A Transcriptomic Signature of Depressive Symptoms in Late Life

Background

Depressive symptoms in late life can impair daily function and accompany cognitive decline. However, the molecular mechanisms that underlie these changes in the brain remain poorly understood.

Methods

Differential expression analysis was performed on bulk-tissue RNA sequencing data generated from dorsolateral prefrontal cortex samples of elderly participants in ROS/MAP (Religious Orders Study and Memory and Aging Project; N = 998, mean age at death = 89.7 years). Bulk tissue RNA sequencing was analyzed against depressive symptoms measured prior to death, controlling for Alzheimer’s disease neuropathology, medication status, and lifestyle factors. Sex-stratified models were also tested.

Results

Increased abundance of the Prader-Willi syndrome–associated gene PWAR1 (corrected p = 5.47 × 10⁻³) and CTDSPL2 (corrected p = .03) were associated with a higher burden of depressive symptoms in the combined sample. An additional 14 genes showed suggestive associations, including several with known links to neuropsychiatric illness (e.g., ACVR2B-AS1, COL19A1). Functional enrichment analysis revealed downregulation of aerobic metabolism and upregulation of both amino acid catabolism and DNA modification processes. Differential expression signatures were poorly correlated between males and females (Pearson r = 0.12; 95% CI, 0.10 to 0.13), and only the male group showed independently significant differential expression. Little overlap was found with previously published analyses of major depressive disorder.

Conclusions

Building on recently published single-nucleus profiling, we present the largest-ever study of transcriptomic correlates of depressive symptoms in late life, revealing new insights into sex-specific regulators. PWAR1 and CTDSPL2 were identified as putative markers of late-life depression in the dorsolateral prefrontal cortex and warrant further study.