Efficacy of Lymphatic-Venous Anastomosis Plus Donepezil Versus Donepezil Alone for Alzheimer's Disease

A Multicenter Randomized Controlled Trial on the Efficacy and Safety of Cervical Lymph Vessel/Node-venous Anastomosis Combined With Donepezil Versus Donepezil Alone in the Treatment of Alzheimer's Disease

This study employed a multicenter, randomized controlled trial (RCT) design to evaluate the efficacy and safety of deep cervical lymphatic/lymph node-venous anastomosis combined with oral donepezil compared to donepezil monotherapy in patients with Alzheimer's disease and moderate dementia. Participants were randomized using a central randomization system with stratified block design, with the study center and age group (50-64 years, 65-80 years) as stratification factors. While study participants and surgical investigators could not be blinded due to the nature of the intervention, efficacy assessors and imaging specialists remained blinded to ensure the objectivity and reliability of the findings. The intervention group received deep cervical lymphatic/lymph node-venous anastomosis (detailed surgical procedure is specified in the protocol) in combination with oral donepezil (5-10 mg/day), while the control group received oral donepezil alone. The total treatment and follow-up period was 18 months, with assessments conducted at baseline, 1 week, 1, 3, 6, 12, and 18 months post-operation. These included neuropsychological evaluations (MMSE, MoCA, CDR, BADL, IADL, NPI, AES), neuroimaging (MRI, PET, ultrasound), fluid biomarker analyses (CSF and blood levels of Aβ, Tau, neuroinflammatory factors, etc.), and safety monitoring. The primary efficacy endpoint was the change in CDR-SB score at 12 months post-treatment. Secondary endpoints included changes in multiple cognitive scales, neuroimaging metrics, and biomarkers at 18 months. Safety indicators encompassed adverse event recording, vital signs, and laboratory tests.

Inclusion Criteria

1. The patient or guardian signs the informed consent form;
2. Age 50-80 years (≥50 years, ≤80 years), male or female;
3. The first diagnosis is Alzheimer's disease with dementia;
4. MMSE score ≤24;
5. Positive β-amyloid protein PET imaging findings;
6. HAMD score ≤17;
7. Hachinski score ≤7;
8. No AD-related drug treatment has been received within the past 1 month;
9. ASA grade 1-3 (≥ grade 1, ≤ grade 3);
10. CDR-SB score of 9.5-15.5.

Exclusion Criteria

1. Presence of contraindications to MRI, ICG angiography, or PET scan;
2. Presence of contraindications to lumbar puncture;
3. Severe heart disease or unstable hemodynamic status;
4. Severe lung disease, including severe obstructive, restrictive, or mixed ventilatory dysfunction, or acute inflammation within 3 months;
5. Hepatic insufficiency, AST or ALT >3 times the upper limit of normal;
6. Renal insufficiency, GFR <60 mL/min or need for blood purification treatment;
7. MRI indicates active or acute intracranial lesions, including intracranial infection, space-occupying lesions, major hemorrhage, and ≥4 lobar microbleeds, etc.;
8. History of cerebral hemorrhage or cerebral infarction with severe residual neurological dysfunction;
9. Blood diseases, bleeding/coagulation disorders, coagulation dysfunction;
10. Abnormal thyroid function;
11. Moderate or severe stenosis of intracranial or cervical vessels with severe residual neurological dysfunction;
12. Severe hypertension not effectively controlled, systolic blood pressure ≥180 mmHg or diastolic blood pressure ≥110 mmHg;
13. The disease requires systemic use of steroids;
14. Drug addiction (including alcohol, narcotics, and alcohol dependence);
15. Severe infectious diseases, including HIV positivity, severe infection, etc.;
16. Severe psychiatric disease or potential suicide risk;
17. Within 3 years after radical surgery for malignant tumor;
18. Participation in other interventional clinical trials within the past three months;
19. In the physician's judgment, poor compliance, inability to complete, or unwillingness to cooperate with regular postoperative follow-up;
20. Other circumstances that the physician considers unsuitable for this clinical trial;
21. Anti-Aβ monoclonal antibody treatment has been received within half a year;
22. Previous neck surgery.