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J Alzheimers Dis. 2016;49(2):343-52. doi: 10.3233/JAD-150555.

MAPT H1 Haplotype is Associated with Late-Onset Alzheimer's Disease Risk in APOEɛ4 Noncarriers: Results from the Dementia Genetics Spanish Consortium.

Author information

1
Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra (CIMA), Pamplona, Spain.
2
Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.
3
Department of Neurology, Hospital Universitari Mutua de Terrassa, University of Barcelona School of Medicine, Barcelona, Spain.
4
Department of Neurology. Hospital Universitario Donostia. San Sebastián, Spain.
5
Neurology Department, Hospital de la Santa Creu i Sant Pau - Biomedical Research Institute Sant Pau - Universitat Autònoma de Barcelona, Barcelona, Spain.
6
Memory Clinic of Fundaciò ACE, Institut Catalá de Neurociències Aplicades, Barcelona, Spain.
7
Neurology Service, University Hospital Marqués de Valdecilla (University of Cantabria and IDIVAL), Santander, Spain.
8
Neurosciences Area, Institute Biodonostia and Department of Neurosciences, University of Basque Country, UPV-EHU San Sebastián, Spain.
9
Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid, Spain.
10
Institute of Sanitary Research"Hospital la Paz" (IdIPaz), Madrid, Spain.
11
BIOMICs Research Group, Centro de Investigación "Lascaray" Ikergunea, Universidad del País Vasco UPV/EHU, Vitoria-Gasteiz, Spain.
12
Neuroscience Group, Instituto de Investigacion Hospital 12 de Octubre (i+12), Madrid, Spain.
13
Alzheimer's disease and other cognitive disorders Unit, Neurology Department, Hospital Clínic, IDIBAPS, Barcelona, Spain.
14
Molecular Genetics Laboratory, Genetics Unit, Hospital Universitario Central de Asturias, Oviedo, Spain.
15
Universitat Oberta de Catalunya (UOC), Barcelona, Spain.
16
Department of Neuropathology and Tissue Bank, Alzheimer Disease Research Unit, CIEN Foundation, Carlos III Institute of Health, Alzheimer Center Reina Sofia Foundation, Madrid, Spain.
17
Alzheimer Disease Research Unit, CIEN Foundation, Alzheimer Center Reina Sofia Foundation, Carlos III Institute of Health, Madrid, Spain.
18
NeurologyService, Hospital Universitario La Paz (UAM), Madrid, Spain.
19
Department of Neurology, Clínica Universidad de Navarra, University of Navarra School of Medicine, Pamplona, Spain.
20
Neuroimaging Laboratory, Division of Neurosciences, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
21
Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany.
22
German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
23
Institute of Human Genetics, University of Bonn, Bonn, Germany.
24
Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) Spain, Hospital Clínico San Carlos, Madrid, Spain.
25
Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, USA.

Abstract

The MAPT H1 haplotype has been linked to several disorders, but its relationship with Alzheimer's disease (AD) remains controversial. A rare variant in MAPT (p.A152T) has been linked with frontotemporal dementia (FTD) and AD. We genotyped H1/H2 and p.A152T MAPT in 11,572 subjects from Spain (4,327 AD, 563 FTD, 648 Parkinson's disease (PD), 84 progressive supranuclear palsy (PSP), and 5,950 healthy controls). Additionally, we included 101 individuals from 21 families with genetic FTD. MAPT p.A152T was borderline significantly associated with FTD [odds ratio (OR) = 2.03; p = 0.063], but not with AD. MAPT H1 haplotype was associated with AD risk (OR = 1.12; p = 0.0005). Stratification analysis showed that this association was mainly driven by APOE ɛ4 noncarriers (OR = 1.14; p = 0.0025). MAPT H1 was also associated with risk for PD (OR = 1.30; p = 0.0003) and PSP (OR = 3.18; p = 8.59 × 10-8) but not FTD. Our results suggest that the MAPT H1 haplotype increases the risk of PD, PSP, and non-APOE ɛ4 AD.

KEYWORDS:

A152T; Alzheimer’s disease; H1H2; MAPT; frontotemporal dementia; genetic association

PMID:
26444794
DOI:
10.3233/JAD-150555
[Indexed for MEDLINE]

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