Alzheimer's disease (AD) represents a pressing global health challenge with far-reaching socio-economic implications. Despite extensive research, the precise molecular mechanisms underlying its pathogenesis remain elusive. This study seeks to decipher the genomic symphony orchestrating the onset and progression of AD, shedding light on novel molecular targets for therapeutic intervention. AD is characterized by progressive cognitive decline, neuronal loss, and the accumulation of amyloid-beta plaques and neurofibrillary tangles. While several genetic risk factors have been identified, their interplay with environmental factors and epigenetic modifications remains poorly understood. This study aims to elucidate the intricate molecular networ (Preprint)
Authors: Chibunna Matthew 
Published: August 2024

BACKGROUND

The etiological tapestry of Alzheimer's disease (AD) is a complex and multifaceted genomic symphony, in which intricate molecular mechanisms orchestrate the pathogenesis of this devastating neurodegenerative disorder. This study embarks on an unprecedented exploration aiming to decode the genomic symphony and unveil the intricate molecular mechanisms underlying AD pathogenesis. The foundational pillars of this research are rooted in cutting-edge genomics technologies, including single-cell sequencing, chromatin conformation capture, and integrative multi-dimensional analyses, employed to dissect the intricate genomic landscape associated with AD.
The seminal discovery by Goate et al. [1] associating missense mutations in the amyloid precursor protein gene (APP) with familial AD forms the cornerstone of genetic exploration of AD. This transformative finding laid the groundwork for subsequent investigations into the role of APP and its proteolytic products in the amyloid cascade hypothesis, a pivotal theory in AD pathogenesis [1]. However, as genomic technologies have advanced, our understanding has evolved to encompass a broader spectrum of genetic and epigenetic factors contributing to the intricate symphony of AD pathogenesis. Expanding beyond the confines of coding sequences, recent studies highlight the crucial role of non-coding RNAs in neurodegenerative diseases, including AD [2]. The non-coding genomic landscape, once considered mere genomic "noise," now emerges as a harmonious participant in the intricate regulatory symphony governing gene expression and cellular processes [2].
Systems biology, as a guiding paradigm, has become indispensable in understanding the dynamic interactions within the genomic symphony. The work of Zhang et al. [3] on late-onset AD has exemplified the power of systems biology approaches in identifying genetic nodes and networks, offering a holistic view of the molecular complexities underpinning AD. Moreover, the exploration of three-dimensional genomic architecture through chromatin conformation capture, as exemplified by studies like the one conducted by Javierre et al. [4], promises to unravel spatial genomic dynamics, adding another layer of complexity to the genomic symphony in AD pathogenesis. As we navigate through this intricate genomic symphony, this study aspires to illuminate the nuanced interactions between genetics and epigenetics, coding and non-coding elements, and single-cell heterogeneity in AD pathogenesis. By integrating diverse layers of genomic information, this research seeks to contribute transformative insights that transcend the current understanding of AD, paving the way for innovative therapeutic strategies in the realm of neurodegenerative disorders.
The main objective of this review is to synthesize and critically analyze current knowledge on the genomic mechanisms contributing to the pathogenesis of Alzheimer's disease, encompassing genetic variations, epigenetic modifications, non-coding RNA regulation, three-dimensional genomic architecture, and the integration of systems biology approaches.

OBJECTIVE

The main objective of this review is to synthesize and critically analyze current knowledge on the genomic mechanisms contributing to the pathogenesis of Alzheimer's disease, encompassing genetic variations, epigenetic modifications, non-coding RNA regulation, three-dimensional genomic architecture, and the integration of systems biology approaches.

METHODS

In order to compile information on Decoding the Genomic Symphony: Unraveling Molecular Mechanisms in Alzheimer's disease Pathogenesis, in-depth assessment of scientific publications and academic research databases was employed for the study, these databases include journal articles, related project materials, and review articles. Therefore, articles were searched using the following keywords: Alzheimer's disease, Pathogenesis, Genomic Symphony and Molecular Mechanisms.
Based on the keywords searched, 5, 121 works related Alzheimer's disease, Pathogenesis, Genomic Symphony and Molecular Mechanisms were found in the chosen databases.
Furthermore, the selection procedure was carried out based on the title of the paper, abstract and English scholarly databases. Only information on the Alzheimer's disease, Pathogenesis, Genomic Symphony and Molecular Mechanisms were considered which amount to 71 articles.

RESULTS

Through our comprehensive review, we identified key genomic signatures associated with disease progression. Our findings reveal dysregulated pathways implicated in neuroinflammation, synaptic dysfunction, and mitochondrial dysfunction. Furthermore, we delineate dynamic epigenetic modifications underlying AD pathogenesis, including alterations in DNA methylation patterns and histone modifications. Importantly, we identify novel candidate genes and non-coding RNAs with potential diagnostic and therapeutic relevance.

CONCLUSIONS

This study provides unprecedented insights into the genomic landscape of AD, unraveling intricate molecular mechanisms underlying disease pathogenesis. Our findings deepen our understanding of the complex interplay between genetic predisposition, environmental factors, and epigenetic modifications in disease onset and progression. Moreover, the identification of novel candidate genes and therapeutic targets opens up avenues for the development of precision medicine approaches tailored to individual patients. Ultimately, our findings have the potential to catalyze the development of effective treatments and diagnostic tools, offering hope to millions of individual affected by AD worldwide

CLINICALTRIAL

In this odyssey through the genomic symphony of Alzheimer's disease (AD) pathogenesis, our exploration has delved into the intricate molecular harmonies and discordances shaping the neurodegenerative landscape. The synthesis of cutting-edge genomics technologies, encompassing single-cell sequencing, chromatin conformation capture, and multi-dimensional integrative analyses, has provided a panoramic view of the genomic symphony, unraveling the complex molecular mechanisms orchestrating AD progression. Therefore, this study envisions a future where the decoding of the genomic symphony not only deepens our understanding of AD but also paves the way for transformative interventions. As we continue this exploration, let the genomic symphony be a guide, resonating with the hope for innovative strategies that may one day harmonize the discordant notes of Alzheimer's disease into a melody of precision therapeutics.