Manual lymph drainage massage of the head and neck improves cognition and reduces pathological biomarkers in the 5x-FAD mouse model of Alzheimers disease

Alzheimers 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 brains lymphatic system. It is well established that the toxic protein, amyloid-beta (A{beta}), accumulates in the AD brain. Recent studies have shown that A{beta} 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 A{beta}, 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 A{beta} 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.