FATTORI DI RISCHIO GENETICI NELLA MALATTIA DI ALZHEIMER E NELLA DEMENZA FRONTOTEMPORALE: STUDIO DI ASSOCIAZIONE DI GENI CANDIDATI POSIZIONALI E FUNZIONALI

Alzheimer’s disease (AD) and Frontotemporal Lobar Degeneration (FTLD) are two neurodegenerative and multifactorial diseases with complex etiology in which several genes involved in inflammation, oxidative damage and neuronal survival have been proposed to be candidate susceptibility factors. Given these premises, aims of this study have been to further analyze the association of candidate functional and positional genes in a population of 374 patient with AD, 291 with FTLD and 344 age matched controls. The first candidates studied have been the cell-dependent kinase inhibitor (CDKN) 2A and 2B, involved in cell cycle G1 phase progression, because abnormal cell cycle re-entry has been hypothesized to play a role in neurodegenerative disease, primarily AD. Allelic and genotypic frequencies of three tagging Single Nucleotide Polymorphisms (SNPs), namely rs3731239 T/C, rs2811710 C/T and rs3217992 G/A, spanning CDKN2A and CDKN2B, and covering 100% gene variability, were analyzed. According to our data, CDKN2A and CDKN2B don’t likely act as risk factors for AD. Given the potential importance of kinesin KIF24, protein expressed in neurons and involved in axonal transport and neuron development, we studied the distribution of five Single Nucleotide Polymorphism (SNPs) located in the chromosome 9 haplotype identified via linkage analysis, including UBAP1 rs7018487, UBAP2 rs1785506 and rs307658, and KIF24 rs17350674 and rs10814083. A statistically significant increased frequency of the KIF24 rs17350674 AA genotype was observed in FTLD patients compared with controls, particularly in bvFTD and female patients, showing that KIF24 rs17350674 polymorphism may act as a risk factor for sporadic FTLD. BCL2-associated athanogene 1 (BAG1) is an anti-apoptotic factor interacting with tau and regulating its proteasomal degradation. A statistically significant decreased allelic frequency of the BAG-1 rs706118 SNP was observed in patients with FTLD, but not in AD. BAG-1 rs706118 SNP likely acts as protective factor for sporadic FTLD, but not for AD. Finally we studied the Heterogeneous nuclear ribonucleoprotein hnRNP-A1, which may be linked to AD, because it could influence the maturation of the Amyloid Precursor Protein (APP) mRNA, but also to FTLD, because it contains a glycine-rich consensus domain included in TAR DNA binding protein (TDP)43. In our study, hnRNP-A1 rs7967622 C/C genotype acts as risk factor only for FTLD in male population, while hnRNP-A1 relative expression levels were increased in AD patients, togheter with decreased levels of its transcription regulatory factor hsa-miR-590-3p. We confirmed the importance of genes influencing neuronal transport, metabolism and survival in both neurodegenerative diseases AD and FTLD; the observed differences are probably related to specific roles of these genes in pathogenic events occurring in FTLD only.