Dementia risk in parkinson disease: Disentangling the role of MAPT Haplotypes

Núria Setó-Salvia, Jordi Clarimón, Javier Pagonabarraga, Berta Pascual-Sedano, Antonia Campolongo, Onofre Combarros, Jose Ignacio Mateo, Daniel Regaña, Merce Martínez-Corral, Marta Marquié, Daniel Alcolea, Marc Suárez-Calvet, Laura Molina-Porcel, Oriol Dols, Teresa Gómez-Isla, Rafael Blesa, Alberto Lleó, Jaime Kulisevsky

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Abstract

Background: Dementia in Parkinson disease (PD) causes nursing home placement, caregiver distress, higher health care burden, and increased mortality. Objective: To determine whether the microtubule-associated protein tau (MAPT) H1 haplotype and MAPT subhaplotypes play a role in the risk of PD and Parkinson disease-dementia (PDD) complex. Design: Case-control genetic analysis. Setting: Movement Disorders and Memory Units, Hospital de Sant Pau, Barcelona, Spain. Participants: Two hundred two patients with PD (48 of whom developed dementia >2 years after disease onset), 41 patients with Lewy body dementia (LBD, pathologically confirmed in 17), 164 patients with Alzheimer disease (AD), and 374 controls. Methods: The MAPT haplotype was determined by testing for a 238-base pair deletion between exons 9 and 10, which is characteristic of the H2 haplotype. Haploview was used to visualize linkage disequilibrium relationships between all genetic variants (5 single-nucleotide polymorphisms and the del-In9 variant) within and surrounding the MAPT region. Results: The H1 haplotype was significantly overrepresented in PD patients compared with controls (P = .001). Stratifying the PD sample by the presence of dementia revealed a stronger association in PDD patients (sex- and age-adjusted odds ratio, 3.73; P = .002) than in PD patients without dementia (sex- and age-adjusted odds ratio, 1.89; P = .04). Examination of specific subhaplotypes showed that a rare version of the H1 haplotype (named H1p) was overrepresented in PDD patients compared with controls (2.3% vs 0.1%; P = .003). No positive signals for any of the MAPT variants or H1 subhaplotypes were found in AD or LBD. Conclusions: Our data confirm that MAPT H1 is associated with PD and has a strong influence on the risk of dementia in PD patients. Our results also suggest that none of the MAPT subhaplotypes play a significant role in other neurodegenerative diseases, such as LBD or AD. ©2011 American Medical Association. All rights reserved.
Original languageEnglish
Pages (from-to)359-364
JournalArchives of Neurology
Volume68
Issue number3
DOIs
Publication statusPublished - 1 Mar 2011

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