Detection of early cognitive change: Linking to clinically meaningful outcomes (Project 4)

项目4：认知。鉴于一系列令人失望的临床试验结果， 随着阿尔茨海默病（AD）的发展，阐明其时间关系变得更加紧迫。 AD的分子病理学的积累与最早的临床症状的出现之间的关系， 表现。在项目4的第二个周期中，我们发现了一致的证据， （a β）与未来的认知能力下降有关;然而， 下降越来越清楚的是，孤立的β不足以立即下降，β有可能 一旦tau病理学和神经变性广泛传播，相关性就变得小得多。因此，我们现在寻求 为了更好地理解与早期积累相关的认知变化模式， a β和tau，甚至低于当前异常阈值，并表征"临床前"阶段 以及促进成功衰老和认知能力下降的因素。在另一端 在临床前AD谱中，我们将研究早期认知改变是否是进展的预测因素 临床损伤，因为我们将有长达15年的随访。在目标1中，我们努力进一步阐明 纵向a β和tau累积与认知轨迹之间的时间关联。除了 我们的工作与临床前阿尔茨海默氏症认知复合（PACC），我们将更深入，并专注于 与β和tau的最早积累相关的特定认知过程， 可能与这些病理相互作用的多种因素。在目标2中，我们将利用数字技术推进 我们的工作是通过更快地检测认知变化，并以更高的特异性和准确性来更快地进行。 我们最初的工作使用家庭iPAD测试显示，尽管反复接触， 每个月在iPad上进行一次面部-姓名配对刺激，与a β升高相关。我们现在建议测试 我们是否能检测到一段时间内练习效果减弱的类似模式。我们还 开始使用人工智能（AI）软件平台，使用数字笔捕捉微妙的 非记忆过程中的认知效率低下。在目标3中，我们将超越认知测试， 每天检查临床相关指标，包括自我和学习伙伴的认知功能报告 活动和神经行为改变，以阐明潜在的双向关系和时间 这些变化的顺序沿着临床前AD的轨迹。我们将使用这些措施来评估 早期认知变化的"临床意义"，并改善我们对临床进展的预测， 损伤，与成像AD标志物组合。项目4将利用丰富的纵向 HABS队列的神经心理学、行为学和多模态成像数据可用于改善我们的研究。 了解衰老大脑中a β和tau的积累与认知能力之间的关系 轨迹，并最终为正在进行的和未来的旨在预防认知能力下降的试验提供信息。

SUMMARY—PROJECT 4: COGNITION. Given the series of disappointing clinical trial results at symptomatic stages of Alzheimer’s disease (AD), it has become even more urgent to elucidate the temporal relationships between accumulation of the molecular pathology of AD and the emergence of the earliest clinical manifestations. Over the second cycle of Project 4, we found consistent evidence that elevated amyloid-beta (aβ) is associated with future cognitive decline; however, there is considerable heterogeneity in rates of decline. It is increasingly clear that aβ in isolation is not sufficient for imminent decline, and it is possible that aβ becomes much less relevant once tau pathology and neurodegeneration are widespread. Thus, we now seek to better understand the patterns of cognitive change associated with the earliest phases of accumulation of both aβ and tau, even below current thresholds for abnormality, and to characterize the “pre-preclinical” phase of AD, as well as the factors that promote successful aging and resilience to cognitive decline. At the other end of the preclinical AD spectrum, we will investigate whether early cognitive change is predictive of progression to clinical impairment, as we will have up to 15 years of follow-up. In Aim 1, we strive to further elucidate the temporal association between longitudinal aβ and tau accumulation and cognitive trajectories. In addition to our work with the Preclinical Alzheimer Cognitive Composite (PACC), we will go deeper and focus on the specific cognitive processes associated with the earliest accumulation of aβ and tau, in the context of the multiple factors that may interact with these pathologies. In Aim 2, we will utilize digital technology to advance our work to go faster by detecting cognitive change more rapidly and with greater specificity and accuracy. Our initial work using home iPAD testing revealed a marked lack of “practice effect” despite repeated exposure to face-name pair stimuli every month on the iPad, associated with elevated aβ. We now propose to test whether we can detect a similar pattern of diminished practice effect over a period of days. We have also begun working with an Artificial Intelligence (AI) software platform using a digital pen to capture subtle cognitive inefficiencies in non-memory processes. In Aim 3, we will go broader, beyond cognitive testing, to examine clinically relevant measures that include self- and study-partner report of cognitive function, every day activities, and neurobehavioral alterations to elucidate potential bi-directional relationships and temporal sequence of these changes along the trajectory of preclinical AD. We will use these measures to assess the “clinical meaningfulness” of early cognitive change, and to improve our predictions of progression to clinical impairment, in combination with imaging AD markers. Project 4 will leverage the rich longitudinal neuropsychological, behavioral, and multi-modality imaging data available on the HABS cohort to improve our understanding of relationships between the accumulation of aβ and tau in the aging brain and cognitive trajectories, and ultimately to inform ongoing and future trials aiming to prevent cognitive decline.