Table 2.

New potential and hypothetical therapeutic methods targeting the impaired brain lymphatic system in Alzheimer's disease (AD).

Risk Factors of AD Associated with Impaired Brain Lymphatic System	New Potential and Hypothetical Therapeutic Methods in AD
age-related changes in mLVs [13]	- promoting the growth of meningeal lymphatic vessels (enhancing of VEGFC-VERFR-3 signaling) [13, 21] - genetic manipulations (e.g. mVEGF-C viral vectors injections) [13] - increase in CSF production - agonists for scavenging receptor class B type 1 (SR-B1), hypothetically present on MLVs endothelium [19, 20]
decreased glymphatic clearance	- potential drugs increasing brain ISF secretion, e.g. brain-derived arginine vasopressin (AVP) [74]
age-related changes in glymphatic system - impaired perivascular AQP4 polarization [48] - reduction of arterial pulsatility of intracortical arterioles [25, 48] - decreased melatonin secretion by the pineal gland and decreased expression of neuronal MT1 and MT2 receptors for melatonin [70, 71]	- AQP4 receptor agonists [51] - hypothetical drugs which increase the expression of AQP4 in astrocytic end feet - hypothetical genetic manipulations that directly target AQP4 polarization [48, 92] - accurate treatment of arterial hypertension, diabetes and CHD [83] - focused ultrasound (FUS) in combination with microbubbles (MB) given into the blood vessel that mimic the arterial pulsality in the brain arterioles [84,86] - melatonin administration [88, 89]
impaired quality of night sleep [37, 39]	- proper sleep hygiene [37, 39] - accurate treatment of sleep apnea [37]
AQP4 mutations and polymorphisms [68, 69]	- hypothetical genetic manipulations targeting AQP4
AQP4 impairment in the reaction to depression [15]	- fluoxetine and hypothetically other antidepressants [15]
traumatic brain injury (TBI) [53]	- hypothetical drugs enhancing the clearence of CSF-ISF through glymphatic system [53]
Aβ and tau deposition (after diagnosis of AD)	- focused ultrasound (FUS) with microbubbles (MB) [84,86] - monoclonal antibody therapy [94] - viral vectors for gene therapy [92, 93]
neuroinflammation within the brain tissue	- modulation of cytokine exchange between CSF and ISF by increased activity of mLVs [95]

Abbreviations: AQP4 - aquaporin 4; Aβ - amyloid – β; CHD - congestive heart failure; CSF - cerebrospinal fluid; ISF - interstitial fluid; mLVs - meningeal lymphatic vessels; VEGFC - vascular endothelial growth factor C; VERFR-3 - vascular endothelial growth factor receptor 3.