Abstract Details

Title Transcriptome Analysis of Single Nucleus RNA-seq from Alzheimer Disease APOE4 Carrier Brains in African American (AA) and Non-Hispanic Whites (NHW) Reveals Differences in APOE Expression

Topic Aging, Dementia, and Behavioral Neurology

Presentation(s) S4 - Aging and Dementia: Risk Factors and Genetics (1:24 PM-1:36 PM)

Poster/Presentation
Number 003

Objective To investigate potential differences in RNA expression between brains of AA Alzheimer Disease (AD) patients that are homozygous carriers of the African Apolipoprotein E4 (APOE4) allele vs homozygous carriers of the NHW APOE4 allele, using single nuclei RNAseq (snRNAseq)

Background APOE4 is the strongest genetic risk factor for late-onset AD. However, the risk of APOE4 carriers for AD is different across ancestral backgrounds, with risk for AA carriers < than NHW carriers < Asian carriers. This difference may be attributed to an unknown protective factor lying in the genomic region surrounding the African APOE4 allele (local ancestry) (Rajabli et al 2018).

Design/Methods

Brain nuclei were isolated from Brodmann area 9 in the frontal cortex from six (three AA and three NHW) AD patients with pathologically confirmed AD. All were APOE4 homozygotes. SnRNA-seq (10X Chromium) was performed and the Seurat pipeline used to identify potential differences in cell specific expression between the ancestries.

Results

We obtained data from ~7000 nuclei per sample sequenced at a median depth of ~120,000 reads per cell and detected ~800 genes/cell. The NHW E4/E4 patients expressed significantly more APOE than AA E4/E4 patients. Further, a unique hybrid cell cluster, expressing a large amount of APOE, was observed primarily in the NHW brains. This novel hybrid cluster appears to be a mix of neurons and astrocytes.

Conclusions This study is unique in its ancestry-specific focus for AD. These data support the hypothesis that NHW AD patients with APOE4 have significantly greater APOE expression in the frontal cortex than in AA APOE4 carriers. This increased APOE expression could be an important contributor to the risk difference for APOE4 observed between the two groups.

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.
	No disclosure on file
Farid Rajabli, PhD (University of Miami)	Farid Rajabli has nothing to disclose.
Patrice Whitehead	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
M. M. Mesulam, MD, FAAN (Cogn Neur & Alzheimer Center, NW Univ)	No disclosure on file
Changiz Geula, PhD (Lab. for Neurodegenerative and Aging Res., Beth Isreal Deaconess Medical Center)	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
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.
William K. Scott, MD (Univ of Miami Miller School of Medicine)	No disclosure on file
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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