Possible Influence of a Non-Synonymous Polymorphism Located in the NGF Precursor on Susceptibility to Late-Onset Alzheimer's Disease and Mild Cognitive Impairment

Article type: Research Article

Authors: Di Maria, Emilio^{a; b; *} | Giorgio, Elisa^{b; 1} | Uliana, Vera^b | Bonvicini, Cristian^c | Faravelli, Francesca^b | Cammarata, Sergio^d | Novello, Maria Cristina^d | Galimberti, Daniela^e | Scarpini, Elio^e | Zanetti, Orazio^f | Gennarelli, Massimo^{c; g} | Tabaton, Massimo^h

Affiliations: [a] Department of Health Sciences, University of Genova, Genova, Italy | [b] Division of Medical Genetics, Galliera Hospital, Genova, Italy | [c] Genetic Unit, IRCCS Centro S. Giovanni di Dio-Fatebenefratelli, Brescia, Italy | [d] Division of Neurology, Galliera Hospital, Genova, Italy | [e] Department of Neurological Sciences, University of Milan, Centro Dino Ferrari, Fondazione Ca' Granda, IRCCS Policlinico, Milan, Italy | [f] Alzheimer Unit, IRCCS Centro S. Giovanni di Dio-Fatebenefratelli, Brescia, Italy | [g] Department of Biomedical Sciences and Biotechnologies, University of Brescia, Brescia, Italy | [h] Department of Internal Medicine, University of Genova, Genova, Italy

Correspondence: [*] Correspondence to: Emilio Di Maria, M.D., Ph.D., Department of Health Sciences, University of Genova, c/o Genetica Medica, Galliera Hospital, Via Volta, 6 - 16128 Genova, Italy. Tel.: +39 0105634368; Fax: +39 01057481222; E-mail: [email protected].

Note: [1] Current address: Department of Genetics, Biology and Biochemistry, University of Torino, Torino, Italy.

Abstract: The complex network of neurotrophic factors is supposed to play a role in neurodegeneration, but the effect of variations in their coding genes on susceptibility to sporadic Alzheimer's disease is not established. The mature form of nerve growth factor (NGF) derives from a precursor, proNGF, which was recently discovered to exert crucial functions in brain. We designed a case-control association study to test the hypothesis as to whether polymorphisms located in the proNGF genomic region influence the liability to Alzheimer's disease and its prodromal form, mild cognitive impairment. Three independent case-control samples, with individuals aged >60 years, were collected in Italian Alzheimer Units. One polymorphism located in the proNGF region, rs6330, demonstrated a minor allele frequency >5% and was used in the association study. The minor allele of rs6330 was more frequent in patients from the three sample series as compared to respective normal controls. Multivariate logistic regression showed a significant association under the dominant model in one cohort (OR 1.83, 95% CI 1.00–3.54) and in the pooled case-control sample (OR 1.47, 95% CI 1.03–2.08). These findings further suggest that proNGF may play a role in Alzheimer-type neurodegeneration and that genetic variations in the NGF locus may influence the occurrence of sporadic, late-onset Alzheimer's disease.

Keywords: Alzheimer's disease, APOE, association study, mild cognitive impairment, NGF, NGFB, proNGF

DOI: 10.3233/JAD-2012-112006

Journal: Journal of Alzheimer's Disease, vol. 29, no. 3, pp. 699-705, 2012