Exploratory RNA Sequencing Reveals Systemic Metabolic Dysregulation in Alzheimer’s Disease: Insights from a Diverse Latin American Cohort

TL;DR

This study uses RNA sequencing in a Latin American cohort to uncover metabolic and synaptic dysregulation in Alzheimer's disease, highlighting the importance of diverse populations in genomic research.

Contribution

The study identifies novel molecular signatures of Alzheimer's disease in a genetically diverse Latin American cohort, emphasizing systemic metabolic and synaptic dysregulation.

Findings

399 differentially expressed genes were identified, with 378 upregulated and 21 downregulated in Alzheimer's disease patients.

Key genes like APOE, MMP2, PPARG, and TUBB3 were enriched in protein metabolism pathways and synaptic signaling.

Molecular signatures linked to cognitive decline and functional impairment were revealed through multiple factor analysis.

Abstract

Alzheimer’s disease (AD) is characterized by an insidious onset and complex pathophysiology, necessitating the development of effective strategies for early detection and intervention. This exploratory study aimed to identify differentially expressed genes (DEGs) and disrupted molecular pathways in AD by analyzing blood samples from participants recruited in Valle del Cauca, Colombia, a region with high genetic admixture and persistent underrepresentation in genomic research. A total of 41 individuals (AD, n = 14; cognitively healthy controls (CHC), n = 27) were included. Groups did not differ significantly in age, education, sex distribution, or vascular comorbidities. Peripheral blood RNA was sequenced using 150-bp paired-end reads, and transcriptomic profiling revealed 399 DEGs, with 378 upregulated and 21 downregulated in the AD group. Key genes such as APOE, MMP2, PPARG, and TUBB3 were enriched in the Metabolism of Proteins pathway. At the same time, TUBB3, CACNA2D1, and GABBR2 were implicated in transmission across chemical synapses, suggesting synaptic signaling and protein metabolism dysregulation. Multiple factor analysis (MFA), integrating gene expression with neurocognitive and functional outcomes, revealed distinct molecular signatures associated with cognitive decline and functional impairment. These findings highlight the role of systemic metabolic dysfunction and synaptic dysregulation in AD pathogenesis. By focusing on an ancestrally diverse cohort, this study underscores the critical need to expand the molecular characterization of AD beyond European-ancestry populations, informing the development of inclusive biomarkers and precision strategies for early diagnosis and intervention.

The online version contains supplementary material available at 10.1007/s12035-025-05597-8.

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