Prediction of Psychosis in Alzheimer Disease

描述(由申请人提供)：大约50%被诊断为阿尔茨海默病(AD+精神病，AD+P)的人会出现精神病症状。AD+P与更大的认知衰退和更高的制度化程度相关。目前的治疗方法对AD+P的益处有限，并且不能改变其不良的预后。我们先前曾估计AD患者精神病的遗传率为61%-70%，这表明有相当大的遗传成分。最近报道了一些新基因与特发性精神病的连锁和/或关联，其中两个基因(NRG1和COMT)在初步研究中发现与AD+P相关。其他数据表明，导致神经退行性病变本身的基因变异(如APP、PS1和MAPI)也会改变精神病风险。我们现在建议分析这组极有可能的候选基因，以解决关于AD+P的几个问题：1)哪些基因显示出与特发性精神病或导致神经退行性病变的连锁和等位基因关联，增加AD+P的风险；2)这些基因的变异对预测AD期间精神病的发生有什么影响，这些影响如何与认知障碍相互作用以增加AD+P的风险？以及，3)AD+P中是否有亚型的证据以及它们是如何受基因影响的？我们将通过三个目标来解决这些问题，涉及三个群体。NRG1、DTNBP1、DISC1、COMT、DAOA(以前的G72)、AKT1、RGS4、APP、PS1、PS2和MAPI与AD+P的单基因座和单倍型关联将在大规模(N=1000)AD+P与AD-P病例对照队列中进行检验。重要的关联将在一个类似的大的家庭队列中得到证实。在786名AD和在研究开始时没有精神病的轻度认知障碍受试者的前瞻性队列中，将进一步评估证实的相关性，以预测AD+P的发病。将评估AD+P发病时遗传变异和认知之间的中介和调节作用。来自前瞻性队列的纵向数据将用于识别具有不同轨迹和遗传决定因素的AD+P亚型。成功完成这些目标将确定AD+P的遗传预测因素，表明它们是否通过影响认知而起作用，并评估它们是否统一影响所有个人或导致亚型。这些发现可能会指导AD中预测、治疗和/或预防精神病和过度认知障碍的干预措施的发展。

DESCRIPTION (provided by applicant): Psychotic symptoms occur in approximately 50% of individuals diagnosed with Alzheimer Disease (AD+Psychosis, AD+P). AD+P is associated with greater cognitive decline and increased institutionalization. Current therapies have limited benefit for AD+P, and do not alter its poor prognosis. We have previously estimated the heritability of psychosis in AD as 61%-70%, indicating a substantial genetic component. Recently linkage and/or association of several novel genes with idiopathic psychosis have been reported, two of which (NRG1 and COMT) we have found to be associated with AD+P in preliminary studies. Other data suggest that variation in genes contributing to neurodegenerative pathology itself (e.g. APP, PS1, and MAPI) also alter psychosis risk. We now propose to analyze this highly probable set of candidate genes to address several questions regarding AD+P: 1) Which genes demonstrating linkage and allelic association with idiopathic psychosis, or leading to neurodegenerative pathology, increase risk for AD+P?; 2) What are the effects of variation in these genes on predicting psychosis onset during AD, and how do these effects interact with cognitive impairment to increase AD+P risk?; and, 3) ls there evidence for subtypes within AD+P and how are they influenced by genotype? We will address these questions in three aims, involving three cohorts. Single locus and haplotype associations of NRG1, DTNBP1, DISC1, COMT, DAOA (formerly G72), AKT1, RGS4, APP, PS1, PS2, and MAPI with AD+P will be tested in a large (N=1000) AD+P vs AD-P Case-Control Cohort. Significant associations will be confirmed in a similarly large Family Cohort. Confirmed associations will be further evaluated for the prediction of AD+P onset in a Prospective Cohort of 786 AD and Mild Cognitive Impairment subjects without psychosis at study entry. Mediating and moderating interactions between genetic variation and cognition on AD+P onset will be evaluated. Longitudinal data from the Prospective Cohort will be used to identify subtypes of AD+P with differing trajectories and genetic determinants. Successful completion of these aims will identify genetic predictors of AD+P, indicate if they act via an effect on cognition, and evaluate if they affect all individuals uniformly or result in subtypes. These findings may guide the development of interventions for the prediction, treatment, and/or prevention of psychosis and excess cognitive morbidity in AD.