Integrated multimodal cell atlas of Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) is the most common cause of dementia in older adults. Neuropathological and imaging studies have demonstrated a progressive and stereotyped accumulation of protein aggregates, but the underlying molecular and cellular mechanisms driving AD progression and vulnerable cell populations affected by disease remain coarsely understood. The current study harnesses single cell and spatial genomics tools and knowledge from the BRAIN Initiative Cell Census Network to understand the impact of disease progression on middle temporal gyrus cell types. We used image-based quantitative neuropathology to place 84 donors spanning the spectrum of AD pathology along a continuous disease pseudoprogression score and multiomic technologies to profile single nuclei from each donor, mapping their transcriptomes, epigenomes, and spatial coordinates to a common cell type reference with unprecedented resolution. Temporal analysis of cell-type proportions indicated an early reduction of Somatostatin-expressing neuronal subtypes and a late decrease of supragranular intratelencephalic-projecting excitatory and Parvalbumin-expressing neurons, with increases in disease-associated microglial and astrocytic states. We found complex gene expression differences, ranging from global to cell type-specific effects. These effects showed different temporal patterns indicating diverse cellular perturbations as a function of disease progression. A subset of donors showed a particularly severe cellular and molecular phenotype, which correlated with steeper cognitive decline. We have created a freely available public resource to explore these data and to accelerate progress in AD research atSEA-AD.org.

Low circulating adropin levels in late-middle aged African Americans with poor cognitive performance

“…We used snRNA-seq data to compare relative expression levels and fraction of cells within each population in the human MTG in a reference neurotypical population of males and females (aged 18-68 years, n=5) ( Fig 1A, B ) and an older cohort of males and female with mixed dementia status (aged from 65 to 90+ years, n=84) ( Fig. 1C, D ) 27 . The data from this study indicates astrocytes are a major site of ENHO expression relative to other cell types, irrespective of age ( Fig.…”

“…ENHO expression in human brain samples was assessed using data from the Seattle Alzheimer’s Disease Cell Atlas consortium (http://portal.brain-map.org/explore/seattle-alzheimers-disease) 27 . ENHO expression was compared in single nuclei isolated from the middle temporal gyrus (MTG) of 84 older individuals (33 males, 51 females; mean and SD of age at time of death, 88 years, 8years; range 65 to 90+ years) and a younger neurotypical reference group (male and females aged 18-68 years, n=5).…”

Enhancer-AAVs allow genetic access to oligodendrocytes and diverse populations of astrocytes across species

“…Enhancer-AAV eHGT-390m, on the other hand, did not show a change of expression. This could be due to it being selected based on cell type identity, and most properties of cell types have not been seen to change character dramatically in the context of disease 22,78,79 . Enhancers can also be selected that do not change activity during development, aging, or disease, in a similar way to avoid selecting enhancers predicted to have activity in off-target tissues.…”

Gene networks and systems biology in Alzheimer's disease: Insights from multi‐omics approaches

“…For demonstrating the pipeline, we have merged snRNA-seq data from the following publications in the field of AD and dementia asso- Alzheimer's Disease Brain Cell Atlas (SEA-AD), 23,42,[55][56][57][58] totaling 349 samples, 1.3 million cells, and 25k genes after the initial QC process (Figure 1B). While analysis approaches are continually evolving, we have adopted the following workflow for single cell/nucleus RNA-seq F I G U R E 1 Schematic workflow of single-cell/nucleus data acquisition and analysis.…”

“…In a recent publication by Miyoshi & Morabito et al, researchers conducted a comprehensive transcriptomic survey of AD using ST and snRNA-seq techniques. They analyzed cortical samples from various AD stages, including early-stage AD, late-stage AD, and AD in individuals with Down syndrome 58. Their study spotlighted significant changes in ANGPTL and CD99 signaling, revealing how astrocytes influence brain vascular integrity in AD.…”