A global consortium mapped gene activity across more than 6.3 million brain cells from 1,494 donors, spanning from infancy to 108 years old, to illuminate normal brain development and disorders such as Alzheimer's, Parkinson's, Lewy body dementia, vascular dementia, schizophrenia, and bipolar disorder.

The study found both shared and disease-specific patterns of gene activity, identifying biological processes and cell populations that could be targeted for therapies.

There are strong similarities across Alzheimer's, Lewy body disease, vascular dementia, and Parkinson's in pathways for nerve-cell development, neuronal signaling, and blood-vessel biology, with shared microglia-related pathways between Alzheimer's and Parkinson's.

Age emerges as the dominant driver of transcriptional change during development, with notable additional aging-related shifts in late life, underscoring dynamic early-life changes and aging effects.

Increasing cell-type resolution boosts discovery of regulatory effects but lowers statistical power; the number of eGenes varies by cell type, with higher counts in abundant cell types and deeper sequencing, such as 10,913 eGenes in excitatory neurons at the class level.

3ʹ UTR usage (APA) varies by cell type, with neurons tending toward longer 3ʹ UTRs and microglia toward shorter ones, reflecting cell-type–specific regulatory environments.

Open chromatin regions near lead eQTLs are enriched in the expected cell types, supporting cell-type–specific regulatory programs, with notable enrichment in glial cells compared with neurons.

Lifespan trajectories show two broad patterns: log-increasing cell types (e.g., excitatory neurons, astrocytes, oligodendrocytes) and log-decreasing ones (e.g., interneurons, OPCs, microglia), indicating early expansion followed by stabilization and late-life changes in glia and select interneurons.

Genetic regulation of APA revealed 4,288 genes with cis 3ʹaQTLs; lead 3ʹaQTLs localize near g‑APAs and are enriched in 3ʹ UTRs, yet also present in promoters and 5ʹ UTRs, implying promoter effects on APA.

Transcriptional convergence in excitatory neurons grows with age, while convergence in interneurons and glia is more modest; convergent genes are broadly expressed and tied to maintenance, with neuronally enriched convergence linked to adhesion and neurotransmitter transport early in life and to DNA repair and antigen processing later.

Across aging and disease, some cell types follow nonlinear gene expression trajectories, suggesting dynamic roles in disease progression and aging rather than simple linear changes.