Deep Cervical Lymphovenous Anastomosis for Moderate Alzheimer's Disease (LYMVA-AD)

The Efficacy and Safety of Deep Cervical LYMphatic-Venous Anastomosis for Moderate Alzheimer's Disease: A Multicenter, Prospective, Randomized Controlled Trial

This is a multicenter, prospective, open-label, endpoint-blinded randomized controlled clinical study. We aim to evaluate the safety and efficacy of deep cervical lymphovenous anastomosis (LVA) combined with routine treatment for patients with moderate Alzheimer's disease, compared with routine treatment alone.

A total of 296 eligible participants aged 50 to 80 years with moderate Alzheimer's disease will be enrolled and randomly divided into two groups at a 1:1 ratio. One group will receive deep cervical lymphovenous anastomosis plus standard routine treatment, while the other group will only receive standard routine treatment for Alzheimer's disease.

All participants will be followed up for 12 months after randomization. We will assess cognitive function using MMSE and CDR-SB scales, evaluate caregiver burden via ZBI scale, and detect changes in Alzheimer's disease related biomarkers including blood amyloid-beta and tau protein, as well as Aβ-PET imaging indicators. The main goal is to observe whether this surgical procedure can improve patients' neurological function and clear abnormal protein deposits in the brain, and confirm its long-term safety.

This study strictly follows ethical principles. Every participant or their legal representative will sign a written informed consent before enrollment. During the whole study period, we will closely monitor all adverse events to ensure the safety of participants.

Study Overview

• Status: Not yet recruiting
• Conditions: Alzheimer's Disease
• Intervention / Treatment: Procedure: Deep cervical lymphovenous anastomosis (LVA); Other: Routine Treatment

Detailed Description

Study Design and Objectives This is an interventional, multicenter, randomized, parallel-group, open-label and endpoint-blinded clinical trial. The primary objective is to verify the efficacy and safety of deep cervical lymphovenous anastomosis (LVA) in patients with moderate Alzheimer's disease. The secondary objectives include analyzing the changes of cognitive function, caregiver burden and cerebral amyloid-beta deposition within 12 months after intervention, and exploring the variation characteristics of peripheral blood biomarkers.

Study Population Eligible participants are patients diagnosed with probable Alzheimer's dementia consistent with 2011 NIA-AA clinical criteria and 2018 NIA-AA biomarker framework. Inclusion criteria: age 50 to 80 years; MMSE score between 10 and 20 points (moderate cognitive impairment); progressive cognitive decline for more than 6 months; no clinical improvement after more than six months of drug treatment; having a designated companion who can accompany follow-up and provide informed consent. Subjects with severe organ dysfunction, recent intracranial injury, drug allergy to study related reagents, PET contraindications or other severe mental disorders will be excluded.

Intervention and Control Measures Participants are randomly assigned to two groups by EDC system at a 1:1 ratio. Intervention group: Bilateral deep cervical lymphovenous anastomosis plus conventional symptomatic treatment for Alzheimer's disease. The operation is performed under surgical microscope with indocyanine green (ICG) lymphatic tracing technology. Postoperative routine anti-inflammatory treatment and rehabilitation training will be conducted.

Control group: Receive only standard drug treatment and routine rehabilitation training for Alzheimer's disease, without surgical intervention.

Evaluation Indicators and Time Points The primary outcome measure is the change of CDR-SB score from baseline to 12 months after randomization. Secondary outcome measures include changes in CDR-SB score at 1 month and 6 months, changes in MMSE and ZBI scores at 1, 6 and 12 months, and changes of Aβ-PET Centiloid value at 12 months. Exploratory indicators cover peripheral blood Aβ42, Aβ40, Aβ42/40 ratio, t-tau, p-tau and other biomarkers at each follow-up time point.

All assessments will be conducted at baseline, 1 month (±7 days), 6 months (±15 days) and 12 months (±15 days) after randomization. All adverse events, vital signs, laboratory tests, electrocardiogram and imaging findings will be continuously collected to evaluate the safety profile of the surgical procedure.

Randomization and Blinding Method Randomization is implemented via electronic data capture (EDC) system. Due to the nature of surgical intervention, participants, surgeons and clinical researchers cannot be blinded. However, all outcome assessors and statistical analysts are fully blinded to group allocation to reduce assessment bias. All raters will be shielded from patients' surgical scars during scale evaluation.

Statistical Analysis The full analysis set (FAS) will be adopted for primary efficacy analysis based on the intention-to-treat principle. Per-protocol set (PPS) will be used for sensitivity analysis, and safety analysis will be performed based on safety analysis set (SAS). Mixed-effects model for repeated measures (MMRM) and analysis of covariance (ANCOVA) will be applied for data analysis. Missing data will be handled by last observation carried forward (LOCF) method. Subgroup analyses stratified by APOEε4 status, age and baseline cognitive level will also be performed.

