The H1 Haplotype of the Tau Gene (MAPT) is Associated with Mild Cognitive Impairment

Article type: Research Article

Authors: Di Maria, Emilio^{a; b; *} | Cammarata, Sergio^c | Parodi, Maria Isola^d | Borghi, Roberta^e | Benussi, Luisa^f | Galli, Marialaura^d | Galimberti, Daniela^h | Ghidoni, Roberta^{f; g} | Gonella, Davide^e | Novello, Cristina^c | Pollero, Valeria^c | Perroni, Lucia^d | Odetti, Patrizio^e | Scarpini, Elio^h | Binetti, Giuliano^f | Tabaton, Massimo^e

Affiliations: [a] Department of Neuroscience, Ophthalmology and Genetics, University of Genova, Genova, Italy | [b] Division of Medical Genetics, Galliera Hospital, Genova, Italy | [c] Division of Neurology, Galliera Hospital, Genova, Italy | [d] Laboratory of Genetics, Galliera Hospital, Genova, Italy | [e] Department of Internal Medicine, University of Genova, Genova, Italy | [f] NeuroBioGen Lab-Memory Clinic, Brescia, Italy | [g] Proteomics Unit, IRCCS “Centro S. Giovanni di Dio-Fatebenefratelli”, Brescia, Italy | [h] Dino Ferrari Centre, Department of Neurological Sciences, University of Milan, IRCCS Foundation Ospedale Maggiore Policlinico Mangiagalli and Regina Elena, Milan, Italy

Correspondence: [*] Correspondence to: Emilio Di Maria, M.D., Ph.D., Dept. of Neuroscience, Ophthalmology and Genetics, 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].

Abstract: Mild cognitive impairment is often considered a transitional condition prodromal to Alzheimer's disease. The dissection of genetic risk factors predisposing to mild cognitive impairment is paramount to assess the individual predisposition and reliably evaluate the effectiveness of early therapeutic interventions. We designed a cross-sectional analysis to test whether the occurrence of mild cognitive impairment is influenced by variations of the tau protein gene. The genotypes of seven polymorphisms tagging the major tau haplotypes were assayed on 186 patients with amnestic mild cognitive impairment and 191 unrelated controls. Association study was conducted by logistic regression including APOE genotype and age as covariates. Case-control analysis showed that the common H1 haplotype is significantly overrepresented in patients (OR, 95% CI: 2.31, 1.52–3.51; p<0.001), whereas did not provide positive signals for any of the H1 sub-haplotypes that had been described as associated with Alzheimer's disease. This finding was confirmed when the ε4 allele of the APOE gene was taken into account (OR, 95% CI: 2.319, 1.492–3.603; p<0.001). These results firstly suggest that the risk of mild cognitive impairment is influenced by tau protein gene variations and that mild cognitive impairment shares a common genetic background with Alzheimer's disease. They may help elucidating the genetic risk to cognitive decline and designing effective clinical trials.

Keywords: Alzheimer's disease, APOP, association study, MAPT, mild cognitive impairment, tau protein

DOI: 10.3233/JAD-2010-1285

Journal: Journal of Alzheimer's Disease, vol. 19, no. 3, pp. 909-914, 2010