Researchers assembled a single-cell atlas of gene activity in the human prefrontal cortex to investigate aging and a range of brain diseases, including Alzheimer’s disease, Lewy body disease, vascular dementia, Parkinson’s disease, tauopathy, frontotemporal dementia, schizophrenia, and bipolar disorder.

In Alzheimer’s disease, progression aligned with neuronal loss and a higher presence of immune and vascular cells, while deeper excitatory neurons in specific brain regions were linked to psychiatric symptoms observed in patients.

A separate analysis mapped lifespan changes in gene activity in healthy brains, showing rapid remodeling from birth to about age 24, relative stability in midlife, and renewed changes after age 65 in some cell types, helping distinguish disease-related changes from normal aging.

The study analyzed gene activity in over 6 million cells from nearly 1,500 individuals, using brain tissue from deceased donors across the lifespan to compare neurotypical brains with diseased ones.

Common gene activity changes across diseases involved basic cellular functions, with some changes being disease-specific; Alzheimer’s disease, diffuse Lewy body disease, vascular dementia, and Parkinson’s disease showed the most similarity in their gene activity patterns.

The PsychAD atlas linked genetic risk for brain diseases to specific cell types, genes, and pathways, and developed computational tools to identify cell states tied to Alzheimer’s, cognitive decline, resilience, and psychiatric symptoms, while introducing methods to compare patients with Alzheimer’s.

Overall, this represents one of the largest single-cell brain analyses to date and creates a resource for potential targets and therapeutic avenues, with researchers noting it’s just the beginning and aiming to scale to roughly 10,000 individuals.