Unlocking the Brain's Lymphatic System: A Novel Surgical and a Non-Invasive Approach to Treating Alzheimer’s Disease - PROJECT SUMMARY/ABSTRACT. Alzheimer’s disease (AD) affects 6.9 million people over 65 years of age in the US and is expected to double by 2060. As our population ages, the social and economic burden continues to grow. Currently, AD/AD-related dementias (ADRD) cost the United States $360 billion, a number expected to rise to $1 trillion by 2050. Moreover, unpaid caregivers provide 18 billion hours of unpaid care, equating to $347 billion in foregone economic growth. AD/ADRD treatment and care will require a multifaceted approach, and the lack of therapeutic options is a critically unmet need. While recently approved immunotherapies slow cognitive decline in some individuals with AD/ADRD, they do not improve cognition, are costly, and have significant side-effects. Therefore, new targets and treatments that are accessible to all is a critically under met need. Despite their recent rediscovery there are no FDA approved therapies for AD/ADRD that target the brain’s lymphatic system. The current hypothesis is that the brain clears toxic metabolites, such as amyloid beta (Aβ), via interstitial and cerebrospinal fluid through the brain’s lymphatics. Therefore, any impairment along this route can lead to inefficient drainage and pathological accumulation of Aβ, progressing to cognitive impairment and eventually ADRD. However, there is promising evidence that enhancing lymphatic function alone can improve cognition and reduce AD-related biomarkers. In this proposal, I aim to characterize the brain’s lymphatic drainage in the TgF344-AD rat model and then expand on my pilot data investigating two therapies, both approved for lymphatic disease, and repurposing them for AD. Manual lymphatic drainage (MLD) is a light skin massage, which increases lymphatic flow, contractility, and protein clearance and lymphaticovenous anastomosis (LVA) is a first-line surgical treatment for lymphedema, in which patent lymphatic vessels are rerouted to veins, redirecting obstructed lymph to the central venous system. Based on pilot data and evidence in the literature, I hypothesize that both therapies can improve brain lymphatic flow, specifically via the cervical lymphatic vessels, which will improve contractility, increase lymph clearance, reduce Aβ accumulation in the brain, and slow the progression of cognitive decline seen in AD. I have assembled a multidisciplinary mentorship committee of scientists and clinicians with the necessary expertise to fill a critical gap in knowledge by rigorously investigating the pathophysiological changes in the brain lymphatics of a well-established rat model of AD and evaluating MLD and LVA as potentially innovative AD therapies. As MLD and LVA are established techniques and approved in humans they can be immediately translated to the clinic. Moreover, they are inexpensive, have limited side effects, and have the potential to act as stand-alone treatments or complementary to other approved AD therapies.
