Author(s) :

Aadith P. Maganti.

Volume/Issue :

Abstract :

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the deposition of extracellular amyloid-beta (Aβ) plaques and intracellular tau protein neurofibrillary tangles (NFTs), accompanied by prominent neuroinflammatory responses. Treating AD is extremely challenging because of its complex etiopathogenesis. AD and type 2 diabetes mellitus (T2D), a chronic metabolic disorder, share common pathophysiological features, such as insulin resistance and sleep and circadian rhythm disruptions, all of which are well-recognized risk factors for AD. Recently, glucagon-like peptide-1 receptor agonists (GLP-1RAs), approved medications for T2D and obesity, have been investigated as candidate disease-modifying agents for AD because of their neuroprotective, anti-inflammatory, improved insulin signaling, and anti-amyloidogenic properties. However, the mechanisms by which GLP-1 signaling affects sleep-wake regulation remain poorly defined. Thus, this review synthesizes the evidence linking GLP-1RAs to sleep architecture, specifically to sleep spindles and non-rapid eye movement (NREM) of the sleep-wake cycle, and to aquaporin 4 (AQP4)-dependent glymphatic clearance pathways, focusing on how these mechanisms could be leveraged to address sleep dysfunction and impaired clearance in AD. GLP-1RAs-driven mechanisms restoring the function of the glymphatic system, as well as the similar treatment benefits of melatonin, the key hormone regulating the sleepwake cycle and circadian rhythm, are discussed. In addition, the rationale for combination strategies (GLP-1RAs plus melatonin) to target complementary sleep and glymphatic clearance is highlighted, while emphasizing the need for prospective clinical testing.