Developing a single cell map of the aging human brain relevant to Alzheimer's disease

National Institute On Aging

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Abstract

In this project, we used single nucleus RNA-sequencing (snRNAseq) to examine cellular transcriptional changes from four different brain regions, comparing donors aged 20-30 years (young) or 60-85 years (old) from n=12 donors per group. We recovered a total of 155,192 nuclei from two cortical regions (entorhinal cortex and middle temporal gyrus) and two subcortical regions (putamen and subventricular zone), each being chosen for their relevance to neurodegenerative diseases or the proliferative niche. We found no changes in cellular composition of different brain regions with healthy aging. Surprisingly, we did find that each brain region has a distinct aging signature, with only minor overlap in differentially associated genes across regions. Moreover, each cell type shows distinct age-associated expression changes, including loss of protein synthesis genes in cortical inhibitory neurons, axonogenesis genes in excitatory neurons and oligodendrocyte precursor cells, enhanced gliosis markers in astrocytes and disease-associated markers in microglia, and genes critical for neuron-glia communication. Importantly, we find cell type-specific enrichments of age associations with genes nominated by Alzheimers disease and Parkinsons disease genome-wide association studies (GWAS), such as apolipoprotein E (APOE), and leucine-rich repeat kinase 2 (LRRK2) in microglia that are independent of overall expression levels across cell types. This data represents a new resource which highlights, first, region- and cell type-specific transcriptomic changes in healthy aging that may contribute to selective vulnerability and, second, provide context for testing GWAS-nominated disease risk genes in relevant subtypes and developing more targeted therapeutic strategies. The data is readily accessible without requirement for extensive computational support in a public website, https://brainexp-hykyffa56a-uc.a.run.app/.