A comprehensive study reveals the complex interplay of immune responses, cell cycles, and protein processing linked to changes in ribosome function associated with the onset of Alzheimer’s disease (AD). This new research provides valuable insights as the global prevalence of dementia is expected to reach alarming levels.
The study, conducted by researchers at the National Center for Geriatrics and Gerontology (NCGG) Biobank, involved analysis of RNA sequencing data from 1,227 blood samples. Among these samples, 424 were from patients diagnosed with Alzheimer’s disease, 543 from individuals with mild cognitive impairment (MCI), and 260 from cognitively normal individuals (CN).
Through advanced statistical methods, the research identified 883 statistically significant differentially expressed genes (DEGs) during the transition from cognitively normal to MCI and 1,169 DEGs from MCI to AD. Significantly, genes involved with ribosomal function were associated with MCI progression, whereas immune system genes, cell-cycle genes, and genes related to protein processing were linked to AD.
The findings indicate alterations in ribosomal genes may play a pivotal role during the early stages of cognitive decline. The researchers state, "Our findings indicate the onset of AD might be associated with gene expression changes following alterations in the expression of ribosomal protein genes during the MCI stage, though validation using brain tissue samples will be necessary." This highlights the pressing need for longitudinal studies and validations to confirm these pathophysiological mechanisms.
With dementia rates projected to reach approximately 152.8 million cases by 2050, this research is timely. The study’s senior researchers emphasized the hereditary and environmental factors throughout the research, noting, "Given the effectiveness of delaying MCI progression to prevent AD, ribosome-related genes may emerge as biomarkers for early diagnosis.”
The study reinforces the significance of comprehensively analyzing gene expression throughout the progression from CN to AD. Histories of cognitive health were major factors as the analysis focused not only on the genes but also on immune cell types and their proportions, supporting the idea of immune dysregulation as part of the Alzheimer's disease continuum.
The immune response pathways explored included the activation of NF-kB, which has been implicated in synaptic dysfunction, as well as stress response mechanisms. Mitochondrial dysfunction was also suggested, paralleling findings commonly associated with other neurodegenerative diseases. Notably, the diversity of T-Cell and B-cell receptor repertoires exhibited no statistically significant differences across the groups, prompting future inquiries.
Despite the limitations of sample size, this analysis sheds light on earlier stages of Alzheimer’s disease. To optimally understand the varied genetic expressions between MCI and AD groups, future research should prioritize the use of brain tissue samples to elucidate how these blood-derived indicators align with pathological changes occurring within the brain.
Considering the substantial role ribosomal proteins play across different forms of neurodegeneration, the potential for these genes to act as biomarkers could provide more refined therapeutic strategies alongside existing interventions aimed at delaying the onset of Alzheimer’s.
This research highlights the complexity of Alzheimer’s disease, where seemingly minor gene expression changes culminate in significant neurological consequences. With the urgent need for effective preventive strategies, this research helps pave the way for developing early intervention methods aiming to mitigate the onset or progression of Alzheimer’s disease.