Transcriptomic and Network Analysis Identifies Shared and Unique Pathways across Dementia Spectrum Disorders.

Area of Science:

• Neuroscience
• Genomics
• Molecular Biology

Background:

• Dementia affects 50 million globally, posing a significant public health challenge.
• Alzheimer's disease (AD), vascular dementia (VaD), and frontotemporal dementia (FTD) exhibit overlapping clinical, genetic, and pathological features, complicating diagnosis.

Purpose of the Study:

• To identify dysregulated molecular pathways and transcription factors in AD, VaD, and FTD by comparing frontal cortex transcriptomes.
• To uncover shared and distinct molecular signatures that could inform diagnosis and treatment strategies for different dementia types.

Main Methods:

• Transcriptome analysis of frontal cortex tissue from patients diagnosed with AD, VaD, and FTD.
• Differential gene expression analysis to identify upregulated and downregulated pathways in each dementia type.

Main Results:

• Alzheimer's disease (AD) showed enrichment in adherens/tight junctions and MAPK/PI3K-Akt signaling; downregulated genes involved calcium signaling.
• Vascular dementia (VaD) displayed upregulated genes in infectious disease and NF-kappa beta signaling; downregulated genes related to amino acid biosynthesis and pentose phosphate pathway.
• Frontotemporal dementia (FTD) exhibited upregulated genes in ECM receptor interactions and lysosome pathways; downregulated genes involved glutamatergic synapse and MAPK signaling.
• The transcription factor KLF4 was found to be dysregulated across all three dementia types.

Conclusions:

• Distinct and common molecular pathways and transcription factors were identified across AD, VaD, and FTD.
• Shared molecular features suggest potential common underlying etiologies for these dementias.
• Differences in molecular profiles may provide a basis for developing diagnostic biomarkers to differentiate between dementia subtypes.