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Abstract：
The clinical features and pathophysiology of neuropsychiatric symptoms (NPSs) in dementia have been extensively studied. However, the genetic architecture and underlying neurobiological mechanisms of NPSs at preclinical stages of cognitive decline and Alzheimer\'s disease (AD) remain largely unknown. Mild behavioral impairment (MBI) represents an at-risk state for incident cognitive impairment and is defined by the emergence of persistent NPSs among non-demented individuals in later life. These NPSs include affective dysregulation, decreased motivation, impulse dyscontrol, abnormal perception and thought content, and social inappropriateness. Accumulating evidence has recently begun to shed more light on the genetic background of MBI, focusing on its potential association with genetic factors related to AD. The Apolipoprotein E (APOE) genotype and the MS4A locus have been associated with affective dysregulation, ZCWPW1 with social inappropriateness and psychosis, BIN1 and EPHA1 with psychosis, and NME8 with apathy. The association between MBI and polygenic risk scores (PRSs) in terms of AD dementia has been also explored. Potential implicated mechanisms include neuroinflammation, synaptic dysfunction, epigenetic modifications, oxidative stress responses, proteosomal impairment, and abnormal immune responses. In this review, we summarize and critically discuss the available evidence on the genetic background of MBI with an emphasis on AD, aiming to gain insights into the potential underlying neurobiological mechanisms, which till now remain largely unexplored. In addition, we propose future areas of research in this emerging field, with the aim to better understand the molecular pathophysiology of MBI and its genetic links with cognitive decline.
摘要：
痴呆的神经精神症状（NPSs）的临床特征和病理生理学已得到广泛研究。然而,认知衰退和阿尔茨海默病(AD)的临床前阶段NPSs的遗传结构和潜在神经生物学机制在很大程度上仍然未知。轻度行为障碍（MBI）代表了偶发性认知障碍的危险状态，其定义是在以后的生活中，非痴呆个体中持续NPS的出现。这些NPS包括情感失调，动机减少，冲动控制失调,异常的感知和思想内容，和社会不恰当。越来越多的证据最近开始进一步阐明MBI的遗传背景，重点研究其与AD相关遗传因素的潜在关联。载脂蛋白E（APOE）基因型和MS4A基因座与情感失调有关，ZCWPW1具有社交不称职和精神病，BIN1和EPHA1伴精神病，和NME8冷漠。MBI和多基因风险评分（PRS）之间的关联在AD痴呆方面也被探索。潜在的相关机制包括神经炎症，突触功能障碍,表观遗传修饰,氧化应激反应，蛋白酶体损伤，和异常的免疫反应。在这次审查中,我们总结并批判性地讨论了MBI遗传背景的现有证据，重点是AD，旨在深入了解潜在的潜在神经生物学机制，到目前为止，这在很大程度上仍未被探索。此外,我们提出了这个新兴领域的未来研究领域，目的是更好地了解MBI的分子病理生理学及其与认知衰退的遗传联系。
