ImportancePhase 3 trials of successful antiamyloid therapies in Alzheimer disease (AD) have demonstrated improved clinical efficacy in people with less severe disease. Plasma biomarkers will be essential for efficient screening of participants in future primary prevention clinical trials testing antiamyloid therapies in cognitively unimpaired (CU) individuals with initially low brain β-amyloid (Aβ) levels who are at high risk of accumulating Aβ.ObjectiveTo investigate if combining plasma biomarkers could be useful in predicting subsequent development of Aβ pathology in CU individuals with subthreshold brain Aβ levels (defined as Aβ levels <40 Centiloids) at baseline.Design, Setting, and ParticipantsThis was a longitudinal study including Swedish BioFINDER-2 (enrollment 2017-2022) and replication in 2 independent cohorts, the Knight Alzheimer Disease Research Center (Knight ADRC; enrollment 1988 and 2019) and Swedish BioFINDER-1 (enrollment 2009-2015). Included for analysis was a convenience sample of CU individuals with baseline plasma phosphorylated tau 217 (p-tau217) and Aβ42/40 assessments and Aβ assessments with positron emission tomography (Aβ-PET) or cerebrospinal fluid (CSF) Aβ42/40. Data were analyzed between April 2023 and May 2024.ExposuresBaseline plasma levels of Aβ42/40, p-tau217, the ratio of p-tau217 to nonphosphorylated tau (%p-tau217), p-tau231, and glial fibrillary acidic protein (GFAP).Main Outcomes and MeasuresCross-sectional and longitudinal PET and CSF measures of brain Aβ pathology.ResultsThis study included 495 (BioFINDER-2), 283 (Knight ADRC), and 205 (BioFINDER-1) CU participants. In BioFINDER-2, the mean (SD) age was 65.7 (14.4) with 261 females (52.7%). When detecting abnormal CSF Aβ-status, a combination of plasma %p-tau217 and Aβ42/40 showed better performance (area under the curve = 0.949; 95% CI, 0.929-0.970; P <.02) than individual biomarkers. In CU participants with subthreshold baseline Aβ-PET, baseline plasma %p-tau217 and Aβ42/40 levels were significantly associated with baseline Aβ-PET (n = 384) and increases in Aβ-PET over time (n = 224). Associations of plasma %p-tau217 and Aβ42/40 and their interaction with baseline Aβ-PET (%p-tau217: β = 2.77; 95% CI, 1.84-3.70; Aβ42/40: β = −1.64; 95% CI, −2.53 to −0.75; %p-tau217 × Aβ42/40: β = −2.14; 95% CI, −2.79 to −1.49; P < .001) and longitudinal Aβ-PET (%p-tau217: β = 0.67; 95% CI, 0.48-0.87; Aβ42/40: β = −0.33; 95% CI, −0.51 to −0.15; %p-tau217 × Aβ42/40: β = −0.31; 95% CI, −0.44 to −0.18; P < .001) were also significant in the models combining the 2 baseline biomarkers as predictors. Similarly, baseline plasma p-tau217 and Aβ42/40 were independently associated with longitudinal Aβ-PET in Knight ADRC (%p-tau217: β = 0.71; 95% CI, 0.26-1.16; P = .002; Aβ42/40: β = −0.74; 95% CI, −1.26 to −0.22; P = .006) and longitudinal CSF Aβ42/40 in BioFINDER-1 (p-tau217: β = −0.0003; 95% CI, −0.0004 to −0.0001; P = .01; Aβ42/40: β = 0.0004; 95% CI, 0.0002-0.0006; P < .001) in CU participants with subthreshold Aβ levels at baseline. Plasma p-tau231 and GFAP did not provide any clear independent value.Conclusions and RelevanceResults of this cohort study suggest that combining plasma p-tau217and Aβ42/40 levels could be useful for predicting development of Aβ pathology in people with early stages of subthreshold Aβ accumulation. These biomarkers might thus facilitate screening of participants for future primary prevention trials.

