Single-cell atlas of transcriptomic vulnerability across multiple neurodegenerative and neuropsychiatric diseases

This paper introduces the PsychAD cohort, a comprehensive single-nucleus RNA sequencing (snRNA-seq) atlas comprising over 6.3 million nuclei from 1,494 donors. The study investigates the transcriptomic landscape of the dorsolateral prefrontal cortex (DLPFC) across eight major brain disorders: Alzheimer's disease (AD), diffuse Lewy body disease (DLBD), vascular dementia (Vas), Parkinson's disease (PD), tauopathy, frontotemporal dementia (FTD), schizophrenia (SCZ), and bipolar disorder (BD). By integrating this data with clinical and pathological metadata, the researchers aimed to disentangle shared versus disease-specific molecular mechanisms.

The researchers found that inter-individual variation accounts for approximately 10% of gene expression variation in the DLPFC, with highly variable genes often linked to basic housekeeping functions. After accounting for universal cross-disease signatures—such as those involved in mRNA splicing and protein localization—the study identified strong transcriptomic and genetic concordance among AD, DLBD, Vas, and PD, primarily driven by synaptic signaling alterations in neurons. Furthermore, the study modeled AD progression using variational autoencoders, revealing that immune and vascular cell responses are highly nonlinear and play critical roles in dementia resilience, with specific cell types like interneurons exhibiting protective effects against amyloid-beta plaque accumulation.

This atlas provides a foundational resource for understanding the molecular convergence of neurodegenerative and neuropsychiatric conditions. By identifying shared vulnerabilities and cell-type-specific responses, the study offers a roadmap for prioritizing therapeutic targets that address common pathological pathways across multiple brain disorders. The integration of genetic risk with transcriptomic data further validates the role of specific cell types in mediating disease susceptibility.