Abstract Details

Title Investigation of MAPT Subhaplotypes as Risk Factors for Late-Onset Alzheimer's Disease

Topic Aging and Dementia

Presentation(s) S34 - (-)

Poster/Presentation
Number 003

Objective

Background Neurofibrillary tangles composed of tau protein (MAPT) are a classic neuropathological feature of AD. MAPT variants associate with primary tauopathies, however evidence for genetic involvement of MAPT in LOAD has been inconsistent. We sought to examine well-established MAPT subhaplotype-tagging variants in our LOAD case-control series to determine their effect on risk for LOAD. We also hypothesize that some of the MAPT variants may confer disease risk by influencing brain expression levels of MAPT, based on our expression GWAS (eGWAS).

Design/Methods We genotyped four SNPs which tag the most common MAPT subhaplotypes (frequencies >5%), in three Caucasian LOAD case-control series (N-cases=1,886; N-controls=3,236). SNPs were tested for association with LOAD risk using logistic regression, adjusted for covariates. We measured gene expression levels in the cerebellum (N=197) and temporal cortex (N=202) of autopsied AD subjects as part of our eGWAS. We tested associations of the four MAPT SNPs with expression of MAPT, using linear regression with appropriate covariate adjustments.

Results The H2-tagging SNP (rs8070723), known to associate with decreased risk of other tauopathies, was significantly associated with decreased risk of LOAD (OR = 0.783, p=3.05E-04). This SNP was also associated with decreased MAPT expression in both brain regions (beta=-0.16 to -0.47, p=6.2E-03 to 8.92E-31). The H1b tagging SNP (rs1467967) had nominally significant association with increased risk of LOAD (OR=1.25, p=0.04) and increased expression of MAPT in both brain regions. Though the H1c-tagging SNP (rs242557) associated with higher brain MAPT levels, it did not associate with AD risk.

Conclusions In our large LOAD series we find significant evidence for association of MAPT variants with risk of LOAD and brain gene expression. It will be important to investigate the effects of the rarer MAPT subhaplotypes, which is underway.

Authors/Disclosures
Mariet Allen, PhD (Mayo Clinic) PRESENTER	No disclosure on file
	No disclosure on file
Michaela Kachadoorian	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Ronald C. Petersen, MD, PhD, FAAN (Mayo Clinic)	Dr. Petersen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. Dr. Petersen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Genentech. Dr. Petersen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eli Lilly and Co.. Dr. Petersen has received personal compensation in the range of $0-$499 for serving as a Consultant for Eisai, Inc.. Dr. Petersen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novo Nordisk. Dr. Petersen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Dr. Petersen has received publishing royalties from a publication relating to health care. Dr. Petersen has received publishing royalties from a publication relating to health care. Dr. Petersen has received publishing royalties from a publication relating to health care. Dr. Petersen has a non-compensated relationship as a Board of Directors with American Brain Foundation that is relevant to AAN interests or activities.
	No disclosure on file
	No disclosure on file
	No disclosure on file
Minerva Carrasquillo (Mayo Clinic Florida)	Minerva Carrasquillo has nothing to disclose.
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Ronald C. Petersen, MD, PhD, FAAN (Mayo Clinic)	Dr. Petersen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. Dr. Petersen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Genentech. Dr. Petersen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eli Lilly and Co.. Dr. Petersen has received personal compensation in the range of $0-$499 for serving as a Consultant for Eisai, Inc.. Dr. Petersen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novo Nordisk. Dr. Petersen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Dr. Petersen has received publishing royalties from a publication relating to health care. Dr. Petersen has received publishing royalties from a publication relating to health care. Dr. Petersen has received publishing royalties from a publication relating to health care. Dr. Petersen has a non-compensated relationship as a Board of Directors with American Brain Foundation that is relevant to AAN interests or activities.
Neill R. Graff-Radford, MD, FAAN (Mayo Clinic Jacksonville)	The institution of Dr. Graff-Radford has received research support from Biogen. The institution of Dr. Graff-Radford has received research support from Lilly. The institution of Dr. Graff-Radford has received research support from Eisai. The institution of Dr. Graff-Radford has received research support from Biogen. Dr. Graff-Radford has received publishing royalties from a publication relating to health care.
Dennis W. Dickson, MD (Mayo Clinic)	Dr. Dickson has nothing to disclose.
Steven G. Younkin, MD, PhD (Mayo Clinic Jacksonville)	No disclosure on file
Nilufer Taner, MD, PhD, FAAN (Mayo Clinic)	The institution of Dr. Taner has received research support from NIH.

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