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.

Bulk and Single-Nucleus Transcriptomics Highlight Intra-Telencephalic and Somatostatin Neurons in Alzheimer's Disease.

Cortical neuron loss is a pathological hallmark of late-onset Alzheimer's disease (AD). However, it remains unclear which neuronal subtypes beyond broad excitatory and inhibitory classes are most vulnerable. Here, we analyzed cell subtype proportion differences in AD compared to non-AD controls using 1037 post-mortem brain samples from six neocortical regions. We identified the strongest associations of AD with fewer somatostatin (SST) inhibitory neurons (ß = -0.48, p bonf = 8.98 × 10-9) and intra-telencephalic (IT) excitatory neurons (ß = -0.45, p bonf = 4.32 × 10-7). Replication in three AD case-control single-nucleus RNAseq datasets most strongly supported the bulk tissue association of fewer SST neurons in AD. In depth analyses of cell type proportions with specific AD-related neuropathological and cognitive phenotypes revealed fewer SST neurons with greater brain-wide post-mortem tau and beta amyloid, as well as a faster rate of antemortem cognitive decline. In contrast, greater IT neuron proportions were associated with a slower rate of cognitive decline as well as greater residual cognition-a measure of cognitive resilience-but not canonical AD neuropathology. Our findings implicate somatostatin inhibitory and intra-telencephalic excitatory neuron subclasses in the pathogenesis of AD and in cognitive resilience to AD pathology, respectively.