ROLE OF -850 TNF-Á AND PSEN1 IN DOWN SYNDROME-RELATED DEMENTIA

Objectives: the majority of individuals with Down syndrome (DS) develops dementia during their life. However, genetic determinants of dementia in this population are still poorly defined. To this aim, we investigated the association between DS and gene polymorphisms known to be involved in Alzheimer disease (AD), such as Tumor Necrosis Factor-á (TNF-á), apolipoprotein E (APOE), presenilin-1 (PSEN1), and the insulin-degrading enzyme (IDE).

Methods: we conducted three casecontrol studies and compared: i) 136 DS and 113 apparently healthy controls in order to assess the association between DS and -850 TNF-á and APOE polymorphisms; ii) 260 DS patients and 197 controls to check the association with the 48C/T genotype and allele distribution; iii) 287 DS patients and 251 controls to assess the association with two single nucleotide polymorphisms located on the introns 14 and 24 of the IDE gene. Results: in the three studies we found that i) the –850T frequency in DS was significantly higher than in controls (p<.005), whereas the APOE E4 allele was less common among cases compared to controls (p<.005); ii) cases were less likely than controls to have the CC genotype (p=0.05). DS individuals had also a lower frequency of the allele C compared with the control population (p=0.01); iii) there was no evidence of association between DS and the IDE polymorphisms. Conclusion: the –850T allele of the TNF-á and the -48 C/T polymorphism of the PSN1 gene appear to play a role in DS related dementia. Our findings show that only some gene polymorphisms involved in AD are also associated to DS-related dementia, suggesting partially different pathogenetic mechanisms.