Possible Association between SNAP-25 Single Nucleotide Polymorphisms and Alterations of Categorical Fluency and Functional MRI Parameters in Alzheimer's Disease

Article type: Research Article

Authors: Guerini, Franca Rosa^{a; *} | Agliardi, Cristina^a | Sironi, Manuela^b | Arosio, Beatrice^c | Calabrese, Elena^a | Zanzottera, Milena^a | Bolognesi, Elisabetta^a | Ricci, Cristian^{a; g} | Costa, Andrea Saul^a | Galimberti, Daniela^d | Griffanti, Ludovica^{a; e} | Bianchi, Anna^a | Savazzi, Federica^a | Mari, Daniela^c | Scarpini, Elio^d | Baglio, Francesca^a | Nemni, Raffaello^{a; f} | Clerici, Mario^{a; f}

Affiliations: [a] Don C. Gnocchi Foundation IRCCS, Milano, Italy | [b] Scientific Institute IRCCS E. Medea, Bosisio Parini (LC), Italy | [c] Geriatric Unit, Department of Clinical Sciences and Community, University of Milano, Fondazione Ca' Granda, IRCCS Ospedale Maggiore Policlinico, Milano, Italy | [d] Dino Ferrari Center, Department of Pathophysiology and Transplantation, University of Milano, Fondazione Ca' Granda, IRCCS Ospedale Maggiore Policlinico, Milano, Italy | [e] Bioengineering Department, Politecnico of Milano, Milano, Italy | [f] Department of Pathophysiology and Transplantation University of Milano, Milano, Italy | [g] Department of Epidemiology and Preventative Medicine, University of Regensburg, Regensburg, Germany

Correspondence: [*] Correspondence to: Franca Rosa Guerini, PhD, Don Gnocchi Foundation IRCCS, Pzle Morandi 6, 20121 Milano, Italy. Tel.: +39 02 40308376; Fax: +39 02 40308438; E-mail: fguerini@dongnocchi.it.

Abstract: Synaptosomal-associated protein of 25 kDa (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 = 148) 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 AD and aMCI and are associated with pathological scores of categorical fluency in AD. Notably, functional MRI analyses indicated that SNAP-25 genotypes correlate 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. SNAP-25 polymorphisms may be associated with AD and correlate with alterations in categorical fluency and a reduced localized brain activity. SNAP-25 polymorphisms could be used 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.

Keywords: Alzheimer's disease, categorical fluency, cognitive impairment, functional MRI, genetic polymorphisms, SNAP-25

DOI: 10.3233/JAD-140057

Journal: Journal of Alzheimer's Disease, vol. 42, no. 3, pp. 1015-1028, 2014