Bartlett Mitchell J, Erickson Robert P, Frye Jennifer, Doyle Kristian P, Pires Paulo W, Witte Marlys H
bioRxiv. 2025 Aug 12:2025.08.08.669361. doi: 10.1101/2025.08.08.669361.
Alzheimer's disease (AD) affects 6.9 million people over the age of 65 in the US and is expected to double by 2060. While FDA approved immunotherapies slow cognitive decline in some individuals with AD, they do not improve cognition, are costly, and have significant side-effects. Therefore, new targets, approaches, and treatments for AD are a necessity. There are no FDA approved therapies for AD that target the brain's lymphatic system. It is well established that the toxic protein, amyloid-beta (Aβ), accumulates in the AD brain. Recent studies have shown that Aβ is cleared via interstitial fluid and cerebrospinal fluid through a pathway involving the glymphatic system-meningeal lymphatic vessels-leading to deep and superficial cervical lymphatic vessels and nodes. Therefore, any blockage along this route can cause inefficient drainage and result in pathological buildup of Aβ, which can lead to AD. Here, we propose a new approach to treating AD by manual lymph drainage (MLD), which is a light skin massage traditionally used to reduce fluid accumulation in lymphedema. This therapy has also been demonstrated to be safe in individuals with AD, but its effects on cognition and biomarkers of AD has never been investigated. In this study we demonstrate that repeated MLD of the head and neck, including the superficial cervical lymphatic vessels (scLVs), improves cognitive function in AD as measured in both the Y-maze and nest-building tests. We also show that this coincides with a reduction in plasma levels of neurofilament light chain (NfL), a non-specific biomarker for neuronal cell death and axonal damage. MLD was also shown to reduce Aβ in the hippocampus of these mice. Combined, this data provides compelling proof-of-principle evidence for the potential of MLD as a standalone or adjunct therapy in the treatment of AD.
在美国，阿尔茨海默病（AD）影响着690万65岁以上的人群，预计到2060年这一数字将翻倍。虽然美国食品药品监督管理局（FDA）批准的免疫疗法能减缓部分AD患者的认知衰退，但它们无法改善认知功能，成本高昂，且有显著的副作用。因此，针对AD的新靶点、新方法和新治疗手段必不可少。目前尚无FDA批准的针对大脑淋巴系统的AD治疗方法。众所周知，有毒蛋白质β-淀粉样蛋白（Aβ）在AD患者的大脑中会累积。最近的研究表明，Aβ通过间质液和脑脊液，经一条涉及类淋巴系统——脑膜淋巴管——通向颈深和颈浅淋巴管及淋巴结的途径被清除。因此，这条路径上的任何堵塞都可能导致引流不畅，进而导致Aβ病理性积聚，引发AD。在此，我们提出一种通过手动淋巴引流（MLD）治疗AD的新方法，MLD是一种传统的轻度皮肤按摩手法，用于减少淋巴水肿中的液体积聚。该疗法在AD患者中也已被证明是安全的，但其对AD认知功能和生物标志物的影响从未被研究过。在本研究中，我们证明对头颈部进行反复的MLD，包括颈浅淋巴管（scLVs），在Y迷宫试验和筑巢试验中均显示能改善AD患者的认知功能。我们还表明，这与血浆中神经丝轻链（NfL）水平的降低相一致，NfL是神经元细胞死亡和轴突损伤的非特异性生物标志物。MLD还被证明能减少这些小鼠海马体中的Aβ。综合来看，这些数据为MLD作为AD独立或辅助治疗方法的潜力提供了令人信服的原理验证证据。
