Overview
Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with the accumulation of abnormal proteins, including amyloid-beta and tau, in the brain. Recent evidence suggests that the glymphatic and meningeal lymphatic systems, which contribute to the removal of waste products from the brain, may play a role in AD. In particular, impaired drainage through the deep cervical lymphatic system may contribute to the accumulation of disease-related proteins.
The LymphDAD study is a prospective, single-center pilot study designed to explore whether surgically improving cervical lymphatic drainage may be associated with changes in biological markers, brain imaging, and cognitive and clinical measures in selected patients with AD who are not eligible for currently available disease-modifying treatments.
Five participants with AD will undergo a minimally invasive microsurgical procedure called lymphovenous anastomosis (LVA), in which small cervical lymphatic vessels are connected to nearby small veins to facilitate lymphatic drainage. During the procedure, a small sample of lymphatic fluid will also be collected for exploratory analysis of amyloid-beta and tau proteins.
Participants will undergo clinical and neuropsychological assessments, blood sampling, magnetic resonance imaging (MRI), and amyloid positron emission tomography (PET) before the procedure and during follow-up. Follow-up assessments will be performed at 1, 3, 6, and 12 months after surgery.
The study is exploratory and is not designed to demonstrate a definitive clinical benefit. Its primary purpose is to obtain preliminary information on the feasibility, safety, and possible biological and clinical effects of cervical LVA in AD, which may support the design of future controlled studies.
Description
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-beta (Aβ) and pathological tau, accompanied by neuronal loss and progressive cognitive impairment. Recent evidence suggests that the glymphatic and meningeal lymphatic systems contribute to the clearance of brain waste products, including Aβ and tau, and that impaired drainage through the deep cervical lymphatic system may be involved in AD pathophysiology.
Emerging preclinical and clinical evidence has suggested that restoration or enhancement of cervical lymphatic drainage may represent a potential therapeutic approach. Preliminary clinical studies have reported possible improvements in cognitive and clinical measures and favorable changes in AD-related biomarkers following cervical lymphatic surgery, although the available evidence remains limited and further prospective studies are needed.
The LymphDAD study is a prospective, single-center, pilot interventional study designed to explore the effects of restoring cervical lymphatic drainage in selected patients with AD who are not eligible for currently available disease-modifying therapies. Five participants will be enrolled.
All enrolled participants will undergo cervical lymphovenous anastomosis (LVA). LVA is a minimally invasive supermicrosurgical procedure in which patent lymphatic vessels are connected to small-caliber cervical veins to facilitate lymphatic drainage. The procedure will be performed under general anesthesia with indocyanine green fluorescence lymphography to identify lymphatic vessels and assess anastomotic flow. A small sample of lymphatic fluid will be collected intraoperatively from a lymphatic channel already exposed during the procedure for exploratory analysis of Aβ and tau.
The study will evaluate changes in circulating biomarkers, including Aβ42, Aβ40, phosphorylated tau (p-tau181 and p-tau217), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP). Exploratory analyses of Aβ and tau in intraoperative lymphatic fluid will also be performed.
Neuroimaging assessments will include structural magnetic resonance imaging (MRI) for brain volumetry and amyloid positron emission tomography (PET) for assessment of amyloid burden. Clinical and cognitive outcomes will be assessed using standardized instruments, including the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), Neuropsychiatric Inventory (NPI), Clinical Dementia Rating (CDR), and, when feasible, the EQ-5D quality-of-life questionnaire.
Assessments will be performed at baseline and during follow-up. Blood biomarkers will be assessed at baseline, 1 month, and 6 months. Cognitive and clinical assessments will be performed at baseline, 3, 6, and 12 months. MRI volumetry and amyloid PET will be repeated at 6 months.
The primary purpose of this pilot study is exploratory. Outcomes will be evaluated as changes from baseline within each participant. The study does not include a control group and is not designed to establish the efficacy of LVA or demonstrate a definitive clinical benefit. The results will provide preliminary information regarding the feasibility and safety of the procedure and its possible effects on biological, imaging, cognitive, and clinical parameters, supporting the design of future controlled clinical studies.
Eligibility
Inclusion Criteria:
- Diagnosis of Alzheimer's disease according to NIA-AA 2024 criteria.
- Not eligible for other disease-modifying therapies.
- Ability to personally provide written informed consent after clinical evaluation -of decisional capacity.
Exclusion Criteria:
- Coagulopathy or active infection of the head and neck region.
- Prior extensive cervical lymph node dissection or radiotherapy.
- Uncontrolled systemic disease or contraindication to general anesthesia.
- Participation in another interventional trial within the previous 3 months.
- Known hypersensitivity or allergy to indocyanine green.
- Evidence of alternative or concomitant causes of cognitive decline other than Alzheimer's disease, such as subdural hematoma, primary or metastatic brain malignancy, or normal-pressure hydrocephalus.
- Current or recent treatment with immunosuppressive or immunomodulatory therapy within the previous 3 months.
- Clinically significant infectious disease within the previous 6 months.
- Severe psychiatric disorder that could interfere with cognitive assessment or study participation.
- Pregnancy or breastfeeding.
- End-stage malignant disease with an estimated life expectancy of less than 6 months.
- History indicative of systemic autoimmune disease.
- Inability to personally provide valid informed consent.
