Basic Science and Pathogenesis.

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Late-onset Alzheimer's disease (LOAD) frequently co-occurs with neuropsychiatric symptoms, particularly depression and anxiety.
• Major depressive disorder (MDD) is a known risk factor for developing LOAD later in life.
• Previous research identified shared genetic risk loci between LOAD and MDD.

Purpose of the Study:

• To conduct a detailed, cell-type specific comparison of brain transcriptomic landscapes in LOAD and MDD.
• To investigate shared and distinct molecular pathologies underlying both diseases.
• To explore potential early pathophysiological changes common to both LOAD and MDD due to shared genetic etiology.

Main Methods:

• Analysis of single nucleus (sn)RNA-seq data from dorsolateral pre-frontal cortex datasets of LOAD and MDD patients and controls.
• Differential gene expression (DEG) analysis using Nebula to identify significant gene expression changes.
• Intercellular communication network analysis using CellChat.

Main Results:

• Significant differentially expressed genes (DEGs) were identified across multiple cell types, including GABAergic neurons, glutamatergic neurons, interneurons, and microglia.
• Common DEGs in neurons and microglia were downregulated in both LOAD and MDD, enriched for pathways related to oxidative phosphorylation and mitochondrial dysfunction.
• Both MDD and LOAD showed reduced cell-cell communication (CCC) between astrocytes and other cell types; LOAD additionally exhibited increased CCC among neuronal subtypes.

Conclusions:

• Single-cell transcriptomic analysis provides mechanistic insights into shared and divergent molecular etiologies of LOAD and MDD.
• Identified dysregulated pathways and impaired cellular communications offer potential therapeutic targets.
• Findings support targeting depression symptoms early to potentially delay or alleviate LOAD onset.