Abstract Details

Title Chromatin accessibility differences between African and European Alzheimer Disease brains.

Topic Aging, Dementia, and Behavioral Neurology

Presentation(s) P2 - Poster Session 2 (11:45 AM-12:45 PM)

Poster/Presentation
Number 3-002

Objective To assess if differential chromatin accessibility between African (AF) and European (EU) local ancestry (LA) Alzheimer Disease (AD) brains correlates with the APOE4 gene expression difference previously observed.

Background LA surrounding the APOE4 gene is associated with increased risk for AD in EU compared to AF LA. We recently demonstrated that APOE4 has significantly higher expression in astrocytes in brains from EU compared to AF LA APOE4 carriers, but the molecular mechanism leading to this is not known. We investigated whether chromatin accessibility differences between EU and AF brains in the LA region correlates with the difference in APOE4 expression previously observed.

Design/Methods We performed single nuclei Assays for Transposase Accessible Chromatin sequencing from frontal cortex in five AF and six EU LA individuals with AD, all APOE4 carriers.

Results

In total, 57,605 nuclei were sequenced. Using UMAPhCluster at resolution 1.3, we identified 13 clusters and seven different cell types. In one astrocyte cluster the APOE LA region showed significantly increased accessibility in the EU compared to AF LA group. This cluster had significantly higher APOE expression in EU than AF LA samples in matched single nuclei RNA sequencing studies. Further, this astrocyte cluster was found to have differential accessibility between ancestries extending across the entire genome. Analysis of genes with altered chromatin accessibility showed enrichment for AD pathways.

Conclusions

This study provides initial findings at comparing chromatin accessibility from AF and EU AD brains. The higher risk for AD by APOE4 EU LA carriers is associated with increased chromatin accessibility and correlates with the increased expression of APOE4 in EU LA vs. AF LA previously observed. Surprisingly, this increase in accessibility appears to extend beyond the APOE4 region, suggesting global regulatory differences in AD astrocytes between the ancestries. Our results open a window for therapeutic strategies targeting APOE4 towards preventing or treating AD.

Authors/Disclosures
PRESENTER	No disclosure on file
Anthony J. Griswold, PhD (University of Miami)	Dr. Griswold has received research support from National Institutes of Health.
Farid Rajabli, PhD (University of Miami)	Farid Rajabli has nothing to disclose.
	No disclosure on file
Sandra Weintraub, PhD, FAAN (Northwestern Mesulam Center for Cognitive Neurology and Alzheimer'S Disease)	Dr. Weintraub has nothing to disclose.
	No disclosure on file
	No disclosure on file
John Q. Trojanowski, MD, PhD (University of PA School of Med)	Dr. Trojanowski has nothing to disclose.
	No disclosure on file
David A. Bennett, MD (Rush University Medical Center)	Dr. Bennett has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Annovis. Dr. Bennett has received personal compensation in the range of $500-$4,999 for serving as a Consultant for New Amsterdam. Dr. Bennett has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for AbbVie. Dr. Bennett has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for AbbVie.
Margaret A. Pericak-Vance, PhD (University of Miami Miller School of Medicine)	Dr. Pericak-Vance has nothing to disclose.
	No disclosure on file
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.

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