Basic Science and Pathogenesis.

Area of Science:

• Neuroscience
• Genomics
• Psychiatry

Background:

• Neurodegenerative diseases and mental illnesses share molecular pathways, necessitating integrated data for comparative studies.
• Fragmented existing research hinders comprehensive cross-disorder analysis.
• Large-scale integrated data are crucial for understanding complex brain conditions.

Purpose of the Study:

• To create a large-scale, integrated dataset for studying neurodegenerative and psychiatric diseases.
• To facilitate cross-disorder comparisons by linking molecular, cellular, genetic, and clinical data.
• To provide a resource for advancing the understanding of shared and distinct mechanisms in brain disorders.

Main Methods:

• Generated single-nucleus RNA sequencing (snRNA-seq) and genotype data from 1,494 human donors.
• Collected samples from the dorsolateral prefrontal cortex across diverse diagnoses including Alzheimer's, Parkinson's, schizophrenia, bipolar disorder, and controls.
• Employed high-throughput sequencing, rigorous quality control, and computational methods for cell-type-specific profiling.

Main Results:

• Developed a high-resolution cellular taxonomy with 8 major cell classes and 67 subtypes.
• Identified transcriptional and genetic alterations linked to neurodegenerative and psychiatric disorders, highlighting shared molecular pathways.
• Provided donor metadata including neuropsychiatric profiles and neuropathological assessments, alongside open-access tools for data exploration.

Conclusions:

• The PsychAD dataset is a transformative, integrated resource for neuroscience research.
• It is publicly accessible via the AD Knowledge Portal, promoting collaboration and data re-use.
• The dataset provides a foundation for integrative analyses, tool development, and discovery of therapeutic targets for brain disorders.