Abstract
INTRODUCTION
Late-onset Alzheimer’s disease (LOAD) and major depressive disorder (MDD) share genetic etiologies. Here, we investigated brain transcriptomic landscapes to gain insights into shared and divergent molecular and biological etiologies across LOAD and MDD.
METHODS
Brain single-nucleus RNA sequencing (snRNA-seq) datasets from cognitively normal older and young individuals and LOAD patients stratified by comorbid MDD were analyzed to identify differential expressed genes (DEGs). Using cell type–specific DEGs we performed biological pathway and intercellular-communication networks analyses. We investigated shared DEGs across MDD and LOAD cohorts and sex-specific DEGs. Results were validated by comparison with four transcriptomic and proteomic studies of MDD and depression.
RESULTS
MDD-associated dysregulated genes and pathways were shared between LOAD and cognitive-normal individuals, including JUNB and DUSP1 in glutamatergic neurons, and PRAM1 and SNX9 in microglia. DEGs shared between the MDD and LOAD cohorts included HSPA1A and NDUFB7 in glutamatergic neurons. Sex interaction analysis identified numerous new DEGs in the MDD cohorts, whereas there were ≈5 to 10 times more DEGs in female than in male individuals. LOAD and MDD common microglial pathways included neuronal injury, stress, peroxisome proliferator-activated receptor (PPAR) signaling and interferon alpha/beta signaling.
DISCUSSION
LOAD and MDD exhibited common molecular profiles, dysregulated pathways, and cellular communication changes. MDD develops earlier in life, thus, our findings provide a window into early molecular and biological processes preceding LOAD-onset.
If you do not see content above, kindly GO TO SOURCE.
Not all publishers encode content in a way that enables republishing at Neuro.vip.
This post is Copyright: | September 12, 2026
Neuro-Dementia