Older molecular brain age in severe mental illness

Area of Science:

• Neuroscience
• Genetics
• Psychiatry

Background:

• Psychiatric disorders are linked to accelerated brain aging and increased neurodegenerative disease risk.
• Brain aging exhibits significant inter-individual variability despite group-level molecular, cellular, and structural changes.

Purpose of the Study:

• To assess gene expression deviations from normal age-dependent trajectories.
• To evaluate these deviations as predictors for major mental illnesses and neurodegenerative disorders.

Main Methods:

• Large-scale gene expression and genotype analyses in postmortem frontal cortical samples (n=214, ages 20-90).
• Derived "molecular age" from age-dependent genes; "delta age" defined as deviation from chronological age.
• Identified genetic variants using cis-eQTL and GWAS, creating polygenic risk scores (PRS^cis-eQTL, PRS^GWAS) for validation.

Main Results:

• Molecular age correlated strongly with chronological age (r=0.88/0.91) using 68/76 age-related genes.
• Molecular age was elevated in bipolar disorder (BP) and schizophrenia (SCZ), but not major depressive disorder (MDD).
• PRSs associated with SCZ/MDD diagnostics, SCZ cognition, and Alzheimer's disease (AD) pathology in validation cohorts.

Conclusions:

• Older molecular brain aging is a shared characteristic of severe mental illnesses and neurodegeneration.
• Gene expression patterns reflecting accelerated aging may serve as biomarkers for psychiatric and neurodegenerative disease risk.