Asymptomatic Alzheimer’s disease (AsymAD) describes the status of individuals with preserved cognition but identifiable Alzheimer’s disease (AD) brain pathology (i.e., beta-amyloid (Aβ) deposits, neuritic plaques, and neurofibrillary tangles) at autopsy. In this study, we investigated the postmortem brains of a cohort of AsymAD subjects to gain insight into the mechanisms underlying resilience to AD pathology and cognitive decline. Our results showed that AsymAD cases exhibit enrichment in core plaques, decreased filamentous plaque accumulation, and increased plaque-surrounding microglia. Less pathological tau aggregation in dystrophic neurites was found in AsymAD brains than in AD brains, and tau seeding activity was comparable to that in healthy brains. We used spatial transcriptomics to characterize the plaque niche further and revealed autophagy, endocytosis, and phagocytosis as the pathways associated with the genes upregulated in the AsymAD plaque niche. Furthermore, the levels of ARP2 and CAP1, which are actin-based motility proteins that participate in the dynamics of actin filaments to allow cell motility, were increased in the microglia surrounding amyloid plaques in AsymAD cases. Our findings suggest that the amyloid-plaque microenvironment in AsymAD cases is characterized by the presence of microglia with highly efficient actin-based cell motility mechanisms and decreased tau seeding compared with that in AD brains. These two mechanisms can potentially protect against the toxic cascade initiated by Aβ, preserving brain health, and slowing AD pathology progression.

无症状阿尔茨海默病 （AsymAD） 描述了在尸检时认知保留但可识别阿尔茨海默病 （AD） 脑病理（即 β-淀粉样蛋白 （Aβ） 沉积、神经炎斑块和神经原纤维缠结）的个体的状态。在这项研究中，我们调查了一组 AsymAD 受试者的死后大脑，以深入了解对 AD 病理和认知能力下降的恢复力机制。我们的结果表明，AsymAD 病例表现出核心斑块的富集，丝状斑块积累减少，斑块周围的小胶质细胞增加。在 AsymAD 大脑中发现的营养不良神经突中的病理性 tau 聚集比在 AD 大脑中发现的要少，并且 tau 播种活性与健康大脑中的相当。我们使用空间转录组学进一步表征斑块生态位，并揭示自噬、内吞作用和吞噬作用是与 AsymAD 斑块生态位中上调的基因相关的途径。此外，在 AsymAD 病例中，ARP2 和 CAP1 的水平在淀粉样斑块周围的小胶质细胞中增加，它们是基于肌动蛋白的运动蛋白，参与肌动蛋白丝的动力学以允许细胞运动。我们的研究结果表明，与 AD 大脑相比，AsymAD 病例中的淀粉样斑块微环境的特征是存在具有高效基于肌动蛋白的细胞运动机制的小胶质细胞，并且 tau 接种减少。这两种机制可以潜在地防止 Aβ 引发的毒性级联反应，保护大脑健康，并减缓 AD 病理进展。