Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
Massachusetts Alzheimer's Disease Research Center, Boston, MA, USA.
Nat Rev Neurol. 2022 Jun;18(6):323-332. doi: 10.1038/s41582-022-00642-9. Epub 2022 Mar 24.
Since the original description of amyloid-β plaques and tau tangles more than 100 years ago, these lesions have been considered the neuropathological hallmarks of Alzheimer disease (AD). The prevalence of plaques, tangles and dementia increases with age, and the lesions are considered to be causally related to the cognitive symptoms of AD. Current schemes for assessing AD lesion burden examine the distribution, abundance and characteristics of plaques and tangles at post mortem, yielding an estimate of the likelihood of cognitive impairment. Although this approach is highly predictive for most individuals, in some instances, a striking mismatch between lesions and symptoms can be observed. A small subset of individuals harbour a high burden of plaques and tangles at autopsy, which would be expected to have had devastating clinical consequences, but remain at their cognitive baseline, indicating 'resilience'. The study of these brains might provide the key to understanding the 'black box' between the accumulation of plaques and tangles and cognitive impairment, and show the way towards disease-modifying treatments for AD. In this Review, we begin by considering the heterogeneity of clinical manifestations associated with the presence of plaques and tangles, and then focus on insights derived from the rare yet informative individuals who display high amounts of amyloid and tau deposition in their brains (observed directly at autopsy) without manifesting dementia during life. The resilient response of these individuals to the gradual accumulation of plaques and tangles has potential implications for assessing an individual's risk of AD and for the development of interventions aimed at preserving cognition.
自 100 多年前首次描述淀粉样蛋白-β斑块和 tau 缠结以来，这些病变一直被认为是阿尔茨海默病 (AD) 的神经病理学标志。斑块、缠结和痴呆的患病率随年龄增长而增加，这些病变被认为与 AD 的认知症状有因果关系。目前评估 AD 病变负担的方案检查死后斑块和缠结的分布、丰度和特征，从而估计认知障碍的可能性。虽然这种方法对大多数个体具有高度预测性，但在某些情况下，病变和症状之间可能存在明显的不匹配。一小部分个体在尸检时存在大量斑块和缠结，这预计会产生破坏性的临床后果，但仍保持其认知基线，表明“有弹性”。对这些大脑的研究可能提供理解斑块和缠结与认知障碍之间“黑箱”的关键，并为 AD 的疾病修饰治疗指明方向。在这篇综述中，我们首先考虑与斑块和缠结存在相关的临床表现的异质性，然后重点关注从那些在大脑中显示大量淀粉样蛋白和 tau 沉积（直接在尸检中观察到）但在生活中没有表现出痴呆的罕见但信息丰富的个体中得出的见解。这些个体对斑块和缠结逐渐积累的弹性反应可能对评估个体患 AD 的风险以及开发旨在保护认知的干预措施具有重要意义。
