Prediction of Psychosis in Alzheimer Disease

描述（由申请人提供）：精神病症状发生在大约50%的被诊断患有阿尔茨海默病（AD+精神病，AD+P）的个体中。AD+P与更大的认知能力下降和更多的机构化有关。目前的治疗对AD+P的益处有限，并且不能改变其不良预后。我们先前估计AD患者精神病的遗传率为61%-70%，表明有大量的遗传成分。近年来，一些新的基因与特发性精神病的连锁和/或关联已被报道，其中两个（NRG 1和COMT），我们已经发现与AD+P的初步研究。其他数据表明，导致神经退行性病变本身的基因（例如APP，PS1和P2P）的变异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）哪些基因与特发性精神病或导致神经退行性病理学相关，增加AD+P的风险？2)这些基因的变异对预测AD患者精神病发作有何影响？这些影响如何与认知障碍相互作用，从而增加AD+P的风险？（3）AD+P是否存在亚型，基因型对亚型的影响如何？我们将在三个目标中解决这些问题，涉及三个群组。将在一个大型（N=1000）AD+P vs AD-P病例对照队列中检验NRG 1、DTNBP 1、DISC 1、COMT、DAOA（以前称为G72）、AKT 1、RGS 4、APP、PS1、PS2和AD-P与AD+P的单基因座和单倍型关联。将在一个类似的大型家族队列中证实显著相关性。将在一个由786例入组研究时无精神病的AD和轻度认知障碍受试者组成的前瞻性队列中，进一步评价经证实的相关性，以预测AD+P发作。将评价遗传变异和认知对AD+P发作的介导和调节相互作用。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的遗传预测因子，表明它们是否通过对认知的影响起作用，并评估它们是否均匀地影响所有个体或导致亚型。这些研究结果可能会指导开发用于预测，治疗和/或预防AD中精神病和过度认知发病率的干预措施。

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.