GENETIC STUDY OF BIOMARKERS INVOLVED IN THE PROCESS OF AGING NEURODEGENERATION

Synaptosomal-associated protein of 25kDa (SNAP-25) is an age-regulated vesicular SNARE protein involved in the exocytosis of neurotransmitters from synapses, a process that is altered in Alzheimer’s disease (AD). Changes in SNAP-25 levels are suggested to contribute to age-related decline of cognitive function, and single nucleotide polymorphisms (SNPs) in the SNAP-25 gene are present in neuropsychiatric conditions and play a role in determining IQ phenotypes. To verify a possible role of SNAP-25 in AD we analyzed five gene polymorphisms in patients with AD (N=607), replicating the study in subjects with amnestic mild cognitive impairment (aMCI)(N=154) and in two groups of age-matched healthy controls (HC1: N=615 and HC2: N=310). Results showed that the intronic rs363050(A) and rs363043(T) alleles, as well as the rs363050/rs363043 A-T haplotype are significantly more frequent in both AD and aMCI. Further analyses indicated that these alleles and haplotype are associated with pathological scores of categorical fluency in AD alone. Finally, SNAP-25 genotypes correlated with a significantly decreased brain activity in the cingulate cortex and in the frontal (middle and superior gyri) and the temporo- parietal (angular gyrus) area, as measured by fMRI. SNAP-25 polymorphisms are associated with AD and correlate with alterations in categorical fluency and a reduced localized brain activity. In conclusion SNAP-25 polymorphisms could be suggested as surrogate markers for the diagnosis of AD and of cognitive deficit; these SNPs might also have a possible predictive role in the natural history of AD. Moreover we investigated a possible correlations between APOE4 and SNAP-25 polymorphisms and the outcome of a multidimensional cognitive, behavioral and functional stimulation (MST). Fifty-eight individuals with mild-to-moderate AD underwent MST for 10 weeks. Mini Mental Scale Evaluation (MMSE), Functional Living Skills Assessment (FLSA) and Neuropsychiatric Inventory scale (NPI) were performed at baseline and after therapy. Molecular genotyping of ApoE4 and SNAP-25 SNPs were correlated with ΔMMSE, ΔNPI and ΔFLSA scores by multinomial logistic regression analysis. Results shown higher overall MMSE scores after rehabilitation in ApoE4 negative compared to ApoE4 positive patients, whereas the SNAP-25 rs363050(G) and rs363039(A) alleles correlated specifically with significant improvements in behavioural parameters after MST. Haplotype analysis of rs363050, rs363039 and rs363043 SNAP-25 SNPs showed the presence of a significant association between SNAP-25 haplotypes and lower ΔNPI. In particular the rs363050(G)-rs363039(A)-rs363043(C): (GAC) haplotype was statistically associated with a better outcome of treatment as measured by the NPI scale. In conclusion polymorphisms in genes known to modulate neural plasticity may predict the outcome of a multistructured rehabilitation protocol in AD.