The Effect of MAPT H1 and APOE ε4 on Transition from Mild Cognitive Impairment to Dementia

Article type: Research Article

Authors: Samaranch, Lluís^{a; 1} | Cervantes, Sebastián^{a; b; 1} | Barabash, Ana^c | Alonso, Alvaro^d | Cabranes, José Antonio^e | Lamet, Isabel^b | Ancín, Inés^c | Lorenzo, Elena^a | Martínez-Lage, Pablo^f | Marcos, Alberto^g | Clarimón, Jordi^{h; i} | Alcolea, Daniel^{h; i} | Lleó, Alberto^{h; i} | Blesa, Rafael^{h; i} | Gómez-Isla, Teresa^{h; i} | Pastor, Pau^{a; b; i; *}

Affiliations: [a] Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra, Pamplona, Spain | [b] Department of Neurology, Clínica Universidad de Navarra, Pamplona, Spain | [c] Laboratory of Psychoneuroendocrinology and Molecular Genetics, Fundación Investigación Biomédica Hospital Clínico San Carlos, Madrid, Spain | [d] Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA | [e] Psychiatry and Mental Health Institute, Hospital Clínico San Carlos, Madrid, Spain | [f] Area de Neurología, Centro de Investigación y Terapias Avanzadas, Fundación CITA Alzheimer, San Sebastián, Spain | [g] Department of Neurology, Hospital Clínico San Carlos, Madrid, Spain | [h] Department of Neurology, Hospital Santa Creu i Sant Pau, Barcelona, Spain | [i] CIBERNED, Instituto de Salud Carlos III, Spain

Correspondence: [*] Correspondence to: Pau Pastor, M.D., Ph.D., Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research (CIMA), Pío XII 55, 31008-Pamplona (Navarra), Spain. Tel.: +34 948194700 ext. 2018; Fax: +34 948194715; E-mail: [email protected].

Note: [1] These authors contributed equally to the manuscript.

Note: [] Handling Associate Editor: Eliecer Coto

Abstract: Microtubule-associated protein tau (MAPT) and apolipoprotein E (APOE) are involved in the pathogenic mechanisms of Alzheimer's disease (AD). We prospectively followed three longitudinal independent samples (total n = 319) with amnestic mild cognitive impairment (MCI) and analyzed whether MAPT H1/H2 haplotypes and APOE ε4 polymorphisms accelerated the rate of progression from MCI to dementia. At the end of the study, 172 subjects remained cognitively stable, whereas 147 progressed to dementia. APOE ε4 and MAPT H1/H1 were independently associated with an increased rate of progression to dementia in the combined sample. Cox regression models of the combined MCI sample showed that MAPT H1/H1 carriers had an increased rate of progression to dementia compared with non carriers (Hazard Ratio = 1.45; 95% CI = 1.04–2.02; p = 0.028) and time-to-progression was shortened by 1.37 years. APOE ε4 allele also accelerated progression to dementia (Hazard Ratio = 1.47; 95% CI = 1.06–2.04; p = 0.020) and reduced the time-to-progression by 0.87 years. Additionally, MAPT H1/H1 genotype and APOE ε4 allele had an additive effect in progression to dementia, increasing progression rate to dementia (Hazard Ratio = 2.24, 95% CI = 1.40–3.58; p = 0.001) and shortening time-to-progression to dementia by 2.92 years. Similar results were obtained when only considering progression to AD-type dementia. Our results suggest that both MAPT H1/H1 genotype and APOE ε4 allele lead to a more rapid progression to dementia among MCI subjects, probably mediating an increased rate of amyloid-β and tau brain deposition.

Keywords: Alzheimer's disease, APOE, interaction, genetics, microtubule-associated tau protein, MAPT, mild cognitive impairment

DOI: 10.3233/JAD-2010-101011

Journal: Journal of Alzheimer's Disease, vol. 22, no. 4, pp. 1065-1071, 2010