Deficits of Alzheimer’s Disease Neuropsychological Architecture Correlate with Specific Exosomal mRNA Expression: Evidence of a Continuum?

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline and complex molecular changes. Extracellular vesicles (EVs), particularly exosomes, play a key role in intercellular communication and disease progression, transporting proteins, lipids, and nucleic acids. While altered exosomal mRNA profiles have emerged as potential biomarkers for AD, the relationship between mRNA expression and AD neuropsychological deficits remains unclear. Here, we investigated the correlation between exosomx10-derived mRNA signatures and neuropsychological performance in a cohort from Barranquilla, Colombia. Expression profiles of 16,585 mRNAs in 15 AD patients and 15 healthy controls were analysed using Generalized Linear Models (GLMs) and the Predictive Power Score (PPS). We identified significant correlations between specific mRNA signatures and key neuropsychological variables, including the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Functional Assessment Screening Tool (FAST), Boston Naming Test, and Rey-Osterrieth Figure test. These mRNAs were in key AD-associated genes (i.e., <i>GABRB3</i> and <i>CADM1</i>), while other genes are novel (i.e., <i>SHROOM3</i>, <i>SLC7A2</i>, <i>GJB4</i>, and <i>XBP1</i>). PPS analyses further revealed predictive relationships between mRNA expression and neuropsychological variables, accounting for non-linear patterns and asymmetric associations. If replicated in more extensive and heterogeneous studies, these findings provide critical insights into the molecular basis governing the natural history of AD, potential personalized and non-invasive diagnosis, prognosis, follow-up, and potential targets for future therapies.