Sleep is essential for physical and mental health, playing a critical role in memory consolidation, behavioral stability, and the regulation of immune and metabolic functions. The incidence of sleep disorders, particularly sleep deprivation (SD), increases with age and is prevalent in neurodegenerative and psychiatric disorders such as Alzheimer’s disease (AD). Nearly 40% of AD patients experience significant chronic sleep impairments. The clinical distinction between late-life sleep disorders and AD is often challenging due to overlapping symptoms, including cognitive decline and behavioral impairments. Although the exact causal relationship between SD and AD remains complex and multifaceted, strong evidence suggests a bidirectional link, with AD patients frequently exhibiting disrupted sleep architecture, reduced slow-wave activity, and shorter total sleep duration. On a pathophysiological level, SD contributes to neuroinflammation, amyloid-β plaque deposition, and tau tangles, which are key features of AD. Current treatments, such as sedatives and antidepressants, often have limitations, including inconsistent efficacy, dependency risks, and poor long-term outcomes/recurrence, highlighting the need for safer and more effective alternatives. This review examines the interplay between SD and AD and proposes omega (n)-3 fatty acids (FAs) as a potential therapeutic intervention. Preclinical and clinical studies suggest that n-3 supplementation may improve sleep onset/quality, reduce neuroinflammation, support synaptic function, and decrease amyloid-β aggregation, thereby alleviating early AD-related neurological changes. Given their safety profile and neuroprotective effects, n-3 FAs represent a promising strategy for managing the comorbidity of sleep disorders in AD.

Endocannabinoid system is an important contributor to body’s immune responses which are significantly impaired by sleep deprivation (SD). Although cannabinoids can modulate the endocannabinoid system, but most are understudied, especially regarding SD. To investigate the therapeutic potential of CBD, CBG, CBC and their combinations, current study analyzed SD-induced memory impairment, depression, glial responses, and cytokine expression and therapeutic effects of cannabinoid treatments. The results showed that memory impairment and depression were more evident in SD groups. Moreover, microglial activation and proinflammatory polarization was also more evident and was supported by increased proinflammatory cytokine concentrations in SD groups. These changes were significantly reversed the cannabinoid groups but the combination of CBD+CBC was more effective than other treatments in revering these SD-induced behavioral and neuro-inflammatory changes.