Alzheimer’s disease (AD) is the most frequent cause of dementia. Recent evidence suggests the involvement of peripheral immune cells in the disease, but the underlying mechanisms remain unclear. We comprehensively mapped peripheral immune changes in AD patients with mild cognitive impairment (MCI) or dementia compared to controls, using cytometry by time-of-flight (CyTOF). We found an adaptive immune signature in AD, and specifically highlight the accumulation of PD1+ CD57+ CD8+ T effector memory cells re-expressing CD45RA in the MCI stage of AD. In addition, several innate and adaptive immune cell subsets correlated to cerebrospinal fluid (CSF) biomarkers of AD neuropathology and measures for cognitive decline. Intriguingly, subsets of memory T and B cells were negatively associated with CSF biomarkers for tau pathology, neurodegeneration and neuroinflammation in AD patients. Lastly, we established the influence of the APOE ε4 allele on peripheral immunity. Our findings illustrate significant peripheral immune alterations associated with both early and late clinical stages of AD, emphasizing the necessity for further investigation into how these changes influence underlying brain pathology. • Peripheral CD8+ TEMRA cells expressing markers associated with senescence accumulate in AD patients before dementia onset. • Peripheral immune cells correlate with AD biomarkers, varying by clinical AD stage. • APOE ε4 modifies peripheral immunity and its association with clinical AD measures.

中文翻译：

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适应性免疫变化与阿尔茨海默病的临床进展相关

阿尔茨海默病（AD）是痴呆症最常见的原因。最近的证据表明外周免疫细胞参与了该疾病，但其潜在机制仍不清楚。我们使用飞行时间细胞计数法 (CyTOF) 全面绘制了患有轻度认知障碍 (MCI) 或痴呆症的 AD 患者与对照组相比的外周免疫变化。我们在 AD 中发现了适应性免疫特征，并特别强调了在 AD 的 MCI 阶段重新表达 CD45RA 的 PD1+ CD57+ CD8+ T 效应记忆细胞的积累。此外，一些先天性和适应性免疫细胞亚群与 AD 神经病理学的脑脊液 (CSF) 生物标志物和认知能力下降的指标相关。有趣的是，AD 患者的记忆 T 细胞和 B 细胞亚群与脑脊液中 tau 病理学、神经退行性疾病和神经炎症的生物标志物呈负相关。最后，我们确定了 APOE ε4 等位基因对外周免疫的影响。我们的研究结果说明了与 AD 早期和晚期临床阶段相关的显着外周免疫改变，强调有必要进一步研究这些变化如何影响潜在的脑病理学。 • 表达与衰老相关的标记物的外周CD8+ TEMRA 细胞在痴呆症发作前在AD 患者体内积聚。 • 外周免疫细胞与AD 生物标志物相关，随临床AD 阶段的不同而变化。 • APOE ε4 改变外周免疫及其与临床 AD 措施的关联。