Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD), affecting ~40 to 60% of individuals with AD (AD with psychosis (AD+P)). In comparison with AD subjects without psychosis, AD+P subjects have more rapid cognitive decline and poor outcomes. Prior studies have estimated the heritability of psychosis in AD at 61%, but the underlying genetic sources of this risk are not known. We evaluated a Discovery Cohort of 2876 AD subjects with (N=1761) or without psychosis (N=1115). All subjects were genotyped using a custom genotyping array designed to evaluate single-nucleotide polymorphisms (SNPs) with evidence of genetic association with AD+P and include SNPs affecting or putatively affecting risk for schizophrenia and AD. Results were replicated in an independent cohort of 2194 AD subjects with (N=734) or without psychosis (N=1460). We found that AD+P is associated with polygenic risk for a set of novel loci and inversely associated with polygenic risk for schizophrenia. Among the biologic pathways identified by the associations of schizophrenia SNPs with AD+P are endosomal trafficking, autophagy and calcium channel signaling. To the best of our knowledge, these findings provide the first clear demonstration that AD+P is associated with common genetic variation. In addition, they provide an unbiased link between polygenic risk for schizophrenia and a lower risk of psychosis in AD. This provides an opportunity to leverage progress made in identifying the biologic effects of schizophrenia alleles to identify novel mechanisms protecting against more rapid cognitive decline and psychosis risk in AD.

中文翻译：

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阿尔茨海默病中精神分裂症和精神病的遗传风险。

精神病症状，定义为妄想或幻觉的发生，在阿尔茨海默病 (AD) 中很常见，影响约 40% 至 60% 的 AD 患者（AD 伴精神病 (AD+P)）。与没有精神病的 AD 受试者相比，AD+P 受试者的认知衰退更快，结果更差。先前的研究估计 AD 中精神病的遗传率为 61%，但这种风险的潜在遗传来源尚不清楚。我们评估了 2876 名患有 (N=1761) 或没有精神病 (N=1115) 的 AD 受试者的发现队列。使用定制的基因分型阵列对所有受试者进行基因分型，该阵列旨在评估单核苷酸多态性 (SNP)，具有与 AD+P 遗传关联的证据，包括影响或推定影响精神分裂症和 AD 风险的 SNP。结果在 2194 名患有 (N=734) 或没有精神病 (N=1460) 的 AD 受试者的独立队列中重复。我们发现 AD+P 与一组新基因座的多基因风险相关，与精神分裂症的多基因风险负相关。精神分裂症 SNP 与 AD+P 的关联所确定的生物学途径包括内体运输、自噬和钙通道信号传导。据我们所知，这些发现首次明确证明 AD+P 与常见的遗传变异有关。此外，它们在精神分裂症的多基因风险与 AD 中精神病的较低风险之间提供了公正的联系。