Alzheimer’s disease is characterised by progressive pathophysiological changes that correspond roughly to preclinical (ie, cognitively unimpaired), mild cognitive impairment, and dementia stages. Biomarkers continue to be developed, tested, and used to detect and track the pathophysiological manifestations of this disease. Although neuropsychological tests, clinical ratings, and composite cognitive test scores have shown initial promise, the field would benefit from additional ways to detect and track cognitive, behavioural, and functional manifestations of Alzheimer’s disease with optimal power, ease, and availability, particularly in the preclinical and early clinical stages. In this issue of The Lancet Neurology, Philip Weston and colleagues show the promise of a baseline and 7-day follow-up assessment strategy to measure accelerated long-term forgetting in presymptomatic Alzheimer’s disease. 35 cognitively unimpaired autosomal dominant Alzheimer’s disease mutation carriers and non-carriers were studied on average 7 years before their affected parents’ age at symptom onset. Standard 15-item word list, short story, and complex figure learning and recall memory tests were done during an initial in-person assessment. Recall and recognition memory tests were done during a 7-day follow-up telephone call. Although the groups did not differ in their learning or 30-min recall memory scores, carriers did less well in measures of recall and recognition memory 7 days later. 7-day forgetting was associated with subjective memory concerns and proximity to age at symptom onset in the carriers. On the basis of these findings, the authors suggest that accelerated long-term forgetting might provide a more sensitive indicator of cognitive decline than do standard learning or 30-min memory tests in presymptomatic Alzheimer’s disease; they suggest that accelerated long-term forgetting reflects an early decline in mediated memory consolidation and associated Alzheimer’s disease pathology in the hippocampus, contributes to some of the earliest subjective memory concerns in at-risk persons, and has the potential to help evaluate preclinical treatments. Additional research is needed, not only to confirm the study findings in the presymptomatic stages of autosomal dominant early-onset Alzheimer’s disease, but also to show generalisability to the preclinical stages of late-onset disease and to consider how these results might be affected by ageing and other age-related disorders. Additional studies are also needed to clarify the extent to which accelerated long-term forgetting is related to biomarker measurements of amyloid burden, tau, and neurodegenerative pathology, other preclinical cognitive changes, and subsequent clinical progression. Refinements in the long-term forgetting framework might be needed to extend the findings of this study to later Alzheimer’s disease stages, account for any initial learning and memory declines, minimise potentially confounding rehearsal and learning effects associated with longitudinal assessments, and provide an indicator of progressive cognitive decline that could be used as an endpoint in preclinical trials. Refinements to the framework might also be needed to minimise participant burden in longitudinal studies and preclinical Alzheimer’s disease trials and support the study of long-term forgetting in observational studies and therapeutic trials. Interest in use of mobile and other digital technologies to detect and track cognitive, behavioural, and functional changes with greater ease, real-world value, and statistical power is growing, and there could be a chance to leverage these technologies in assessment of long-term forgetting. This elegant study illustrates the opportunity now at hand to develop, test, and use new methods to detect and track the earliest cognitive changes associated with Alzheimer’s disease, monitor a person’s risk, and help evaluate promising prevention therapies.

中文翻译：

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临床前阿尔茨海默病中的长期遗忘

阿尔茨海默病的特征在于进行性病理生理变化，大致对应于临床前（即认知未受损）、轻度认知障碍和痴呆阶段。生物标志物不断被开发、测试和用于检测和跟踪这种疾病的病理生理表现。尽管神经心理学测试、临床评级和综合认知测试分数已显示出初步前景，但该领域将受益于其他方法来检测和跟踪阿尔茨海默病的认知、行为和功能表现，并以最佳的能力、易用性和可用性，特别是在临床前和早期临床阶段。在本期《柳叶刀神经病学》中，Philip Weston 及其同事展示了基线和 7 天随访评估策略的前景，以测量症状前阿尔茨海默病中加速的长期遗忘。研究了 35 名认知未受损的常染色体显性阿尔茨海默病突变携带者和非携带者，平均比他们受影响的父母出现症状的年龄早 7 年。在最初的面对面评估期间进行了标准的 15 项单词表、短篇小说和复杂图形学习和回忆记忆测试。回忆和识别记忆测试是在 7 天的随访电话中进行的。尽管各组的学习或 30 分钟回忆记忆得分没有差异，但携带者在 7 天后的回忆和识别记忆测量方面表现不佳。7 天遗忘与主观记忆问题和携带者症状出现时的年龄接近相关。基于这些发现，作者认为，在症状前阿尔茨海默病中，与标准学习或 30 分钟记忆测试相比，加速的长期遗忘可能提供更敏感的认知能力下降指标；他们认为，长期遗忘的加速反映了海马中介导的记忆巩固和相关阿尔茨海默病病理学的早期下降，有助于高危人群中一些最早的主观记忆问题，并有可能帮助评估临床前治疗。需要额外的研究，不仅要证实常染色体显性早发性阿尔茨海默病症状前阶段的研究结果，同时也展示了对迟发性疾病的临床前阶段的普遍性，并考虑这些结果可能如何受到衰老和其他与年龄相关的疾病的影响。还需要更多的研究来阐明加速的长期遗忘与淀粉样蛋白负荷、tau 和神经退行性病理学、其他临床前认知变化和随后的临床进展的生物标志物测量相关的程度。可能需要对长期遗忘框架进行改进，以将本研究的结果扩展到阿尔茨海默病后期阶段，解释任何最初的学习和记忆下降，最大限度地减少与纵向评估相关的潜在混杂的排练和学习效果，并提供一个指标可用作临床前试验终点的进行性认知衰退。可能还需要对框架进行改进，以最大限度地减少纵向研究和临床前阿尔茨海默病试验中的参与者负担，并支持观察性研究和治疗性试验中的长期遗忘研究。对使用移动和其他数字技术更轻松地检测和跟踪认知、行为和功能变化、现实世界价值和统计能力的兴趣正在增长，并且可能有机会利用这些技术来评估长期术语遗忘。这项优雅的研究说明了现在有机会开发、测试和使用新方法来检测和跟踪与阿尔茨海默病相关的最早认知变化，监测一个人的风险，并帮助评估有希望的预防疗法。