Tiwari Prabhakar, Dwivedi Rekha, Kaushik Meenakshi, Tripathi Manjari, Dada Rima
Department of Anatomy, All India Institute of Medical Sciences (AIIMS), New Delhi, 110029, India.
Department of Neurology, All India Institute of Medical Sciences (AIIMS), New Delhi, 110029, India.
J Mol Neurosci. 2025 May 30;75(2):72. doi: 10.1007/s12031-025-02363-2.
Alzheimer's disease (AD) is a complex, multifactorial neurodegenerative disorder that affects millions of individuals globally. Despite extensive research efforts, effective treatments for AD remain elusive. AD pathogenesis is driven by a combination of genetic, epigenetic, and environmental factors. However, challenges persist in AD genetic and epigenetic research, including the need for larger and more diverse cohorts, the integration of multi-omic data, and the development of advanced computational and experimental tools. A comprehensive understanding of these factors is crucial for the development of effective treatments and ultimately a cure for this debilitating condition. In this review, we summarize key regulatory pathways involved in AD pathogenesis, emphasizing genetic factors such as the apolipoprotein E (APOE) gene and high-impact genetic mutations in amyloid precursor protein (APP) and presenilin 1 (PSEN1). We also explore significant epigenetic regulators, including DNA methylation, histone deacetylases (HDACs), and microRNAs (miRNAs), which modulate gene expression and contribute to disease progression. Furthermore, we discuss the interplay between genetic and epigenetic factors, highlighting their combined impact on β-amyloid deposition, tau pathology, neuroinflammation, and synaptic dysfunction. Finally, we examine the potential of epigenetic modifications as promising therapeutic targets for AD, due to their reversible nature, and propose future research directions to address current knowledge gaps. This review offers an updated perspective on AD genetics and epigenetics, providing insights into novel avenues for therapeutic intervention.
阿尔茨海默病（AD）是一种复杂的、多因素的神经退行性疾病，全球有数百万患者受其影响。尽管进行了广泛的研究，但仍未找到有效的AD治疗方法。AD的发病机制是由遗传、表观遗传和环境因素共同驱动的。然而，AD的遗传和表观遗传研究仍面临挑战，包括需要更大、更多样化的队列，整合多组学数据，以及开发先进的计算和实验工具。全面了解这些因素对于开发有效的治疗方法以及最终治愈这种使人衰弱的疾病至关重要。在这篇综述中，我们总结了AD发病机制中涉及的关键调控途径，重点强调了遗传因素，如载脂蛋白E（APOE）基因以及淀粉样前体蛋白（APP）和早老素1（PSEN1）中的高影响基因突变。我们还探讨了重要的表观遗传调节因子，包括DNA甲基化、组蛋白去乙酰化酶（HDAC）和微小RNA（miRNA），它们调节基因表达并促进疾病进展。此外，我们讨论了遗传和表观遗传因素之间的相互作用，强调它们对β淀粉样蛋白沉积、tau病理、神经炎症和突触功能障碍的综合影响。最后，鉴于表观遗传修饰具有可逆性，我们研究了其作为AD有前景的治疗靶点的潜力，并提出了未来的研究方向以填补当前的知识空白。这篇综述提供了关于AD遗传学和表观遗传学的最新观点，为治疗干预的新途径提供了见解。
