Variation In MAPT Is Associated With Tau Deposition In Hippocampus

Background:Alzheimer disease（AD）is the most common type of dementia.With the aging of the social population,the annual growth rate of AD has been more than cardiovascular disease and become the third major threat to human health.In the recent thirty years,with the in-depth study of AD it has clearly defined that the extracellular amyloid senile plaques（Aβ）and intracellular Neurofibrillary Tangles（NFTs）are the major histopathological change in AD.Tau is microtubule-associated protein playing an important role in assembling and stabilizing microtubules in axons.Physiologic Tau is soluble protein in neurons when the Tau protein is over-phosphorylated the Tau protein would become insoluble and thus aggregated in axons,ultimately led neurons to death.MAPT（microtubule-associated protein tau）is the coding gene of Tau protein,regulating alternative splicing,and giving rise to several mRNA species.MAPT gene mutations have been reported to have association with several neurodegenerative disorders such as AD,cortico-basal degeneration（CBD）,Pick’s disease,progressive supranuclear palsy（PSP）and frontotemporal dementia（FTD）.Previous study demonstrated that MAPT mutation is associated with cerebrospinal fluid（CSF）Tau,which are believed to reflect the presence of this aggregates in brain.In recent years,the whole genome association studies have confirmed that the MAPT gene mutation is closely associated to AD.MAPT is the coding gene of Tau protein,and the accumulation of Tau protein in neurons is one of the recognized pathological markers of AD.Therefore,it is concluded that the mutation in MAPT gene may directly or indirectly influence AD by alter the expression of Tau protein.The H1haplotype of the MAPT gene as the risk factor for AD has been most studied.Some scholars use cerebrospinal fluid（CSF）Tau as phenotype to study the association between MAPT H1haplotype and Tau,the results still remain controversial.The probable reason may include that the Tau in CSF maybe obvious heterogeneity or due to the small sample size.What’s more,elevated cerebrospinal fluid（CSF）tau concentrations also appeared in acute stroke suggest that CSF tau comes from cell death or injury,so it can’t directly reflect AD brain.At present,with the invention of Positron Emission Tomography（PET）ligand to Tau,¹⁸F-AV-1451 PET has been proved to be effective in measuring Tau in different brain regions in human.The disordered Tau deposition in hippocampus is specific to AD which can be a biomarker to distinguish AD from others tauopathies.Objective:We used hippocampal Tau PET as phenotype to study the association between MAPT H1 haplotype and Tau deposition.Materials and Methods:The samples in our study are from Alzheimer’s Disease Neuroimaging Initiative（ADNI-2）database.The ADNI was launched in 2003,including AD,mild cognitive impairment（MCI）and healthy controls who were recruited from more than 50 sites across the Canada and USA.The participants in our study were all accepted Tau PET ¹⁸F-AV-1451 and gene sequencing.The hippocampus area was selected as the region of interest（ROI）for our study.We used ¹⁸F-AV-1451 positron emission tomography（PET）to localize and quantify hippocampal Tau deposition and we corrected the values for partial volume effects.Five MAPT single nucleotide polymorphisms（SNPs）specific to the H1 haplotype were selected as candidate locus.We used the linear regression model to explore the association between hippocampal Tau deposition and genetic polymorphisms.The P value<0.05 was regarded as statistical significance.Results:Date with both imaging and neuropsychological evaluation were available for 42HCs,36 MCI,and 9 participants with AD at baseline.There were no significant differences in age,gender,APOEε4 allele status and educational years among the diagnostic groups（P>0.05）.Cognitive impairment assessment including MMSE,CDR-SB were significantly different among diagnostic groups（P<0.0001）.As expected,participants with AD showed a severer cognitive impairments than MCI and HCs with a lower MMSE score and higher CDR-SB scores（P<0.0001）.Even participants with MCI showed a higher CDR-SB score（P<0.0001）than HCs but without significant difference in MMSE score.The proportion of amyloid positivity(¹⁸F-Florbetapir PET scan)was significant differences among the diagnostic groups,participants with AD were all amyloid positive which showed a higher ratio than participants with MCI and HCs（P=0.002,Fisher’s Exact Test）.The mean hippocampal volume in AD participants were observed significantly smaller than MCI and HCs groups（P=0.002,P<0.0001 respectively）but without significantly difference between MCI and HCs（P=0.394）.The hippocampus Tau PET showed a negatively correlation with mean hippocampus volume（r=-.281,P=0.008）,a positively correlation with ¹⁸F-florbetaben（r=.439,P<0.0001）.The higher Tau PET was associated with more serious cognitive score.Rs242557 was associated with hippocampal Tau deposition（P=0.007,Bonferroni correction）in a linear regression model accounting for age,sex,and diagnosis APOEε4.The minor allele rs242557-A was associated with higher Tau deposition in hippocampus.We divided the sample into two groups,Aβ（+）and Aβ（-）by Aβlevels.The MAPT rs242557 showed significant association with hippocampal Tau deposition only in Aβ（+）group.In the view of the controversial interaction between APOEε4 genotype and MAPT haplotype in neurodegenerative disease,we decided to examine whether APOEε4 status had any influence on H1 haplotype in tau deposition by AV1451.When the APOEε4 status was added controlled as covariates,the Bonferroni corrected P-value increased moderately from 0.003 to 0.005 in hippocampus.In order to further study the association between ApoEε4 allele and H1 haplotype in tau deposition in hippocampus,subjects were stratified into ApoEε4 allele carriers and non-carriers.In the ApoEε4 allele positive subset,hippocampus Tau PET showed significant association with MAPT H1 haplotype rs242557.In the ApoEε4 allele negative subset,hippocampus Tau PET showed no significant association with rs242557（P>0.05,after Bonferroni correction）with controlling for age,gender,educational years,disease and ApoE status.The Aβlevels in ApoEε4（+）group are significant higher compared with ApoEε4（-）group.When we adjusted Aβlevels the association between rs242557 and hippocampus Tau PET became no significant in neither ApoEε4（+）group or ApoEε4（-）group.Therefore the results suggested that it was Aβlevels but not ApoEε4 genotype directly affected the role of rs242557 in hippocampus Tau PET.Conclusions:Only rs242557 showed significant association with Tau deposition in hippocampus among the five MAPT loci.However this association seemed to depend on Aβlevels and the association was only observed in Aβ（+）group.