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文献精选 > 近年高分"阿尔茨海默病"研究（IF≥30，近5年）

Genetic Insights into Alzheimer's Disease. ​

文献信息 ​

DOI10.1146/annurev-pathmechdis-012419-032551
PMID33497263
期刊Annual review of pathology
影响因子34.5
JCR 分区Q1
发表年份2021
被引次数10
关键词阿尔茨海默病, 衰老, 淀粉样蛋白, 遗传学, 神经退行性疾病
文献类型Journal Article, Research Support, N.I.H., Extramural, Review
ISSN1553-4006
页码351-376
期号16()
作者Caitlin S Latimer, Katherine L Lucot, C Dirk Keene, Brenna Cholerton, Thomas J Montine

一句话小结 ​

本文综述了阿尔茨海默病（AD）的遗传学研究进展，强调了遗传性与散发性AD之间的共同病理机制及其对认知功能的影响。研究不仅加深了我们对AD基础病理生理过程的理解，还为未来的治疗靶点开发提供了新的思路和方法。

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阿尔茨海默病 · 衰老 · 淀粉样蛋白 · 遗传学 · 神经退行性疾病

摘要 ​

阿尔茨海默病（AD）是一种普遍存在、不断进展的神经退行性疾病，包括遗传性和散发性两种形式，这两者通过共同的神经病理变化和神经心理表现相联系。临床诊断通常基于最初的记忆功能障碍，该障碍逐渐影响多个认知领域，而确诊则需要通过尸检检查大脑，以识别淀粉样斑块和神经纤维变性。在过去的100年中，我们对AD的基础病理生理过程、病理变化和临床表型的理解取得了显著进展，这在很大程度上得益于对包括但不限于淀粉样加工的遗传通路的揭示。本文综述了当前对AD遗传学的理解，重点讨论这些进展如何塑造我们对该疾病的认知，并为潜在治疗靶点的开发提供新的途径和方法。

英文摘要 ​

Alzheimer's disease (AD) is a pervasive, relentlessly progressive neurodegenerative disorder that includes both hereditary and sporadic forms linked by common underlying neuropathologic changes and neuropsychological manifestations. While a clinical diagnosis is often made on the basis of initial memory dysfunction that progresses to involve multiple cognitive domains, definitive diagnosis requires autopsy examination of the brain to identify amyloid plaques and neurofibrillary degeneration. Over the past 100 years, there has been remarkable progress in our understanding of the underlying pathophysiologic processes, pathologic changes, and clinical phenotypes of AD, largely because genetic pathways that include but expand beyond amyloid processing have been uncovered. This review discusses the current state of understanding of the genetics of AD with a focus on how these advances are both shaping our understanding of the disease and informing novel avenues and approaches for development of potential therapeutic targets.

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主要研究问题 ​

  1. 阿尔茨海默病的遗传机制如何影响其临床表现和进展？
  2. 除了淀粉样蛋白处理外，还有哪些遗传通路在阿尔茨海默病的发展中起关键作用？
  3. 当前在阿尔茨海默病的基因研究中，哪些新发现最有可能转化为临床治疗？
  4. 遗传因素与环境因素在阿尔茨海默病发病机制中如何相互作用？
  5. 在阿尔茨海默病的研究中，基因组编辑技术的应用前景如何？

核心洞察 ​

研究背景和目的 ​

阿尔茨海默病（AD）是一种广泛存在且持续进展的神经退行性疾病，包括遗传性和散发性两种形式，二者均与共同的神经病理变化和神经心理表现相关。尽管临床诊断通常基于初期的记忆功能障碍，但确诊需要通过尸检检查大脑以识别淀粉样斑块和神经纤维缠结。本文综述了阿尔茨海默病遗传学的当前理解，重点探讨这些进展如何塑造我们对该疾病的理解，并为潜在治疗靶点的发展提供新思路。

