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MAPT  encodes for tau, the predominant component of neurofibrillary tangles that are neuropathological hallmarks of Alzheimer’s disease (AD). Genetic association of  MAPT  variants with late-onset AD (LOAD) risk has been inconsistent, although insufficient power and incomplete assessment of  MAPT  haplotypes may account for this.    Methods  We examined the association of  MAPT  haplotypes with LOAD risk in more than 20,000 subjects ( n -cases = 9,814,  n -controls = 11,550) from Mayo Clinic ( n -cases = 2,052,  n -controls = 3,406) and the Alzheimer’s Disease Genetics Consortium (ADGC,  n -cases = 7,762,  n -controls = 8,144). We also assessed associations with brain  MAPT  gene expression levels measured in the cerebellum ( n  = 197) and temporal cortex ( n  = 202) of LOAD subjects. Six single nucleotide polymorphisms (SNPs) which tag  MAPT  haplotypes with frequencies greater than 1% were evaluated.    Results  H2-haplotype tagging rs8070723-G allele associated with reduced risk of LOAD (odds ratio, OR = 0.90, 95% confidence interval, CI = 0.85-0.95, p = 5.2E-05) with consistent results in the Mayo (OR = 0.81, p = 7.0E-04) and ADGC (OR = 0.89, p = 1.26E-04) cohorts. rs3785883-A allele was also nominally significantly associated with LOAD risk (OR = 1.06, 95% CI = 1.01-1.13, p = 0.034). Haplotype analysis revealed significant global association with LOAD risk in the combined cohort (p = 0.033), with significant association of the H2 haplotype with reduced risk of LOAD as expected (p = 1.53E-04) and suggestive association with additional haplotypes.  MAPT  SNPs and haplotypes also associated with brain  MAPT  levels in the cerebellum and temporal cortex of AD subjects with the strongest associations observed for the H2 haplotype and reduced brain  MAPT  levels (β = -0.16 to -0.20, p = 1.0E-03 to 3.0E-03).    Conclusions  These results confirm the previously reported  MAPT  H2 associations with LOAD risk in two large series, that this haplotype has the strongest effect on brain  MAPT  expression amongst those tested and identify additional haplotypes with suggestive associations, which require replication in independent series. These biologically congruent results provide compelling evidence to screen the  MAPT  region for regulatory variants which confer LOAD risk by influencing its brain gene expression.

Association of MAPT haplotypes with Alzheimer’s disease risk and MAPT brain gene expression levels