In recent years, the glymphatic and meningeal lymphatic systems have emerged as promising therapeutic frontiers in neurodegenerative disease. In their review, Yen et al.1 present a compelling case for lymphovenous anastomosis (LVA)—a well-established microsurgical technique in the treatment of lymphedema—as a potential intervention for Alzheimer disease (AD). This innovative concept places plastic surgeons at the crossroads of neuroscience, aging, and cognition. Yet as surgical innovation meets neurodegeneration, the concept offers both immense promise and unavoidable paradoxes. The lymphatic system’s involvement in AD has become increasingly well supported by recent studies. Landmark publications have delineated the molecular consequences of lymphatic dysfunction and revealed the anatomical routes through which cerebrospinal fluid exits the brain.2,3 These findings are progressively completing the puzzle of how meningeal lymphatic impairment contributes to AD pathology. Critically, evidence suggests that the primary bottleneck in this clearance pathway lies within the upstream meningeal lymphatics, which are particularly vulnerable to age-related deterioration. In contrast, the downstream superficial and deep cervical lymphatics—the target of LVA—remain relatively preserved in aged mice.3,4 This anatomical insight yields a compelling rationale: although we cannot yet repair the upstream degenerative segment, enhancing drainage through the intact downstream pathway may still improve overall clearance. In this context, LVA may serve not as a definitive solution but rather as a temporary bypass to support the brain’s failing waste disposal system. However, this highlights the core challenge. LVA targets the only segment of the lymphatic pathway not subject to age-related decline. Unless the anastomosis remains patent and effective over time, any therapeutic benefit may prove fleeting—or potentially counterproductive. If upstream dysfunction persists while downstream flow is increased, the system may become overwhelmed, potentially, and the disease could relapse, with accelerated progression. Safety concerns compound these uncertainties. To date, there is no animal model or preclinical validation to confirm the safety and efficacy of LVA in this context. Surgery in older patients carries inherent risks, which raises the question, if benefits are transient, is it ethically justified to expose patients to invasive intervention, especially when less invasive alternatives—such as cervical lymphatic stimulation3 or drug delivery systems4,5—may offer similar downstream effects? From September to December of 2024, my team conducted a prospective, open-label, exploratory clinical trial in 10 patients with AD who underwent cervical deep lymph node–to-vein anastomosis. Follow-up is nearing completion, and the early findings are thought-provoking. At 1 month, cognitive outcomes were encouraging, as measured by the Alzheimer’s Disease Assessment Scale–Cognitive Subscale, a standard benchmark in AD therapeutic trials. Postoperative complications, however, were not uncommon, occurring in 7 patients and including delirium and, in 1 case, severe aspiration events requiring resuscitation. By the 9-month mark, several families reported signs of cognitive relapse, which suggests that initial improvements may not be durable. Our study does not yet provide conclusive answers, but it does raise critical questions, many of which were thoughtfully addressed by Yen et al. in their review: What is the underlying biological mechanism of benefit? How long does the effect last? Which patients stand to benefit most? Most importantly, can we develop objective, noninvasive tools to measure central lymphatic function and track surgical efficacy over time? This microsurgical approach is a bold step into uncharted territory. It requires—not merely invites—rigorous preclinical validation, mechanistic investigation, and carefully designed clinical trials. As neurolymphatic science advances, surgery may well find its place in the therapeutic armamentarium for AD. For now, our enthusiasm must be tempered by caution and scientific rigor. Even if LVA does not ultimately become a mainstream treatment for AD, its broader impact may be profound. It validates the lymphatic system as a therapeutic target and, more importantly, reframes our understanding of AD from a static model of neuronal decline to a dynamic disorder involving clearance failure and immune dysregulation. This reconceptualization paves the way for new strategies that may be less invasive, more precise, and more sustainable. Whether or not LVA remains in the long-term treatment paradigm, its contribution in pioneering this direction is substantial. DISCLOSURE The author has no financial interests to declare.
Mengqing Zang (Wed,) studied this question.