Lymphatic-venous anastomosis surgery for Alzheimer’s disease

Lymphatic-venous anastomosis (LVA) surgery has recently emerged as a potential treatment for Alzheimer’s disease (AD) in China. This minimally invasive microsurgical procedure has been used for decades to treat lymphoedema, typically in the limbs, to decompress blocked lymphatic drainage pathways. Recently, the technique has been proposed to augment drainage of bilateral cervical lymphatics as a treatment for AD,¹ as evidence suggests that reduced brain lymphatic clearance may contribute to neurodegeneration. Although a growing body of preclinical and clinical studies supports the notion of impaired glymphatic function in AD, no appropriate clinical trials have evaluated LVA for AD treatment. However, isolated case reports of efficacy¹,³ have gained widespread attention on mainstream public online platforms in China, and the treatment has rapidly expanded across China and is now available in over 30 clinical centres across multiple cities. By the end of 2024, more than 500 cases had been publicly reported, with the actual number likely exceeding 1000, based on reports from hospitals and media sources.

In the memory clinic, these microsurgical techniques for lymphatic reconstruction have become the consulting hotspot among patients with cognitive impairments and their families. The reasons for this heightened interest include the lack of effective treatments for AD, the widespread promotion of individual success stories through media and the growing demand for innovative medical solutions among China’s ageing population. Despite this rapid adoption and ‘miraculous effects’ from non-academic sources, no other country has reported clinical applications or clinical trials of LVA for AD treatment so far, raising questions about its mechanism, efficacy and implications.

The current status and efficacy of LVA surgery in China

LVA surgery for AD is primarily performed at private and select public hospitals in China, with the direct microsurgical anastomosis of cervical lymphatic vessels to veins to enhance waste clearance. However, the procedure lacks standardised protocols for surgical approach, patient selection and postoperative management, leading to inconsistent outcomes. Despite the promising theoretical foundation, clinical efficacy data remain largely anecdotal, with most reports highlighting immediate postoperative cognitive improvements based on subjective observations rather than standardised neuropsychological assessments. Short-term improvements in alertness, motor coordination and verbal responses have been documented; however, the sustainability and long-term benefits of these effects remain unproven. Few randomised controlled trials (RCTs) have been conducted to rigorously assess its safety and efficacy, and there is a shortage of biomarker studies, such as cerebrospinal fluid β-amyloid clearance or magnetic resonance imaging-based glymphatic function assessments. Potential risks include surgical complications like infection, haemorrhage and lymphatic leakage, as well as transient postoperative cognitive issues such as confusion or delirium, possibly due to anaesthesia or cerebrovascular stress. Furthermore, the long-term effects of chronic lymphatic-venous shunting on brain homeostasis remain uncertain and require further investigation.

The potential theory for LVA surgery in AD

The theoretical foundation for LVA surgery in AD stems from the proposed link between impaired brain lymphatic clearance and AD pathology.⁴ Evidence suggests that the clearance of β-amyloid/phospho-Tau-181 and other metabolic waste from the brain is closely related to the lymphatic system and cerebrospinal fluid circulation.⁴ Deep cervical lymph nodes play a critical role in brain waste drainage by connecting the glymphatic system to the systemic lymphatic circulation. LVA surgery aims to enhance this process by surgically connecting lymphatic vessels directly to veins, improving waste clearance and reducing pathological protein accumulation, such as β-amyloid. Studies have demonstrated that enhancing lymphatic clearance can reduce β-amyloid accumulation and improve cognitive function,⁵ although clinical data in humans remain sparse. Recent cases,¹ such as a video featuring a patient with advanced dementia who achieved remarkable improvements in behaviour and memory after LVA surgery, have garnered significant attention in the field. However, these claims remain premature, as they lack the rigorous evidence required to substantiate their long-term efficacy, including biomarker measurements, imaging studies and neuropsychological evaluations.

LVA surgery for AD: neither confirm nor deny?

The increasing adoption of LVA surgery highlights the urgent demand for effective AD treatments. Patients and their families are desperate for more effective treatments, as illustrated by the proliferation of this unproven treatment in China, where over 16 million people suffer from AD and other types of dementia.⁶ While improved living standards and extended life expectancy have heightened public awareness of AD, media reports on LVA outcomes may have created biased expectations. Surveys indicate that most LVA recipients are patients with moderate-to-severe AD (table 1), many of whom may be grasping at straws.

