Bridging the gap: Multi-omics profiling of brain tissue in Alzheimer's disease and older controls in multi-ethnic populations

Abstract

Introduction: Multi-omics studies in Alzheimer's disease (AD) revealed many potential disease pathways and therapeutic targets. Despite their promise of precision medicine, these studies lacked Black Americans (BA) and Latin Americans (LA), who are disproportionately affected by AD.

Methods: To bridge this gap, Accelerating Medicines Partnership in Alzheimer's Disease (AMP-AD) expanded brain multi-omics profiling to multi-ethnic donors.

Results: We generated multi-omics data and curated and harmonized phenotypic data from BA (n = 306), LA (n = 326), or BA and LA (n = 4) brain donors plus non-Hispanic White (n = 252) and other (n = 20) ethnic groups, to establish a foundational dataset enriched for BA and LA participants. This study describes the data available to the research community, including transcriptome from three brain regions, whole genome sequence, and proteome measures.

Discussion: The inclusion of traditionally underrepresented groups in multi-omics studies is essential to discovering the full spectrum of precision medicine targets that will be pertinent to all populations affected with AD.

Highlights: Accelerating Medicines Partnership in Alzheimer's Disease Diversity Initiative led brain tissue profiling in multi-ethnic populations. Brain multi-omics data is generated from Black American, Latin American, and non-Hispanic White donors. RNA, whole genome sequencing and tandem mass tag proteomicsis completed and shared. Multiple brain regions including caudate, temporal and dorsolateral prefrontal cortex were profiled.

Keywords: Alzheimer's disease; data descriptor; multi‐omics; precision medicine; proteome; transcriptome; whole genome sequencing.

FIGURE 1

Profiled brain regions. Approximate location of tissue in brain regions sampled for molecular profiling, including RNAseq, WGS, and proteomics. Tissue from the dorsolateral prefrontal cortex (Brodmann areas 8, 9, and/or 46) and caudate nucleus were contributed by all sites, including Mayo Clinic, Mt. Sinai, Columbia, Rush, and Emory. In contrast, tissue from the superior temporal gyrus (Brodmann 22) was provided by all sites except Columbia, which had only the temporal pole available for this lobe. RNAseq, RNA sequencing; WGS, whole genome sequencing. Lobes are demarcated by their different colors shown on the brain schematic. The sites that provided samples from the specific brain regions are shown with the colored circles.

FIGURE 2

Data types by tissue, site, and individual race and ethnicity. Bar graph depicting the number of samples profiled by each assay (whole genome sequencing, RNAseq, or TMT proteomics). Whole genome sequencing data were generated for 626 donors from various contributing sites (an additional 411 donors had WGS from AMP‐AD 1.0 efforts, not shown here). Similarly, 2140 unique transcriptomics profiles from RNAseq of the caudate nucleus (n = 602), dorsolateral prefrontal cortex (n = 779), superior temporal gyrus (716), and temporal pole (n = 43) from 844 donors were generated. Samples sent to other sites for the swap study are not included. A lone superior temporal gyrus RNAseq sample from Columbia was also not included in this summary. One thousand two hundred forty unique TMT proteomes from dorsolateral prefrontal cortex (n = 996) and superior temporal gyrus (n = 244) were generated from 1015 donors. These include the 307 samples from the AMP‐AD 1.0 efforts to balance batches, as described in the Methods section. Pie charts on the right show the number of donors profiled by ethnoracial categories (BA = Black American, NHW = non‐Hispanic White, LA = Latin American, and Other). These categories were defined as follows: donors whose race was encoded as “Black or African American” and ethnicity as "isHispanic = FALSE" in the individual metadata were treated as "BA." Those with race encoded as White and ethnicity as "isHispanic = FALSE" were categorized as "NHW." The remaining donors, for whom ethnicity was encoded as "isHispanic = TRUE" were treated as "LA." All remaining donors from various other races were encoded as "Other." AMP‐AD, Accelerating Medicines Partnership in Alzheimer's Disease; MSSM, Mount Sinai School of Medicine; RNAseq, RNA sequencing; TMT, isobaric tandem mass tag; WGS, whole genome sequencing.

FIGURE 3

RNAseq sample swaps. To evaluate the technical variability of RNA sequencing among the three sites, RNA tissue from the same brain was sequenced at each site for a small number of samples. The number and region of samples exchanged are illustrated with the grayscale brain image with the exchanged tissue highlighted in color (DLPFC in blue and STG in green). Straight arrows represent tissue exchange; circular arrows represent tissue sequenced at the original site, shown in blue, green, and red circular arrows for Mayo Clinic, Rush, and NYGC, respectively. Samples from MSSM (4 DLPFC, 4 STG) and Columbia (5 DLPFC) were used for the swap experiment at NYGC. DLPFC, dorsolateral prefrontal cortex; MSSM, Mount Sinai School of Medicine; NYGC, New York Genome Center; RNAseq, RNA sequencing.