中文翻译：

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血浆磷酸化 Tau 217 和 Aβ42/40 可预测无认知障碍人群的早期大脑 Aβ 积累


重要性 抗淀粉样蛋白疗法成功治疗阿尔茨海默病 (AD) 的第 3 期试验表明，对于病情较轻的患者，临床疗效有所改善。血浆生物标志物对于在未来初级预防临床试验中有效筛查参与者至关重要，这些临床试验在认知未受损 (CU) 个体中测试抗淀粉样蛋白治疗，这些个体最初脑部 β-淀粉样蛋白 (Aβ) 水平较低，且 Aβ 积累风险较高。血浆生物标志物可用于预测基线时大脑 Aβ 水平低于阈值（定义为 Aβ 水平 <40 Centiloids）的 CU 个体的 Aβ 病理学后续发展。设计、设置和参与者这是一项纵向研究，包括瑞典 BioFINDER-2（入组） 2017-2022）并在 2 个独立队列中进行复制，即 Knight 阿尔茨海默病研究中心（Knight ADRC；1988 年和 2019 年入组）和瑞典 BioFINDER-1（2009-2015 年入组）。包括用于分析的是 CU 个体的方便样本，其进行了基线血浆磷酸化 tau 217 (p-tau217) 和 Aβ42/40 评估以及使用正电子发射断层扫描 (Aβ-PET) 或脑脊液 (CSF) Aβ42/40 进行的 Aβ 评估。数据分析于 2023 年 4 月至 2024 年 5 月期间进行。暴露 Aβ42/40、p-tau217 的基线血浆水平、p-tau217 与非磷酸化 tau 的比率 (%p-tau217)、p-tau231 和胶质纤维酸性蛋白 (GFAP)主要结果和测量脑 Aβ 病理学的横断面和纵向 PET 和 CSF 测量。结果本研究包括 495 名 (BioFINDER-2)、283 名 (Knight ADRC) 和 205 名 (BioFINDER-1) CU 参与者。在 BioFINDER-2 中，261 名女性 (52.7%) 的平均 (SD) 年龄为 65.7 岁 (14.4)。 当检测异常 CSF Aβ 状态时，血浆 %p-tau217 和 Aβ42/40 的组合显示出比单独生物标志物更好的性能（曲线下面积=0.949；95% CI，0.929-0.970；P <.02）。在基线 Aβ-PET 低于阈值的 CU 参与者中，基线血浆 %p-tau217 和 Aβ42/40 水平与基线 Aβ-PET (n = 384) 显着相关，并且 Aβ-PET 随着时间的推移而增加 (n = 224)。血浆 %p-tau217 和 Aβ42/40 的关联及其与基线 Aβ-PET 的相互作用（%p-tau217：β = 2.77；95% CI，1.84-3.70；Aβ42/40：β = -1.64；95% CI， -2.53 至 -0.75；%p-tau217 × Aβ42/40：β = -2.14；95% CI，-2.79 至 -1.49；P < .001）和纵向 Aβ-PET（%p-tau217：β = 0.67） ; 95% CI, 0.48-0.87; Aβ42/40: β = -0.33; 95% CI, -0.51 至 -0.15; %p-tau217 × Aβ42/40: β = -0.31; 0.18；P < .001）在结合 2 个基线生物标志物作为预测因子的模型中也很显着。同样，Knight ADRC 中基线血浆 p-tau217 和 Aβ42/40 与纵向 Aβ-PET 独立相关（%p-tau217：β = 0.71；95% CI，0.26-1.16；P = .002；Aβ42/40：β = -0.74；95% CI，-1.26 至 -0.22；P = .006) 和 BioFINDER-1 中的纵向 CSF Aβ42/40 (p-tau217：β = -0.0003；95% CI，-0.0004 至 -0.0001；P基线时 Aβ 水平低于阈值的 CU 参与者中，Aβ42/40：β = 0.01；95% CI，0.0002-0.0006；P < 0.001。血浆 p-tau231 和 GFAP 没有提供任何明确的独立价值。结论和相关性该队列研究的结果表明，结合血浆 p-tau217 和 Aβ42/40 水平可用于预测处于阈下 Aβ 积累早期阶段的人群中 Aβ 病理的发展。 。因此，这些生物标志物可能有助于筛选未来初级预防试验的参与者。