Prediction of Psychosis in Alzheimer Disease

精神病症状，定义为妄想或幻觉的出现，在阿尔茨海默病患者中很常见 疾病(AD+精神病，AD+P)，影响约40%至60%的AD患者。精神错乱是一种 阿尔茨海默病的亚型与认知和功能衰退更快相关，预后不良，包括早产 制度化，并加剧了照顾者的痛苦。目前对AD+P的治疗效果有限， 导致过高的死亡率。因此，开发一种促进发现的翻译方法势在必行 关于AD+P的生物学，并确定干预机会，以防止其不利轨迹。 我们最初报告AD+P聚集在遗传率为~61%的家庭中，这一发现在 独立的队列。这些观察，以及我们基因研究的其他发现，引导我们进入了 目前的资金间隔假设AD+P是由一组风险等位基因引起的，其中包括 精神分裂症(Sz)，但不是AD的风险等位基因。我们在当前资金间隔期间的发现进一步 阐明了AD+P的遗传结构：1)我们独立地复制了我们的发现 常见遗传变异与AD+P的关联；2)我们类似地重复了我们之前的发现 AD+P与Sz相关的多基因变异显著相关，包括我们的先证者，生物学上 有趣的是，观察到大多数等位基因对风险的影响方向与Sz和AD+P相反；3) 与我们的假设相反，我们发现与AD风险相关的基因座上的多基因变异与 AD中的精神病风险，这种多基因贡献与Sz风险的贡献是独立相加的 变种；4)我们开发了新的方法来描绘个体的认知和认知行为 在预测转化为精神病的概率时结合了遗传变异的轨迹。 这些发现使我们得出了一个修正的假设：AD+P是由包含独特AD+P的风险等位基因导致的。 与Sz和AD相关的风险等位基因和等位基因子集；这些等位基因结合在一起可以更快地产生 认知轨迹恶化，转变为精神错乱的可能性增加。我们现在将测试我们的 假设首先对基因组进行无偏见的调查，包括使用创新的分析方法 我们和其他人为进一步识别与AD+P相关的遗传变异而开发的方法(目标1)； 然后利用AD和Sz基因组学的进展来提炼多基因风险对这些疾病的贡献 障碍到AD+P(目标2)；跨队列验证不良认知和障碍的预测 前述目标(目标3)中确定的变种的AD+P的行为轨迹。 通过识别预测阿尔茨海默病发病的基因变异，这些研究在完成后可能 提供一种方法来识别与AD+P相关的不良结果的风险个人，以便他们能够 针对其他干预措施。在已确定的SNPs中，将有那些预测大脑转录的SNPs 为今后的翻译研究提供了强有力的AD+P机制假说。

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. We initially reported that AD+P aggregates in families with a heritability of ~61%, findings since replicated in independent cohorts. These observations, and additional findings from our genetic studies, led us in the current funding interval to hypothesize that AD+P results from a set of risk alleles that includes risk alleles for schizophrenia (Sz), but not risk alleles for AD. Our findings during the current funding interval have further illuminated the genetic architecture of AD+P: 1) We have independently replicated our finding of the association of common genetic variation with AD+P; 2) We have similarly replicated our prior finding of a significant association of AD+P with polygenic variation associated with Sz, including our prior, biologically intriguing, observation that the direction of most allelic effects on risk are opposite for Sz and AD+P; 3) Contrary to our hypothesis, we found that polygenic variation at loci associated with AD risk associate with psychosis risk in AD, and this polygenic contribution is independently additive with the contribution of Sz risk variants; 4) We have developed novel methods to map individual cognitive and cognitive-behavioral trajectories that incorporate genetic variation in predicting the probability of transition to psychosis. These findings have led us to a revised hypothesis: AD+P results from risk alleles that include unique AD+P risk alleles and subsets of alleles associated with Sz and AD; these alleles combine to yield a more rapidly deteriorating cognitive trajectory and an increased probability of transition to psychosis. We will now test our hypothesis by first performing an unbiased survey of the genome, including the use of innovative analytic methods that we and others have developed to further identify genetic variants associated with AD+P (Aim 1); then leveraging advances in the genomics of AD and Sz to refine the contribution of polygenic risk for these disorders to AD+P (Aim 2); and validating across cohorts the prediction of the adverse cognitive and behavioral trajectory of AD+P by variants identified in the preceding Aims (Aim 3). By identifying genetic variants that predict psychosis onset in AD, upon completion, these studies may provide a means to identify individuals at risk for the poor outcomes associated with AD+P so they can be targeted for additional interventions. Among the identified SNPs will be those predicting brain transcript expression, providing strong mechanistic hypotheses of AD+P for future translational studies.