Cervical Lymphatico-Venous Bypass for Treatment of Alzheimer's Disease - Proof of Concept Study (CLyVeB-AD-1 Study) (CLyVeB-AD-1)

Alzheimer's disease (AD), one of the most common causes of dementia in Singapore and the developed world, is a neurodegenerative disorder with high socioeconomic impact. Accumulation of neurotoxic proteins (ie. amyloid, tau) are purported to lead to neuroinflammation, synaptic dysfunction and cognitive decline. The available pharmacotherapy provide limited symptomatic control, modest effect on disease progression with significant risk of side effects. Patients with AD eventually run out of effective pharmacotherapy and deteriorate.

Recent evidence implicated the glymphatic system, meningeal lymphatics of the brain, and downstream drainage to the cervical lymphatic system in the accumulation of neurotoxic proteins in AD. This presented the opportunity for extra-cranial intervention, and has since been demonstrated in preclinical models. Based on these development, Xie and colleagues pioneered the deep cervical lymph node to venous bypass (DCLNV-BP) procedure with very promising early outcomes. The observed improvement had been attributed to enhanced clearance of the neurotoxic proteins. Knowledge gap and clinical equipoise remain, and clinical trials are required to understand the safety, mechanism of action, patient selection, and long-term outcomes.

In this proof of concept study, the investigators aim to assess safety and preliminary efficacy of DCLNV-BP in AD. An approach using objective clinical assessments, biomarkers and neuroimaging, to assess safety, evaluate preliminary efficacy and elucidate the possible mechanism underlying the observed effects, is undertaken. Since there are limited effective treatment for AD, this procedure is potentially ground breaking if it proves to halt progression or even improve patients' cognition, function and behaviour. Indirectly, this will have enormous health economic benefit for Singapore and the developed world that is facing the silver tsunami. Findings from this pilot study will lay the groundwork for future trials and research collaboration in AD and other neurodegenerative diseases.

Study Overview

• Status: Recruiting
• Conditions: Alzheimer's Disease (AD); Alzheimer Disease; Alzheimer's Disease; Dementia Alzheimer's Type; Dementia Alzheimer Type
• Intervention / Treatment: Procedure: Deep cervical lymph node to venous bypass (DCLNV-BP)

• Study Type: Interventional
• Enrollment (Estimated): 10
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Vincent KS Tay, MD, FAMS; Phone Number: +65 6788 8833; Email: vincent.tay.k.s@singhealth.com.sg
• Study Contact Backup: Name: Jeremy MF Sun, MBBS, FAMS; Phone Number: +65 90304976; Email: jeremy.sun.m.f@singhealth.com.sg

Study Locations

• Singapore
  • Singapore, Singapore
    • Recruiting
    • Changi General Hospital
    • Contact: Vincent K S Tay, BSc(Hons), MD, MRCS, MMed, MCI; Email: vincent.tay.k.s@singhealth.com.sg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosis of mild-moderate Alzheimer's disease (based on NIA-AA criteria);
• Mini-Mental State Examination (MMSE) score 10-22;
• Both participants and caregiver are able to understand English or Mandarin
• Ability to provide informed consent or have a legally authorised representative to provide informed consent;
• Good family support for post-treatment care and rehabilitation;
• Fit for general anaesthesia/deep sedation and surgery (ASA 1-2; excluding the diagnosis of Alzheimer's Disease).

Exclusion Criteria:

• Cognitive decline due to prior infection or autoimmune diseases;
• History of major cerebrovascular events or significant cardiovascular diseases;
• Inability to have the head turned passively by at least 40 degrees;
• Previous neck lymph node surgery or irradiation;
• Active infection or malignancy;
• Any contraindications to surgery or lumbar puncture
• Any contraindication to MRI/PET scan (eg. metallic implant that are not MRI-safe, known radiotracer allergy)
• Experimental Alzheimer's Disease treatment within the past 6 months. • Current use of monoclonal antibodies treatment (eg. lecanemab/donanemab)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Surgical Intervention; This is single-arm, open-label proof of concept study.	Procedure: Deep cervical lymph node to venous bypass (DCLNV-BP); Participants will under bilateral deep cervical lymph node to venous bypass procedure under general anaesthesia.; Other Names: Lymphaticovenous anastomosis