Ethical Requirements The whole study complies with the Declaration of Helsinki and relevant Chinese clinical research regulations. The study has been reviewed and approved by the Ethics Committee of the First Affiliated Hospital of Army Medical University. Written informed consent will be obtained from each participant or their legal surrogate before any study-related procedures. Vulnerable population protection measures are strictly implemented for patients with cognitive impairment.

• Study Type: Interventional
• Enrollment (Estimated): 296
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Rong Hu, Dr; Phone Number: +8602368765911; Email: huchrong@tmmu.edu.cn

Study Locations

• China
  • Chongqing Municipality
    • Chongqing, Chongqing Municipality, China, 400038
      • The First Affiliated Hospital of Army Medical University (Southwest Hospital)
      • Contact: Jingyu Chen, Dr; Phone Number: +8602368765911; Email: 283686484@qq.com

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Aged 50 to 80 years old, male or female.
• Clinically diagnosed with moderate probable Alzheimer's disease according to the NIA-AA criteria.
• Baseline Mini-Mental State Examination (MMSE) score between 10 and 20 points.
• Clinical cognitive decline duration of at least 6 months.
• Stable routine anti-dementia drug treatment for more than 6 months without obvious clinical improvement.
• Able to complete neuropsychological scale assessments, blood biomarker detection and Aβ-PET examination.
• Have a reliable caregiver who can accompany follow-up visits and assist in completing evaluations.
• The participant or legal surrogate voluntarily signs the written informed consent.

Exclusion Criteria:

• Severe cardiac, hepatic, renal, respiratory or hematopoietic system dysfunction unable to tolerate surgery or anesthesia.
• A history of intracranial surgery, severe craniocerebral trauma, stroke, brain tumor or other central nervous system diseases.
• Other types of dementia, including vascular dementia, frontotemporal dementia, Lewy body dementia, or mixed dementia.
• Psychiatric disorders requiring long-term medication that may affect cognitive assessment results.
• Contraindications for PET imaging or contrast agent allergy.
• Active infection, malignant tumor or severe wasting disease.
• Pregnancy or breastfeeding status.
• Participation in other interventional clinical trials within 3 months before enrollment.
• Poor compliance or inability to complete scheduled follow-up.
• Any other condition judged inappropriate for enrollment by the investigator.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention Group (Surgery plus routine treatment); Participants undergo bilateral deep cervical lymphovenous anastomosis (LVA), combined with standard routine drug treatment for moderate Alzheimer's disease.	Procedure: Deep cervical lymphovenous anastomosis (LVA); A microsurgical lymphatic drainage procedure performed under operative microscope with ICG lymphography tracing. Bilateral deep cervical lymphovenous anastomosis is conducted to improve cerebral lymphatic clearance in patients with moderate Alzheimer's disease.; Other: Routine Treatment; Participants receive only standard routine drug treatment for moderate Alzheimer's disease, with no surgical procedure performed.
Active Comparator: Control Group (Routine treatment only); Participants receive only standard routine drug treatment for moderate Alzheimer's disease, with no surgical procedure performed.	Other: Routine Treatment; Participants receive only standard routine drug treatment for moderate Alzheimer's disease, with no surgical procedure performed.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in CDR-SB score from baseline to 12 months after randomization	Change of Clinical Dementia Rating-Sum of Boxes (CDR-SB) score at 12 months compared with baseline, to evaluate overall cognitive and functional status of patients with moderate Alzheimer's disease.	12 months after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in CDR-SB score at 1 month and 6 months after randomization	Serial changes of CDR-SB score at 1 month and 6 months post randomization.	1 month, 6 months after randomization
Change in MMSE score	Change of Mini-Mental State Examination (MMSE) score reflecting general cognitive function.	1 month, 6 months, 12 months after randomization
Change in Zarit Burden Interview (ZBI) score	Change of caregiver burden assessed by Zarit Burden Interview scale.	1 month, 6 months, 12 months after randomization
Change in Aβ-PET Centiloid value	Variation of cerebral amyloid-beta deposition measured by Aβ-PET imaging.	12 months after randomization

Collaborators and Investigators

• Sponsor: Southwest Hospital, China

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2026
• Primary Completion (Estimated): June 30, 2028
• Study Completion (Estimated): June 30, 2029

Study Registration Dates

• First Submitted: June 13, 2026
• First Submitted That Met QC Criteria: June 13, 2026
• First Posted (Actual): June 22, 2026

Study Record Updates

• Last Update Posted (Actual): June 22, 2026
• Last Update Submitted That Met QC Criteria: June 13, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: randomized controlled trial; Alzheimer's Disease; cognitive function; multicenter study; deep cervical lymphovenous anastomosis
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Neurocognitive Disorders; Dementia; Tauopathies; Neurodegenerative Diseases; Alzheimer Disease
• Other Study ID Numbers: KY2026125; (A)KY2026125 (Other Identifier: Ethics Committee of the First Affiliated Hospital of Army Medical University)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual participant data will not be shared externally to protect participants' personal privacy and comply with domestic clinical research regulations. All trial data are stored securely for internal use, inspection and audit only, and will not be provided to outside researchers without formal approval from the ethics committee.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No