主要方法/材料/实验设计 ​

本文主要采用文献综述的方法，综合分析近年来在阿尔茨海默病遗传学方面的研究进展。通过对比不同的遗传途径和机制，探讨其对疾病理解和治疗策略的影响。

以下是研究的技术路线图：

Mermaid diagram

关键结果和发现 ​

  • 近年来，基因组关联研究（GWAS）揭示了多个与阿尔茨海默病相关的新基因，这些基因超出了传统的淀粉样蛋白处理途径。
  • 功能基因组学研究帮助我们理解这些基因在神经元功能和病理过程中的作用。
  • 动物模型的研究提供了对疾病机制的深入理解，特别是在神经退行性变化的早期阶段。

主要结论/意义/创新性 ​

本综述强调了遗传学研究在阿尔茨海默病理解中的重要性，揭示了新的遗传因子和机制，这些发现可能为开发新的治疗策略提供基础。特别是，超越传统淀粉样蛋白假说的研究为寻找新的治疗靶点开辟了道路。

研究局限性和未来方向 ​

  • 本文的局限性在于主要依赖文献综述，缺乏原始实验数据的支持。
  • 未来的研究方向应包括更大规模的纵向研究，以验证新发现的遗传因子与疾病进展之间的因果关系。
  • 进一步探索这些遗传因素如何影响阿尔茨海默病的不同临床表型，可能有助于个性化治疗策略的发展。

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引用本文的文献 ​

  1. Sex-specific accelerated decay in time/activity-dependent plasticity and associative memory in an animal model of Alzheimer's disease. - Sheeja Navakkode;Jessica Ruth Gaunt;Maria Vazquez Pavon;Vibhavari Aysha Bansal;Riya Prasad Abraham;Yee Song Chong;Toh Hean Ch'ng;Sreedharan Sajikumar - Aging cell (2021)
  2. TDP-43 promotes tau accumulation and selective neurotoxicity in bigenic Caenorhabditis elegans. - Caitlin S Latimer;Jade G Stair;Joshua C Hincks;Heather N Currey;Thomas D Bird;C Dirk Keene;Brian C Kraemer;Nicole F Liachko - Disease models & mechanisms (2022)
  3. Amyloid Formation by Globular Proteins: The Need to Narrow the Gap Between in Vitro and in Vivo Mechanisms. - Giulia Faravelli;Valentina Mondani;P Patrizia Mangione;Sara Raimondi;Loredana Marchese;Francesca Lavatelli;Monica Stoppini;Alessandra Corazza;Diana Canetti;Guglielmo Verona;Laura Obici;Graham W Taylor;Julian D Gillmore;Sofia Giorgetti;Vittorio Bellotti - Frontiers in molecular biosciences (2022)
  4. An Alzheimer's Disease Mechanism Based on Early Pathology, Anatomy, Vascular-Induced Flow, and Migration of Maximum Flow Stress Energy Location with Increasing Vascular Disease. - Conrad N Trumbore;Aditya Raghunandan - Journal of Alzheimer's disease : JAD (2022)
  5. Finding new and better treatments for psychiatric disorders. - Steven M Paul;William Z Potter - Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology (2024)
  6. Retinal electrophysiology in central nervous system disorders. A review of human and mouse studies. - Paul A Constable;Jeremiah K H Lim;Dorothy A Thompson - Frontiers in neuroscience (2023)
  7. Paradigm Shift: Multiple Potential Pathways to Neurodegenerative Dementia. - Amalia Perna;Kathleen S Montine;Lon R White;Thomas J Montine;Brenna A Cholerton - Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics (2023)
  8. Whole exome sequencing analyses identified novel genes for Alzheimer's disease and related dementia. - Ya-Ru Zhang;Bang-Sheng Wu;Shi-Dong Chen;Liu Yang;Yue-Ting Deng;Yu Guo;Xin-Rui Wu;Wei-Shi Liu;Ju-Jiao Kang;Jian-Feng Feng;Wei Cheng;Jin-Tai Yu - Alzheimer's & dementia : the journal of the Alzheimer's Association (2024)
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