive value of TOMM40 rs10524523 poly-T length in cognitive decline. Results: Patients with S/L, L/L and L/VL genotypes exhibited worse cognitive performance (ADAS-Cog11: P<0.05; ADAS-Cog13: P<0.05), and exhibited higher CSF total tau, phospho-tau and decreased CSF A42 levels (P<0.05) in comparison to other groups. 309 subjects (75.7%) had an annual decline of 2 or more points on MMSE and 176 subjects (43.1%) had an annual increase of 5.5 points on ADAS-Cog11. L/L genotype (MMSE: [HR]= 2.218, Confidence Interval [CI]= 1.325-3.715, P=0.002; ADAS-Cog11: [HR]= 2.094, [CI]= 1.120-3.917, P=0.021) was a predictor of cognitive decline. Conclusion: Our results demonstrate a pathogenic role of the L TOMM40 rs10524523 variant in MCI and AD patients and its value in predicting cognitive decline.