The H1c haplotype of the MAPT locus is associated with autopsy confirmed late onset Alzheimer’s disease

Recent studies have shown that genetic variability at the MAPT locus is associated with increased risk for sporadic tauopathies. These associations divide the MAPT locus between two divergent clades of MAPT haplotypes, H1 and H2. Recently, our group and others have shown that while the H2 clade is essentially a single haplotype, H1 shows considerable diversity. We have further shown that a variant of this clade, H1c, is largely responsible for the association between the H1 haplotype and the sporadic tauopathies. Several studies have examined variability within MAPT and the occurrence of Alzheimer's disease (AD) with inconclusive results. These reports have compared variants that existed on the H1 or H2 background, but did not consider the variability within these two clades and any putative association with disease. Following our observation that a specific variant of the H1 clade was responsible for the association with tauopathies (H1c), we examined the association of this variant with late onset, autopsy confirmed AD. We genotyped 6 SNPs which we have shown effectively tag the haplotype diversity in MAPT in Caucasians in a series of 254 autopsy confirmed controls and 359 autopsy confirmed late onset cases. We performed a test of the H1c variant using the program Whap and found a significant result testing the H1c variant against all other major haplotypes (empirical p-value=0.006, 1 df). The dominant hypothesis for the etiology of AD has been the amyloid hypothesis. This hypothesis is based on the observation that autosomal dominant mutations in either the APP gene or in the presenilin genes, cause AD by changing APP/Aβ metabolism. However, experiments crossing mice with APP mutations and mice containing MAPT mutations have shown that the process by which Aβ kills neurons involves tau and tangle formation. We believe our data suggests that in the presence of an amyloid load, individuals with MAPT loci that are either highly expressing or express a more pathogenic species of tau through alternate splicing, are more prone to disease. These data suggest that modulating tau expression is a worthwhile approach to consider for the treatment of AD.