The incidence of Alzheimer’s disease (AD), the leading cause of dementia, increases rapidly with age, but why age constitutes the main risk factor is still poorly understood. Brain ageing affects oligodendrocytes and the structural integrity of myelin sheaths¹, the latter of which is associated with secondary neuroinflammation^2,3. As oligodendrocytes support axonal energy metabolism and neuronal health^4,5,6,7, we hypothesized that loss of myelin integrity could be an upstream risk factor for neuronal amyloid-β (Aβ) deposition, the central neuropathological hallmark of AD. Here we identify genetic pathways of myelin dysfunction and demyelinating injuries as potent drivers of amyloid deposition in mouse models of AD. Mechanistically, myelin dysfunction causes the accumulation of the Aβ-producing machinery within axonal swellings and increases the cleavage of cortical amyloid precursor protein. Suprisingly, AD mice with dysfunctional myelin lack plaque-corralling microglia despite an overall increase in their numbers. Bulk and single-cell transcriptomics of AD mouse models with myelin defects show that there is a concomitant induction of highly similar but distinct disease-associated microglia signatures specific to myelin damage and amyloid plaques, respectively. Despite successful induction, amyloid disease-associated microglia (DAM) that usually clear amyloid plaques are apparently distracted to nearby myelin damage. Our data suggest a working model whereby age-dependent structural defects of myelin promote Aβ plaque formation directly and indirectly and are therefore an upstream AD risk factor. Improving oligodendrocyte health and myelin integrity could be a promising target to delay development and slow progression of AD.

阿尔茨海默病（AD）是痴呆症的主要原因，其发病率随着年龄的增长而迅速增加，但为什么年龄构成主要危险因素仍知之甚少。大脑衰老会影响少突胶质细胞和髓鞘的结构完整性¹，后者与继发性神经炎症相关^2,3。由于少突胶质细胞支持轴突能量代谢和神经元健康^4,5,6,7，我们假设髓鞘完整性的丧失可能是神经元淀粉样蛋白-β (Aβ) 沉积的上游危险因素，而神经元淀粉样蛋白-β (Aβ) 沉积是 AD 的中枢神经病理学标志。在这里，我们确定髓磷脂功能障碍和脱髓鞘损伤的遗传途径是 AD 小鼠模型中淀粉样蛋白沉积的有效驱动因素。从机制上讲，髓磷脂功能障碍会导致 Aβ 生成机制在轴突肿胀内积聚，并增加皮质淀粉样前体蛋白的裂解。令人惊讶的是，髓鞘功能障碍的 AD 小鼠尽管数量总体有所增加，但缺乏斑块聚集的小胶质细胞。具有髓磷脂缺陷的 AD 小鼠模型的批量和单细胞转录组学表明，同时诱导高度相似但不同的疾病相关小胶质细胞特征，分别针对髓磷脂损伤和淀粉样斑块。尽管成功诱导，但通常清除淀粉样蛋白斑块的淀粉样蛋白疾病相关小胶质细胞（DAM）显然会分散注意力到附近的髓磷脂损伤上。我们的数据表明了一种工作模型，年龄依赖性髓磷脂结构缺陷直接和间接促进 Aβ 斑块形成​​，因此是 AD 的上游危险因素。改善少突胶质细胞的健康和髓磷脂的完整性可能是延缓 AD 发展和进展的一个有希望的目标。