Abstract Details

Title African Locus Reduces the Effect of ApoE e4 Allele in Alzheimer’s Disease

Topic Aging and Dementia

Presentation(s) S15 - Aging and Dementia 1 (3:54 PM-4:06 PM)

Poster/Presentation
Number 003

Background African descent populations have a lower risk from ApoEε4 compared to other populations. Identifying the mechanism of this protection could lead to greater insight into the mechanism of disease and eventual therapeutic intervention.

Objective Identify areas of the genome that interact with ApoEε4 in African ancestry and result in a lower risk for developing Alzheimer disease (AD).

Design/Methods We performed association analyses using a logistic regression model with ApoEε4 allele as an interaction term and adjusted for genome-wide ancestry, age, and sex. Discovery analysis included imputed SNP data from 1,850 African American (AA) individuals with AD and 4,331 AA controls. We performed replication analysis on whole-genome sequenced (WGS) 63 Ibadan AD individuals and 648 Ibadan controls; WGS 273 Puerto Rican (PR) AD individuals and 275 PR controls and SNP imputed 8,463 non-Hispanic White (NHW) AD individuals and 11,365 NHW controls.

Results We identified a significant interaction with the ApoE ε4 allele and the SNP rs10423769_A allele, (β=-0.54,SE=0.12,p-value=7.50x10^-6) in the discovery AA dataset, and replicated this finding in Ibadan(β = -1.32,SE = 0.52,p-value = 1.15x10^-2) and PR(β=-1.27,SE=0.64,p-value=4.91x10^-2) individuals, but not in NHW(β=-1.51,SE=0.84,p-value=7.26x10^-2). The presence of a rs10423769 A allele reduces the odds ratio for AD risk from 7.2 for ApoEε4/ε4 without the A allele to 2.1 for allele ApoEε4/ε4 carriers with the A allele. The A allele is common in African-descent populations (MAF=0.12), but very rare in European (MAF=0.003) and monomorphic in East Asian populations. This locus is located approximately 2 megabases distal to ApoE, in a large cluster of pregnancy specific beta-1 glycoproteins on chromosome 19.

Conclusions

This study identifies a new African-ancestry specific locus that reduces the risk effect of ApoEε4 for developing Alzheimer disease. The mechanism of the interaction with ApoEε4 is not known but suggests a novel mechanism for reducing the risk for ε4 carriers and potential for therapeutic intervention.

Authors/Disclosures
Farid Rajabli, PhD (University of Miami) PRESENTER	Farid Rajabli has nothing to disclose.
Gary W. Beecham, PhD (University of Miami, Hussman Institute for Human Genomics)	The institution of Dr. Beecham has received research support from NIH. The institution of an immediate family member of Dr. Beecham has received research support from NIH.
	No disclosure on file
	No disclosure on file
Adesola Ogunniyi, MD	Dr. Ogunniyi has nothing to disclose.
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Derek Dykxhoorn, PhD (University of Miami Miller School of Medicine)	No disclosure on file
Karen Nuytemans, PhD (U of Miami, John P. Hussman Institute)	The institution of Dr. Nuytemans has received research support from NIH. The institution of Dr. Nuytemans has received research support from NIH. The institution of Dr. Nuytemans has received research support from Department of Defense. The institution of Dr. Nuytemans has received research support from Margaret Q. Landenberger Foundation. The institution of Dr. Nuytemans has received research support from American Parkinson Disease Association. The institution of Dr. Nuytemans has received research support from Florida Department of Health.
	No disclosure on file
	No disclosure on file
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	No disclosure on file
Briseida E. Feliciano Astacio, MD, FAAN	Dr. Feliciano Astacio has received research support from NIA/NIH.
	No disclosure on file
	No disclosure on file
Anthony J. Griswold, PhD (University of Miami)	Dr. Griswold has received research support from National Institutes of Health.
	No disclosure on file
Christiane Reitz, MD, PhD (Columbia University)	No disclosure on file
Jonathan Haines, MD (Vanderbilt University)	No disclosure on file
Margaret A. Pericak-Vance, PhD (University of Miami Miller School of Medicine)	Dr. Pericak-Vance has nothing to disclose.
Jeffery Vance, MD, PhD (University of Miami)	Dr. Vance has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for neurology genetics.