MAPT H1 Haplotype is Associated with Late-Onset Alzheimer’s Disease Risk in APOE ɛ4 Noncarriers: Results from the Dementia Genetics Spanish Consortium

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.

A152T tau allele causes neurodegeneration that can be ameliorated in a zebrafish model by autophagy induction

“…In the present study, we find significant risk associations in our independent FTD and PSP-S cohorts with the p.A152T variant. This replicates the effect for FTD we reported initially (Coppola et al , 2012) and is consistent with the trend observed by Pastor et al (2016). Thus, we feel that this constitutes good genetic support for p.A152T as a tauopathy risk variant.…”

“…After the initial study that reported significant risks for p.A152T carriers to develop Alzheimer’s disease and FTD spectrum disorders (Coppola et al , 2012), Labbe et al (2015) reported significant associations with cohorts with clinically-diagnosed or pathologically-confirmed dementia with Lewy bodies. However, Pastor et al (2016) did not show a significant association between p.A152T and Alzheimer’s disease, and the association with FTD was of borderline significance (OR = 2.03; 95% CI = 0.95–4.34 P = 0.063) (Pastor et al , 2016). …”

“…The term ‘syndrome’ is used because the underlying neuropathology for these disorders is variable, particularly corticobasal syndrome. Together, these studies suggest that p.A152T is a risk factor for diverse neurodegenerative disease syndromes related to FTLD-tau and possibly synucleinopathy, although recently, a study of 11 572 subjects in Spain did not observe an increased association between p.A152T and Alzheimer’s disease, while the association with FTD spectrum approached significance [odds ratio (OR) = 2.03; P = 0.063] (Pastor et al , 2016). …”

Gene expression, methylation and neuropathology correlations at progressive supranuclear palsy risk loci

“…The extent of LD in the MAPT region poses great difficulty in discerning the gene(s) and functional variants that impose risk for PSP and other neurodegenerative diseases that associate with SNPs in this region, such as Alzheimer’s (AD)[24,31,1] and Parkinson’s disease(PD)[11,40]. The hallmark of tau pathology in AD, PSP and other tauopathies and presence of deterministic MAPT mutations that lead to neurodegeneration (reviewed[17]) strongly implicate MAPT as the culprit in these disease associations.…”

Genetic Comparison of Symptomatic and Asymptomatic Persons With Alzheimer Disease Neuropathology

“…37 Another study found an increased risk of clinical AD for carriers of MAPT H1 haplotype, but only in APOE ε4-negative strata. 38 The current study found changes in MAPT to be associated with altered risk of cognitive symptoms, primarily driven by altered risk in the APOE ε4-positive strata.…”