ImportanceThe emergence of psychotic symptoms in Alzheimer disease (AD) is associated with accelerated cognitive and functional decline that may be related to disease pathology.ObjectiveTo investigate the longitudinal dynamics of plasma tau phosphorylated at threonine 181 (p-tau181) and neurofilament light chain protein (NfL) levels in association with the emergence of psychotic symptoms (delusions and hallucinations) in the context of AD.Design, Setting, and ParticipantsThis cohort study used longitudinal data from the Alzheimer Disease Neuroimaging Initiative (ADNI). Baseline analyses compared patients with mild cognitive impairment (MCI) and AD (both with psychosis [AD+P] and without psychosis [AD-P]) and participants who were cognitively unimpaired (CU). For the longitudinal analysis, participants with MCI and AD were subdivided into patients with evidence of psychosis at baseline (AD+P baseline) and patients free of psychosis at baseline who showed incidence of psychosis over the course of the study (AD+P incident). Study data were analyzed between June and November 2023.ExposuresPlasma p-tau181 and NfL measures in individuals with MCI and AD, both with and without psychosis.Main Outcomes and MeasuresPlasma p-tau181 and NfL quantifications up to 48 months and concurrent assessments of presence or absence of delusions and hallucinations via the Neuropsychiatric Inventory (NPI) questionnaire.ResultsThe cohort included 752 participants with AD (mean [SD] age, 74.2 [7.7] years; 434 male [57.7%]). A total of 424 CU participants had a mean (SD) age of 75.4 (6.6) years of whom 222 were female (52.4%). In the longitudinal analysis of p-tau181 trajectories of the AD+P group, the group of patients who showed incidence of psychosis over the course of follow-up (AD+P incident) demonstrated an associated increase in plasma p-tau181 levels compared with the group of patients who had psychosis at baseline (AD+P baseline) and showed an associated decrease in plasma p-tau181 levels (F4, 117 = 3.24; P = .01). The mean slope of p-tau181 change was significantly different in AD+P incident and AD+P baseline groups (F5,746 = 86.76, P < .0001) and when only individuals with amyloid-β positivity (Aβ+), which was determined using positron emission tomography, were compared (F5,455 = 84.60, P < .001). Patients who experienced psychosis at any time had increased levels of NfL relative to those who never experienced psychosis.Conclusions and RelevanceResults of this cohort study suggest that the emergence of psychosis in AD was associated with elevations in plasma levels of p-tau181, highlighting the potential utility of plasma p-tau181 as a biomarker of neuropsychiatric illness in AD, which could have implications for predictive and treatment response strategies.

中文翻译：

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阿尔茨海默病中的精神病和疾病相关生物标志物的升高


重要性阿尔茨海默病 （AD） 中精神病症状的出现与认知和功能加速下降有关，这可能与疾病病理有关。目的研究在苏氨酸 181 （p-tau181） 和神经丝轻链蛋白 （NfL） 水平磷酸化的血浆 tau 的纵向动力学与精神病症状（妄想和幻觉）的出现 AD.Design、环境和参与者该队列研究使用了来自阿尔茨海默病神经影像学计划 （ADNI） 的纵向数据。基线分析比较了轻度认知障碍 （MCI） 和 AD 患者 （有精神病 [AD+P] 和无精神病 [AD-P]）和认知无障碍 （CU） 的参与者。对于纵向分析，患有 MCI 和 AD 的参与者被细分为基线时有精神病证据的患者 （AD+P 基线） 和基线时没有精神病但在研究过程中表现出精神病发生率的患者 （AD + P 事件）。研究数据在 2023 年 6 月至 11 月期间进行了分析。主要结局和措施长达 48 个月的血浆 p-tau181 和 NfL 量化，并通过神经精神病学量表 （NPI） 问卷同时评估是否存在妄想和幻觉。结果该队列包括 752 名 AD 参与者 （平均 [SD] 年龄，74.2 [7.7] 岁;434 名男性 [57.7%]）。共有 424 名 CU 参与者的平均 （SD） 年龄为 75.4 （6.6） 岁，其中 222 名为女性 （52.4%）。 在 AD+P 组 p-tau181 轨迹的纵向分析中，在随访过程中表现出精神病发生率 （AD+P 事件） 的患者组显示血浆 p-tau181 水平与基线时出现精神病的患者组 （AD+P 基线） 相比相关增加，并显示血浆 p-tau181 水平相关降低 （F4， 117 = 3.24;P = .01）。p-tau181 变化的平均斜率在 AD+P 事件组和 AD+P 基线组 （F5,746 = 86.76，P < .0001） 和仅比较淀粉样蛋白β阳性 （Aβ+） 的个体时差异显著（使用正电子发射断层扫描确定）（F5,455 = 84.60，P < .001）。相对于从未经历过精神病的患者，在任何时间经历过精神病的患者 NfL 水平升高。结论和相关性该队列研究的结果表明，AD 中精神病的出现与血浆 p-tau181 水平升高有关，突出了血浆 p-tau181 作为 AD 神经精神疾病生物标志物的潜在效用，这可能对预测和治疗反应策略产生影响。