Prediction of Psychosis in Alzheimer Disease

描述（由申请人提供）：精神病症状，定义为妄想或幻觉的发生，在阿尔茨海默病（AD+精神病，AD+P）中常见，影响约40%至60%的AD患者。精神病是AD亚型的标志物，与更快的认知和功能下降、不良结局（包括过早的机构化）和护理者痛苦升高相关。目前AD+P的治疗效果有限，并导致死亡率过高。因此，必须开发一种转化方法，以促进发现AD+P的生物学，并确定干预的机会，以防止其不利的轨迹。为了实现这一目标，我们利用了我们对AD+P家族聚集性的初步观察，现在在两个独立的队列中复制。在目前的资助期间，我们已经完成了AD+P的第一个全基因组关联研究（GWAS），发现了与新基因座和与精神分裂症共享的精神病风险基因座相关的强有力的初步证据。我们同样发现了AD+P与假定的精神分裂症风险基因neuregulin 1（NRG 1）的遗传变异相关的证据，我们证明这会影响新型NRG 1外显子的mRNA转录本的表达。相比之下，我们发现AD+P与几个已建立的神经变性风险基因无关。最后，我们澄清了AD+P的不良认知轨迹出现在AD的最早阶段，并开发了创新的分析方法来绘制认知下降的个人轨迹，并测试遗传变异对它们的影响。这些发现使我们假设AD+P由一组风险等位基因引起，包括常见的精神病风险等位基因，但独立于那些赋予AD风险的等位基因;并且这些风险等位基因改变了大脑内的分子环境，导致更迅速恶化的神经退行性轨迹。我们将测试我们的假设，利用我们GWAS的初步成功，在近10，000名受试者的阶段性分析中进一步鉴定与AD+P相关的常见遗传变异（目标1），利用这些变异预测两个充分表征的队列中AD+P的不良认知和行为轨迹（目标2），并利用高质量的大脑皮层转录组数据集来鉴定与AD+P风险等位基因相关的分子变化（Aim 3）。完成后，计划中的研究将确定一组常见的遗传变异，预测AD的认知和行为结果，并将确定这些变异改变的基因转录水平。这些发现可以提供AD+P“基因芯片”的生成，以预测与AD+P相关的不良结果，从而针对个体进行更积极的干预。同样，研究结果将指导研究描绘导致AD精神病发展的大脑机制。

DESCRIPTION (provided by applicant): Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer Disease (AD+Psychosis, AD+P), affecting ~ 40% to 60% of individuals with AD. Psychosis is a marker for a subtype of AD associated with more rapid cognitive and functional decline, poor outcomes including premature institutionalization, and elevated caregiver distress. Current treatments for AD+P have limited efficacy and cause excess mortality. It is thus imperative to develop a translational approach to promote discovery regarding the biology of AD+P and identify opportunities to intervene to prevent its adverse trajectory. To address this goal, we have exploited our initial observation of the familial aggregation of AD+P, now replicated in two independent cohorts. During the current funding period we have completed the first Genome-Wide Association Study (GWAS) of AD+P, finding strong preliminary evidence for association with novel loci and with psychosis risk loci shared with schizophrenia. We have similarly found evidence of association of AD+P with genetic variation in the putative schizophrenia risk gene, neuregulin1 (NRG1), which we demonstrated impacts expression of mRNA transcripts of novel NRG1 exons. In contrast we have found that AD+P is not associated with several established risk genes for neurodegeneration. Finally, we have clarified that the adverse cognitive trajectory of AD+P emerges within the earliest stages of AD, and have developed innovative analytic methods to chart personal trajectories of cognitive decline and test the impact of genetic variation on them. These findings have led us to hypothesize that AD+P results from a set of risk alleles that includes common psychosis risk alleles, but is independent of those conferring risk for AD; and that these risk alleles alter the molecular milieu within the brain resulting in a more rapidly deteriorating neurodegenerative trajectory. We will test our hypotheses, capitalizing on the initia success of our GWAS to further identify common genetic variants associated with AD+P in a staged analysis of nearly 10,000 subjects (Aim 1), utilize these variants to predict the adverse cognitive and behavioral trajectory of AD+P in two well characterized cohorts (Aim 2), and leverage a high quality cerebral cortex transcriptome dataset to identify the molecular changes associated with the AD+P risk alleles (Aim 3). Upon completion, the planned studies will have identified a set of common genetic variants which predict cognitive and behavioral outcomes in AD and will have established gene transcript levels altered by these variants. Such findings could provide for generation of an AD+P "gene chip" to predict the poor outcomes associated with AD+P and thus target individuals for more aggressive intervention. Similarly, findings will guide studies to delineate the brain mechanisms leading to the development of psychosis in AD.