Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
JAMA Neurol. 2016 Jun 1;73(6):698-705. doi: 10.1001/jamaneurol.2016.0194.
Clinical trials testing treatments for Alzheimer disease (AD) are increasingly focused on cognitively normal individuals in the preclinical phase of the disease. To optimize observing a treatment effect, such trials need to enroll cognitively normal individuals likely to show cognitive decline over the duration of the trial.
To identify which group of cognitively normal individuals shows the greatest cognitive decline over time based on their cerebrospinal fluid biomarker profile.
DESIGN, SETTING, AND PARTICIPANTS: In this cohort study, cognitively normal participants were classified into 1 of the following 4 hypothetical preclinical AD groups using baseline cerebrospinal fluid levels of Aβ and tau or Aβ and phosphorylated tau (p-tau): stage 0 (high Aβ and low tau), stage 1 (low Aβ and low tau), stage 2 (low Aβ and high tau), and suspected non-AD pathology (SNAP) (high Aβ and high tau). The data presented herein were collected between August 1995 and August 2014.
An a priori cognitive composite score based on the following 4 tests previously shown to predict progression from normal cognition to symptom onset of mild cognitive impairment or dementia: Paired Associates immediate recall, Logical Memory delayed recall, Boston Naming, and Digit-Symbol Substitution. Linear mixed-effects models were used to compare the cognitive composite scores across the 4 groups over time, adjusting for baseline age, sex, education, and their interactions with time.
Two hundred twenty-two cognitively normal participants were included in the analyses (mean follow-up, 11.0 years [range, 0-18.3 years] and mean baseline age, 56.9 years [range, 22.1-85.8 years]). Of these, 102 were stage 0, 46 were stage 1, 28 were stage 2, and 46 were SNAP. Individuals in stage 2 (low Aβ and high tau [or p-tau]) had lower baseline cognitive scores and a greater decline in the cognitive composite score relative to the other 3 groups (β ≤ -0.06 for all and P ≤ .001 for the rate of decline for all). Individuals in stage 0, stage 1, and SNAP did not differ from one another in cognitive performance at baseline or over time (11.0 years) and showed practice-related improvement in performance. The APOE ε4 genotype was not associated with baseline cognitive composite score or the rate of change in the cognitive composite score.
These results suggest that, to optimize observing a treatment effect, clinical trials enrolling cognitively normal individuals should selectively recruit participants with abnormal levels of both amyloid and tau (ie, stage 2) because this group would be expected to show the greatest cognitive decline over time if untreated.
临床试验越来越关注疾病临床前期认知正常的阿尔茨海默病（AD）患者。为了优化观察治疗效果，此类试验需要招募在试验期间可能出现认知下降的认知正常个体。
根据脑脊液生物标志物谱确定哪个认知正常个体随时间推移认知下降最大。
设计、地点和参与者：在这项队列研究中，根据基线时 Aβ 和 tau 或 Aβ 和磷酸化 tau（p-tau）的脑脊液水平，将认知正常参与者分为以下 4 个假设性的临床前期 AD 组之一：阶段 0（高 Aβ 和低 tau）、阶段 1（低 Aβ 和低 tau）、阶段 2（低 Aβ 和高 tau）和疑似非 AD 病理（SNAP）（高 Aβ 和高 tau）。本文中呈现的数据收集于 1995 年 8 月至 2014 年 8 月之间。
根据先前显示可预测从正常认知到轻度认知障碍或痴呆症状发作的以下 4 项测试的认知综合评分：配对联想即时回忆、逻辑记忆延迟回忆、波士顿命名和数字符号替代。使用线性混合效应模型比较 4 组随时间推移的认知综合评分，同时调整基线年龄、性别、教育程度以及它们与时间的交互作用。
对 222 名认知正常参与者进行了分析（平均随访时间 11.0 年[范围，0-18.3 年]，平均基线年龄 56.9 岁[范围，22.1-85.8 岁]）。其中，102 名处于阶段 0，46 名处于阶段 1，28 名处于阶段 2，46 名处于 SNAP。处于阶段 2（低 Aβ 和高 tau[或 p-tau]）的个体基线认知评分较低，且认知综合评分下降幅度大于其他 3 组（所有组的β值均≤-0.06，所有组的下降率均≤0.001）。阶段 0、阶段 1 和 SNAP 组在基线或 11.0 年随访期间的认知表现无差异，且表现出与练习相关的改善。APOE ε4 基因型与基线认知综合评分或认知综合评分的变化率无关。
这些结果表明，如果不进行治疗，为了优化观察治疗效果，招募认知正常个体的临床试验应选择性地招募 Aβ 和 tau 水平异常的参与者（即阶段 2），因为与其他组相比，该组随时间推移认知下降幅度最大。
