Dementia risk in Parkinson disease: disentangling the role of MAPT haplotypes

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.