Table 1. Clinical trial registrations: lymphatic-venous anastomosis surgery for Alzheimer’s disease in China.

Public title	Registered unit	Registration number	Date of registration
Randomised controlled clinical trial of deep cervical lymphangiovenous anastomosis in the treatment of Alzheimer’s disease	The First People’s Hospital of Zunyi City	ChiCTR2400094603	12/25/2024
A study to investigate the clinical efficacy of deep cervical lymphovenous anastomosis in the treatment of type 2 diabetes mellitus combined with Alzheimer’s disease	Zhengzhou Central Hospital	ChiCTR2400093030	11/27/2024
Evaluation of comprehensive diagnosis and treatment efficacy of Alzheimer’s disease based on bilateral cervical deep lymphatic vein anastomosis	Zhengzhou Central Hospital	ChiCTR2400092975	11/26/2024
A single-centre, prospective, single-arm exploratory study on deep cervical lymphaticovenous anastomosis for improving neurological function in patients with Alzheimer’s disease	Department of Neurosurgery, First Affiliated Hospital of Army Medical University	ChiCTR2400089883	09/19/2024
Randomised controlled clinical trial of deep cervical lymphatic vessel vein anastomosis and lymphatic stemnectomy for the treatment of Alzheimer’s disease	The Ninth People’s Hospital affiliated to Shanghai Jiao Tong University School of Medicine	ChiCTR2400084617	05/21/2024
Deep cervical lymphatic-venous anastomosis surgery for the treatment of Alzheimer’s disease: a pilot study (DIVA study)	Zhejiang Provincial People’s Hospital	Clinical Trial NCT06530732	07/31/2024
An exploratory study of deep cervical lymphovenous bypass (LVB) in Alzheimer’s disease	Affiliated Hospital of Jiangnan University	Clinical Trial NCT06448975	07/10/2024

Despite its minimally invasive nature, LVA surgery requires general anaesthesia that carries risks of delirium and potential exacerbation of cognitive impairment. The procedure’s mechanism remains speculative, with no conclusive evidence proving its long-term benefits in patients with AD. Additionally, the lack of RCT evidence and standardised surgical protocols makes it difficult to assess reproducibility and efficacy. Potential risks such as surgical complications, anaesthesia-induced delirium and unforeseen long-term effects on brain homeostasis remain unaddressed. Given these concerns, it is crucial to approach LVA surgery with caution, ensuring that patients and families are well-informed about its experimental nature and the need for further research. Clinical trial registrations are beginning to provide a framework for systematic evaluation (table 1). However, AD is a multifactorial disease, and no single intervention is likely to be sufficient. Moreover, the safety of LVA must be rigorously tested through clinical studies.⁷ We advocate for integrating LVA with other interventions, such as anti-β-amyloid therapies, cognitive rehabilitation and lifestyle management, to achieve synergistic benefits.

LVA surgery for AD should be approached with caution. Informed consent, comprehensive risk–benefit assessments and rigorous scientific validation are essential. Large-scale, multicentre RCTs are necessary to establish its safety, efficacy and long-term benefits. Additionally, basic and translational research should further elucidate the mechanisms, including enhanced glymphatic clearance and reduced neuroinflammation.

Overall, we call for a global collaborative effort to harmonise clinical protocols, share data and accelerate the evaluation of LVA as a potential therapy for AD. Continued observation of patients undergoing this procedure and close monitoring of ongoing research are critical to ensuring its safe and effective implementation.

Biography

Hualong Wang received his PhD in Medicine from Hebei Medical University, China in 2014. Since 2024, he has been working at the Department of Neurology, Renji Hospital, affiliated with Shanghai Jiao Tong University School of Medicine in China, where he serves as a Chief Physician and Deputy Director of the Department of Neurology. Dr Wang holds several academic positions, including Member of the Neurodegenerative Diseases Branch of the Chinese Neuroscience Society, Member of the Vascular Cognitive Impairment Branch of the Chinese Stroke Association. Additionally, he serves as an editorial board member of the Chinese Journal of Neurology and Neurorehabilitation. His main research interests include the pathogenesis and treatment of neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease.