Molecular Links Between Circadian Rhythm Disruption, Melatonin, and Neurodegenerative Diseases: An Updated Review

In mammals, the central circadian rhythm regulator is the SCN, which resides in the anterior part of the hypothalamus. Composed of approximately 20,000 neurons, the SCN generates self-sustaining rhythmic signals that synchronize peripheral clocks throughout the body [20]. Photic signals are transmitted to the SCN via the retinohypothalamic tract, a monosynaptic pathway derived from photosensitive retinal ganglion cells (ipRGCs) that detect ambient light and convey circadian information to the brain. This light input activates intracellular signaling pathways in SCN neurons, triggering calcium influx and phosphorylation of cAMP response element-binding protein (CREB), thereby inducing clock gene expression [21].

SCN neurons exhibit intrinsic circadian oscillations in membrane excitability and neuropeptide release. Key signaling molecules such as vasoactive intestinal peptide (VIP) and arginine vasopressin (AVP) help maintain synchronization within the SCN and transmit time cues to peripheral tissues. The SCN exerts systemic control via neuroendocrine pathways, autonomic innervation, and behavioral regulators, including circadian-driven activity patterns and feeding [22].

Peripheral circadian oscillators are distributed throughout almost all bodily tissues and follow a similar transcriptional framework. However, unlike the SCN, they are more strongly influenced by non-light-related signals such as nutrient intake, thermal conditions, and glucocorticoid levels. The interplay between central and peripheral oscillators is crucial for maintaining circadian coherence and physiological homeostasis [23].

While the SCN orchestrates systemic timing, the fundamental rhythm of each cell is governed by molecular feedback loops known as TTFLs. The positive limb of the core loop is driven by CLOCK and BMAL1 transcription factors, which dimerize and interact with E-box sequences located within the promoter domains of downstream genes. This interaction initiates the expression of Period (PER1, PER2, PER3) and Cryptochrome (CRY1, CRY2) genes, forming the inhibitory branch of the loop [24].

After translation, PER and CRY proteins undergo post-translational modifications, particularly phosphorylation by Casein Kinase 1δ/ε (CK1δ/ε), which regulates their stability, nuclear translocation, and function. Inside the nucleus, the PER–CRY complexes inhibit CLOCK–BMAL1 activity, establishing a classic negative feedback mechanism that completes approximately every 24 h [25].

A secondary interlocking loop involving REV-ERBα and retinoic acid receptor-related orphan receptor alpha (RORα) further stabilizes the rhythm by modulating BMAL1 transcription through RREs (ROR response elements). RORα acts as a transcriptional activator, while REV-ERBα serves as a repressor, maintaining amplitude and phase consistency in circadian gene expression [24,25]. The central and peripheral circadian regulators, along with the roles of core clock genes in TTFLs, are summarized in Table 1.

As illustrated in Figure 2, TTFLs ensure the rhythmic expression of circadian clock genes through coordinated transcriptional activation and feedback repression mechanisms.

Circadian clocks govern various physiological functions such as metabolism, oxidative balance, mitochondrial function, and synaptic plasticity. For instance, BMAL1 was shown to influence glucose homeostasis, lipid metabolism, and the rhythmic expression of metabolic enzymes. Dysregulation of BMAL1 impairs mitochondrial biogenesis and leads to increased reactive oxygen species (ROS) production, thereby contributing to cellular stress [26].

In the central nervous system, clock genes also regulate synaptic activity, neuronal excitability, and neurotransmitter release. For instance, BMAL1 deficiency impairs synaptic vesicle cycling and increases susceptibility to oxidative damage and inflammation, indicating that circadian control is vital for maintaining neuronal function and plasticity [26,27].

In addition to these systemic and neurophysiological roles, circadian rhythms also fine-tune fundamental cellular processes such as apoptosis, autophagy, DNA repair, and cell cycle regulation. These cellular pathways follow time-of-day-dependent patterns and are directly modulated by clock gene activity [28,29]. For example, the circadian regulation of autophagy ensures optimal clearance of damaged organelles and misfolded proteins during rest phases—an especially important mechanism in neurodegenerative contexts where protein aggregation and mitochondrial dysfunction are key pathological features [30].

Furthermore, multiple epigenetic and regulatory layers, including histone modifications, non-coding RNAs, chromatin remodeling, and metabolic feedback loops, have emerged as integral components of circadian regulation. These additional mechanisms increase the adaptability of the molecular clock and enhance its responsiveness to environmental cues such as light, nutrition, and stress [31].

Melatonin, which is predominantly released by the pineal gland at night, is crucial for stabilizing biological rhythms and aligning peripheral clocks with the SCN. Melatonin is synthesized through a multi-step pathway starting with tryptophan, an essential amino acid. This precursor undergoes hydroxylation to form 5-hydroxytryptophan, followed by a decarboxylation step resulting in serotonin production [32,33]. Subsequently, serotonin is converted via acetylation by the enzyme arylalkylamine N-acetyltransferase (AANAT), which acts as a key regulatory step in the process. The activity of AANAT is tightly regulated by noradrenergic stimulation from the SCN and converted to melatonin via hydroxyindole-O-methyltransferase (HIOMT), also known as ASMT (acetylserotonin O-methyltransferase). The light-dark cycle, through retinal input to the SCN, modulates the sympathetic output to the pineal gland and ultimately dictates melatonin synthesis [34,35].

Melatonin exerts its physiological actions through two high-affinity G-protein-coupled receptors, MT1 (melatonin receptor 1A) and MT2 (melatonin receptor 1B), which are widely expressed in both central and peripheral tissues. MT1 is primarily involved in the acute suppression of neuronal firing in the SCN, contributing to sleep promotion and phase regulation. Conversely, MT2 is significantly involved in adjusting circadian timing and contributes notably to the realignment of misaligned biological clocks [36,37].

Beyond their canonical roles in regulating circadian rhythms, melatonin receptors MT1 and MT2 initiate several intracellular signaling cascades that are critically involved in the molecular pathogenesis of neurodegenerative diseases. One key pathway involves phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT), where receptor activation leads to phosphorylation and subsequent inhibition of glycogen synthase kinase-3 beta (GSK3β). GSK3β is a serine/threonine kinase implicated in tau protein hyperphosphorylation and amyloid-beta (Aβ) accumulation, both of which are hallmarks of Alzheimer’s disease (AD) pathology [38].

In parallel, melatonin upregulates the expression and activity of sirtuin 1 (SIRT1), a nicotinamide adenine dinucleotide (NAD⁺)-dependent deacetylase. SIRT1 enhances mitochondrial biogenesis by activating peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and contributes to chromatin remodeling, circadian gene regulation, and resistance to cellular stress in neurons. Additionally, melatonin was shown to suppress the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome, a multiprotein complex involved in innate immune signaling and chronic neuroinflammation. By inhibiting NLRP3, melatonin mitigates oxidative damage and glial overactivation [38].

In aging and several neurodegenerative disorders, melatonin secretion is reduced, and receptor responsiveness is impaired. This dysregulation contributes to circadian desynchronization, disrupted cellular homeostasis, and progressive neurodegeneration [39,40]. Understanding how melatonin signaling intersects with disease-relevant molecular targets offers promising opportunities for therapeutic intervention.

The receptor-mediated molecular pathways of melatonin are illustrated in Figure 3, which integrates circadian signaling with neurodegenerative mechanisms such as tau hyperphosphorylation, oxidative stress, and neuroinflammation.

Melatonin was shown to exert a protective influence on the blood–brain barrier (BBB), acting through a range of molecular pathways that preserve barrier function and structural integrity. One of its key mechanisms involves the activation of melatonin receptors, which enhances the activity of P-glycoprotein transporters, crucial components for regulating the efflux of neurotoxic substances [41,42,43,44]. This effect was particularly noted in in vivo experimental rat models of methamphetamine-induced toxicity, where melatonin prevented endothelial damage in brain capillaries by inhibiting NADPH oxidase 2 through receptor-mediated pathways [45,46,47,48].

