Basic Science and Pathogenesis.

Area of Science:

• Neuroscience
• Genomics
• Pharmacology

Background:

• Late-onset Alzheimer's disease (LOAD) is a heterogeneous dementia influenced by genetic, epigenetic, and environmental factors.
• This variability complicates the development of broadly effective therapies for Alzheimer's disease.

Purpose of the Study:

• To identify molecular subtypes of LOAD using multi-omics data.
• To uncover molecular signatures specific to each subtype.
• To predict and validate subtype-specific therapeutic candidates through drug repurposing.

Main Methods:

• Sample clustering analyses were performed on transcriptomic, proteomic, and methylomic data.
• Differential gene expression analysis identified molecular signatures for each subtype.
• Drug repurposing approaches were employed to identify targeted therapeutic candidates for each LOAD subtype.

Main Results:

• Five transcriptomic subtypes of LOAD were identified across independent cohorts, each with distinct gene dysregulation.
• Corresponding proteomic and DNA methylation subtypes were found, aligning with transcriptomic classifications.
• Several repurposed drug candidates targeting specific LOAD subtypes have been experimentally validated, demonstrating accelerated drug discovery.

Conclusions:

• Integrating LOAD subtype analysis with drug repurposing offers a novel strategy for precision medicine.
• Targeted treatments based on unique molecular profiles of homogeneous patient subgroups are feasible.
• This approach lays the foundation for developing personalized therapies for Alzheimer's disease.