Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. Autosomal dominant, familial AD (fAD) is very rare and caused by mutations in amyloid precursor protein (APP), presenilin-1 (PSEN-1), and presenilin-2 (PSEN-2) genes. The pathogenesis of sporadic AD (sAD) is more complex and variants of several genes are associated with an increased lifetime risk of AD. Nuclear and mitochondrial DNA integrity is pivotal during neuronal development, maintenance and function. DNA damage and alterations in cellular DNA repair capacity have been implicated in the aging process and in age-associated neurodegenerative diseases, including AD. These findings are supported by research using animal models of AD and in DNA repair deficient animal models. In recent years, novel mechanisms linking DNA damage to neuronal dysfunction have been identified and have led to the development of noninvasive treatment strategies. Further investigations into the molecular mechanisms connecting DNA damage to AD pathology may help to develop novel treatment strategies for this debilitating disease. Here we provide an overview of the role of genome instability and DNA repair deficiency in AD pathology and discuss research strategies that include genome instability as a component.

中文翻译：

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阿尔茨海默病的基因组不稳定性。

阿尔茨海默病 (AD) 是一种进行性神经退行性疾病，也是最常见的痴呆症。常染色体显性家族性 AD (fAD) 非常罕见，由淀粉样前体蛋白 (APP)、早老素-1 (PSEN-1) 和早老素-2 (PSEN-2) 基因突变引起。散发性 AD (sAD) 的发病机制更为复杂，多个基因的变异与 AD 终生风险增加相关。核和线粒体 DNA 完整性在神经元发育、维护和功能过程中至关重要。DNA 损伤和细胞 DNA 修复能力的改变与衰老过程和与年龄相关的神经退行性疾病（包括 AD）有关。这些发现得到了使用 AD 动物模型和 DNA 修复缺陷动物模型的研究的支持。近年来，人们发现了将 DNA 损伤与神经元功能障碍联系起来的新机制，并促进了非侵入性治疗策略的发展。进一步研究 DNA 损伤与 AD 病理学之间的分子机制可能有助于为这种使人衰弱的疾病开发新的治疗策略。在这里，我们概述了基因组不稳定和 DNA 修复缺陷在 AD 病理学中的作用，并讨论了将基因组不稳定作为一个组成部分的研究策略。