The MAPT H1 Haplotype Is a Risk Factor for Alzheimer's Disease in APOE ε4 Non-carriers.

Pascual Sánchez-Juan,Sonia Moreno,Montse Alegret,Eloy Rodrííguez-Rodríguez,Sara López-García,Lluís Tárraga,Mercè Boada,Sergi Valero,Agustín Ruiz,Itziar De Rojas,Adelina Orellana,Pablo García González,Laura Montrreal,Carmen Lage,Isabel Hernández

doi:10.3389/fnagi.2019.00327

Abstract

An ancestral inversion of 900 kb on chromosome 17q21, which includes the microtubule-associated protein tau (MAPT) gene, defines two haplotype clades in Caucasians (H1 and H2). The H1 haplotype has been linked inconsistently with AD. In a previous study, we showed that an SNP tagging this haplotype (rs1800547) was associated with AD risk in a large population from the Dementia Genetics Spanish Consortium (DEGESCO) including 4435 cases and 6147 controls. The association was mainly driven by individuals that were non-carriers of the APOE ε4 allele. Our aim was to replicate our previous findings in an independent sample of 4124 AD cases and 3290 controls from Spain (GR@ACE project) and to analyze the effect of the H1 sub-haplotype structure on the risk of AD. The H1 haplotype was associated with AD risk (OR = 1.12; p = 0.0025). Stratification analysis showed that this association was mainly driven by the APOE ε4 non-carriers (OR = 1.15; p = 0.0022). Pooled analysis of both Spanish datasets (n = 17,996) showed that the highest AD risk related to the MAPT H1/H2 haplotype was in those individuals that were the oldest [third tertile (>77 years)] and did not carry APOE ε4 allele (p = 0.001). We did not find a significant association between H1 sub-haplotypes and AD. H1c was nominally associated but lost statistical significance after adjusting by population sub-structure. Our results are consistent with the hypothesis that genetic variants linked to the MAPT H1/H2 are tracking a genuine risk allele for AD. The fact that this association is stronger in APOE ε4 non-carriers partially explains previous controversial results and might be related to a slower alternative causal pathway less dependent on brain amyloid load.

Highlights

Dementia is related to many underlying pathologies, with Alzheimer’s disease (AD) being the most common
We found a statistically significant overrepresentation of the microtubule-associated protein tau (MAPT) H1 haplotype, present in 73.3% of AD compared to 71.1% of controls (p = 0.00025)
When we stratified the sample by APOE ε4 status, the association of the H1 haplotype was driven by noncarriers of APOE ε4 (p = 0.0022) (Table 2)

Summary

Introduction

Dementia is related to many underlying pathologies, with Alzheimer’s disease (AD) being the most common. MAPT H1 and Alzheimer’s Risk clinical syndrome that is likely to be reached by different routes influenced by genetic and environmental factors This complexity is likely to have contributed to the constant failures of AD clinical trials. Therapies based on the amyloid cascade hypothesis have not demonstrated any disease-modifying effect, despite some of these attempts have been proved to be effective in permanently removing brain β-amyloid plaques (Nicoll et al, 2019). This has led the pharmaceutical industry to focus on other therapeutic targets such as the tau protein (Corvol and Buée, 2019)

Objectives

Methods

Results

Conclusion