Clinical Memory Research Unit, Faculty of Medicine, Lund University, Lund, Sweden.
Department of Neurology, Skåne University Hospital, Lund University, Lund, Sweden.
JAMA Neurol. 2023 Apr 1;80(4):360-369. doi: 10.1001/jamaneurol.2022.5272.
Alzheimer disease (AD) pathology starts with a prolonged phase of β-amyloid (Aβ) accumulation without symptoms. The duration of this phase differs greatly among individuals. While this disease phase has high relevance for clinical trial designs, it is currently unclear how to best predict the onset of clinical progression.
To evaluate combinations of different plasma biomarkers for predicting cognitive decline in Aβ-positive cognitively unimpaired (CU) individuals.
DESIGN, SETTING, AND PARTICIPANTS: This prospective population-based prognostic study evaluated data from 2 prospective longitudinal cohort studies (the Swedish BioFINDER-1 and the Wisconsin Registry for Alzheimer Prevention [WRAP]), with data collected from February 8, 2010, to October 21, 2020, for the BioFINDER-1 cohort and from August 11, 2011, to June 27, 2021, for the WRAP cohort. Participants were CU individuals recruited from memory clinics who had brain Aβ pathology defined by cerebrospinal fluid (CSF) Aβ42/40 in the BioFINDER-1 study and by Pittsburgh Compound B (PiB) positron emission tomography (PET) in the WRAP study. A total of 564 eligible Aβ-positive and Aβ-negative CU participants with available relevant data from the BioFINDER-1 and WRAP cohorts were included in the study; of those, 171 Aβ-positive participants were included in the main analyses.
Baseline P-tau181, P-tau217, P-tau231, glial fibrillary filament protein, and neurofilament light measured in plasma; CSF biomarkers in the BioFINDER-1 cohort, and PiB PET uptake in the WRAP cohort.
The primary outcome was longitudinal measures of cognition (using the Mini-Mental State Examination [MMSE] and the modified Preclinical Alzheimer Cognitive Composite [mPACC]) over a median of 6 years (range, 2-10 years). The secondary outcome was conversion to AD dementia. Baseline biomarkers were used in linear regression models to predict rates of longitudinal cognitive change (calculated separately). Models were adjusted for age, sex, years of education, apolipoprotein E ε4 allele status, and baseline cognition. Multivariable models were compared based on model R2 coefficients and corrected Akaike information criterion.
Among 171 Aβ-positive CU participants included in the main analyses, 119 (mean [SD] age, 73.0 [5.4] years; 60.5% female) were from the BioFINDER-1 study, and 52 (mean [SD] age, 64.4 [4.6] years; 65.4% female) were from the WRAP study. In the BioFINDER-1 cohort, plasma P-tau217 was the best marker to predict cognitive decline in the mPACC (model R2 = 0.41) and the MMSE (model R2 = 0.34) and was superior to the covariates-only models (mPACC: R2 = 0.23; MMSE: R2 = 0.04; P < .001 for both comparisons). Results were validated in the WRAP cohort; for example, plasma P-tau217 was associated with mPACC slopes (R2 = 0.13 vs 0.01 in the covariates-only model; P = .01) and MMSE slopes (R2 = 0.29 vs 0.24 in the covariates-only model; P = .046). Sparse models were identified with plasma P-tau217 as a predictor of cognitive decline. Power calculations for enrichment in hypothetical clinical trials revealed large relative reductions in sample sizes when using plasma P-tau217 to enrich for CU individuals likely to experience cognitive decline over time.
In this study, plasma P-tau217 predicted cognitive decline in patients with preclinical AD. These findings suggest that plasma P-tau217 may be used as a complement to CSF or PET for participant selection in clinical trials of novel disease-modifying treatments.
阿尔茨海默病（AD）的病理学始于无明显症状的β-淀粉样蛋白（Aβ）积聚的漫长阶段。该阶段在个体之间的持续时间差异很大。虽然该疾病阶段与临床试验设计密切相关，但目前尚不清楚如何最好地预测临床进展的开始。
评估不同血浆生物标志物组合对预测 Aβ 阳性认知正常（CU）个体认知下降的作用。
设计、地点和参与者：这是一项前瞻性基于人群的预后研究，评估了两项前瞻性纵向队列研究（瑞典生物标志物发现者 1 号研究和威斯康星州阿尔茨海默病预防注册研究[WRAP]）的数据，这些数据于 2010 年 2 月 8 日至 2020 年 10 月 21 日在生物标志物发现者 1 号研究中收集，于 2011 年 8 月 11 日至 2021 年 6 月 27 日在 WRAP 研究中收集。从记忆诊所招募了 CU 个体，这些个体的脑 Aβ 病理学通过生物标志物发现者 1 号研究中的脑脊液（CSF）Aβ42/40 和 WRAP 研究中的匹兹堡化合物 B（PiB）正电子发射断层扫描（PET）来定义。共有 564 名符合条件的 Aβ 阳性和 Aβ 阴性 CU 参与者，他们在生物标志物发现者 1 号和 WRAP 队列中具有相关的可用数据，其中 171 名 Aβ 阳性参与者被纳入主要分析。
基线 P-tau181、P-tau217、P-tau231、神经胶质原纤维丝蛋白和神经丝轻链在血浆中的含量；生物标志物发现者 1 号队列中的 CSF 标志物，WRAP 队列中的 PiB PET 摄取。
主要结局是纵向认知测量（使用迷你精神状态检查[MMSE]和改良临床前阿尔茨海默病认知综合评分[mPACC]），中位随访时间为 6 年（范围 2-10 年）。次要结局是转化为 AD 痴呆。使用线性回归模型，根据基线生物标志物预测纵向认知变化的速度（分别计算）。模型调整了年龄、性别、受教育年限、载脂蛋白 E ε4 等位基因状态和基线认知。根据模型 R2 系数和校正 Akaike 信息准则比较多变量模型。
在纳入主要分析的 171 名 Aβ 阳性 CU 参与者中，119 名（平均[标准差]年龄，73.0[5.4]岁；60.5%为女性）来自生物标志物发现者 1 号研究，52 名（平均[标准差]年龄，64.4[4.6]岁；65.4%为女性）来自 WRAP 研究。在生物标志物发现者 1 号队列中，血浆 P-tau217 是预测 mPACC（模型 R2=0.41）和 MMSE（模型 R2=0.34）认知下降的最佳标志物，优于仅包含协变量的模型（mPACC：R2=0.23；MMSE：R2=0.04；两者比较 P 值均<0.001）。结果在 WRAP 队列中得到验证；例如，血浆 P-tau217 与 mPACC 斜率相关（与仅包含协变量的模型相比，R2=0.13 对 0.01；P=0.01）和 MMSE 斜率相关（R2=0.29 对 0.24；与仅包含协变量的模型相比，P=0.046）。确定了稀疏模型，血浆 P-tau217 是认知下降的预测因子。对假设性临床试验进行富集的功效计算表明，当使用血浆 P-tau217 来富集随着时间推移认知下降的 CU 个体时，临床试验的样本量相对减少幅度很大。
在这项研究中，血浆 P-tau217 预测了有临床前 AD 的患者的认知下降。这些发现表明，血浆 P-tau217 可能可用于 CSF 或 PET 的补充，以选择有临床意义的新型疾病修饰治疗的临床试验参与者。