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety: Number of treatment-related adverse events	Treatment related adverse events and postoperative side effects eg. anaesthetic complications, infection, seroma, nerve or vascular injuries, wound healing issues, death.	Over 2 years
Mini Mental State Examination	Quick assessment of the cognitive domain. Assessment to be performed at: (1) Baseline; (2) Postoperative(PO) day 3; (3) PO day 7; (4) PO day 14; (5) PO 6 week; (6) PO 3 months; (7) PO 6 months; (8) PO 1 year; (9) PO 2 years.	Over 2 years
Montreal Cognitive Assessment	Brief assessment of the cognitive domains, especially in mild cognitive impairment, for memory, visuospatial skills, executive function. Assessment to be performed at: (1) Baseline; (2) Postoperative(PO) day 14; (3) PO 6 week; (4) PO 3 months; (5) PO 6 months; (6) PO 1 year; (7) PO 2 years.	Over 2 years
Clinical Dementia Rating (CDR)	Assessment administered to the participant and caregiver to test various cognitive domains (ie. orientation, attention and working memory, memory, visuospatial, language, executive function) and activities of daily living. Assessment to be performed at: (1) Baseline; (2) Postoperative(PO) day 14; (3) PO 6 week; (4) PO 3 months; (5) PO 6 months; (6) PO 1 year; (7) PO 2 years.	Over 2 years
Neuropsychiatric Inventory (NPI)	A comprehensive assessment of neuropsychiatric symptoms in patients with dementia, specifically behavioral changes, and administered to the main caregiver over about 5 minutes. Assessment to be performed at: (1) Baseline; (2) Postoperative(PO) day 14; (3) PO 6 week; (4) PO 3 months; (5) PO 6 months; (6) PO 1 year; (7) PO 2 years.	Over 2 years
Geriatric Depression Scale-Short Form (GDS-SF)	This assessment will take 5-7 minutes and will be administered to the participant to measure depressive symptoms. Assessment to be performed at: (1) Baseline; (2) Postoperative(PO) day 14; (3) PO 6 week; (4) PO 3 months; (5) PO 6 months; (6) PO 1 year; (7) PO 2 years.	Over 2 years
Quality of Life - Alzheimer's Disease (QoL-AD)	This assessment will take 5-10 minutes and will be administered to the participant to measure Quality of Life measures in AD. Assessment to be performed at: (1) Baseline; (2) Postoperative(PO) day 14; (3) PO 6 week; (4) PO 3 months; (5) PO 6 months; (6) PO 1 year; (7) PO 2 years.	Over 2 years
Zarit Burden Score	This assessment will take take 5-10 minutes and will be administered to the main caregiver to ascertain changes in caregiver burden.. Assessment to be performed at: (1) Baseline; (2) Postoperative(PO) day 14; (3) PO 6 week; (4) PO 3 months; (5) PO 6 months; (6) PO 1 year; (7) PO 2 years.	Over 2 years
Basic and instrumental Activities of Daily Living	This evaluation checklist will take under 5 minutes to assess participant's function status. Assessment to be performed at: (1) Baseline; (2) Postoperative(PO) day 14; (3) PO 6 week; (4) PO 3 months; (5) PO 6 months; (6) PO 1 year; (7) PO 2 years.	Over 2 years
Basic Gait Assessment	Basic gait assessment will be performed including (A) Gait Speed, (B) Timed up and go test, (C) 5X sit to stand test. Assessment to be performed at: (1) Baseline; (2) Postoperative(PO) day 14; (3) PO 6 week; (4) PO 3 months; (5) PO 6 months; (6) PO 1 year; (7) PO 2 years.	Over 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fluid biomarkers	Blood plasma and cerebrospinal fluids will be analysed for biomarkers related to Alzheimer's disease, neurodegeneration and lymphatic dysfunction. Blood plasma will be sampled at (1) Operative day; (2) Postoperative(PO) day 3; (3) PO day 7; (4) PO day 14; (5) PO 6 weeks; (6) PO 3 months; (7) PO 6 months; (8) PO 1 year. CSF will be sampled at (1) Operative day; (2) PO day 7; (3) PO 6 weeks [Optional]; (4) PO 3 months [Optional].	Over 1 year
Positron Emission Tomography (PET) of the brain	Participants will undergo pre- and post-intervention PET fluorodeoxyglucose (FDG) brain scan to provide functional spatial information on changes before and after the surgery (at 3 months).	Over 3 months
Magnetic Resonance Imaging (MRI) of the Brain	Participants will undergo pre- and post-intervention MRI of the brain for evaluation of neuroanatomical pathology and surrogate markers of glymphatic function (eg. DTI-ALPS). The scans will be performed at (1) Baseline, (2) Postoperative Day 7, (3) Postoperative 3 months.	Over 1 year

Collaborators and Investigators

• Sponsor: Vincent Tay Khwee Soon
• Collaborators: Singapore General Hospital; Changi General Hospital; National Neuroscience Institute

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2025
• Primary Completion (Estimated): March 31, 2028
• Study Completion (Estimated): March 31, 2030

Study Registration Dates

• First Submitted: January 17, 2025
• First Submitted That Met QC Criteria: May 1, 2025
• First Posted (Actual): May 11, 2025

Study Record Updates

• Last Update Posted (Actual): January 13, 2026
• Last Update Submitted That Met QC Criteria: January 11, 2026
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: Dementia; glymphatic system; lymphatic surgery; Alzheimer's Disease; lymphaticovenous anastomosis; lymphaticovenous bypass; cervical lymph node; meningeal lymphatic system
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Neurocognitive Disorders; Tauopathies; Neurodegenerative Diseases; Alzheimer Disease; Dementia
• Other Study ID Numbers: ClyVeB-AD-1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No