Robust differences in cortical cell type proportions across healthy human aging inferred through cross-dataset transcriptome analyses.

Age-related declines in cognitive function are driven by cell type-specific changes in the brain. However, it remains challenging to study cellular differences associated with healthy aging as traditional approaches scale poorly to the sample sizes needed to capture aging and cellular heterogeneity. Here, we employed cellular deconvolution to estimate relative cell type proportions using frontal cortex bulk gene expression from individuals without psychiatric conditions or brain pathologies. Our analyses comprised 8 datasets and 6 cohorts (1142 subjects and 1429 samples) with ages of death spanning 15-90 years. We found aging associated with profound differences in cellular proportions, with the largest changes reflecting fewer somatostatin- and vasoactive intestinal peptide-expressing interneurons, more astrocytes and other non-neuronal cells, and a suggestive "U-shaped" quadratic relationship for microglia. Cell type associations with age were markedly robust across bulk-and single nucleus datasets. Altogether, we present a comprehensive account of proportional differences in cortical cell types associated with healthy aging.