Evidence from various preclinical models further supported melatonin’s role in maintaining BBB integrity. In in vivo neonatal rat models subjected to excitotoxic insults, melatonin significantly reduced BBB disruption. Likewise, in young C57BL/6 mouse models exposed to transient focal cerebral ischemia, melatonin administration attenuated vascular leakage and preserved barrier function, underscoring its potential as a neurovascular protector in ischemic and excitotoxic conditions [49,50].

At the molecular level, melatonin contributes to the maintenance of tight junction integrity by upregulating proteins such as claudin-5, zonula occludens-1 (ZO-1), and occludin—key structural components that prevent paracellular diffusion of harmful blood-borne substances into the brain parenchyma [51]. In in vitro models using human brain microvascular endothelial cells (hBMECs), melatonin was shown to increase the expression of these tight junction proteins and strengthen barrier integrity.

In addition, melatonin may interfere with angiotensin-converting enzyme 2 (ACE2), a membrane receptor facilitating viral entry into brain endothelial cells. Experimental findings indicated that consistent use of melatonin and related melatonergic compounds can reduce ACE2-dependent neuroinvasion by SARS-CoV-2, which is notable given the virus’s potential to intensify Aβ toxicity and oxidative burden in AD patients [52].

Moreover, melatonin modulates the activity of matrix metalloproteinases (MMPs), enzymes known to compromise BBB stability by degrading extracellular matrix proteins [53,54]. In vitro experiments conducted on human gastric adenocarcinoma (AGS) cell lines indicated that melatonin decreases MMP activity, suggesting a broader role in extracellular matrix regulation.

In aged (18–20-month-old) C57BL/6 mouse models challenged with lipopolysaccharide to induce neuroinflammation and increased BBB permeability, melatonin activated AMP-activated protein kinase (AMPK) in endothelial cells, an essential kinase involved in homeostasis and vascular integrity. These findings collectively point to melatonin as a potent modulator of BBB function, with therapeutic implications in conditions characterized by vascular dysfunction and neuroinflammation [55,56,57,58]. Table 2 presents preclinical evidence demonstrating how melatonin modulates key molecular mechanisms to protect the BBB.

In modern society, circadian disruption is prevalent due to environmental and lifestyle-related factors. Exposure to artificial light at night (ALAN), irregular sleep–wake cycles, shift work, and frequent transmeridian travel (jet lag) can profoundly disturb endogenous circadian rhythms. These external cues, or “zeitgebers”, are crucial for entraining the central and peripheral clocks, and their disruption leads to a desynchronization between internal physiological processes and the external environment [59,60,61,62]. Night-shift workers, for instance, exhibit a significantly higher prevalence of metabolic syndrome, mood disturbances, and cognitive impairment—conditions also associated with circadian misalignment and neurodegenerative vulnerability [63]. Moreover, chronic exposure to ALAN was shown to suppress nocturnal melatonin production, disrupt sleep architecture, and interfere with core body temperature rhythms, leading to increased oxidative stress and neuroinflammatory activity [64]. A recent experimental model further supported these findings, demonstrating that artificial light exposure induces hippocampal neuronal loss and impairs memory consolidation in rodents [65]. These results highlighted the potential neurobiological consequences of persistent lifestyle-related chronodisruption and suggested its role as a modifiable environmental risk factor for neurodegenerative disease.

Aging is intrinsically associated with the progressive attenuation of circadian rhythms, both behaviorally and at the molecular level. Age-related changes in the SCN include reduced neuronal synchronization, impaired responsiveness to light cues, and diminished expression of core clock genes such as BMAL1, PER2, and CRY1. These molecular alterations contributed to weakened circadian amplitude and phase shifts, often manifested as fragmented sleep, advanced sleep phase syndrome, and reduced melatonin secretion [66]. Importantly, aging also affects the epigenetic regulation of clock genes, including changes in DNA methylation and histone acetylation patterns, which may compromise the plasticity of circadian responses [67]. Disruption of circadian rhythms amplifies critical aging-related impairments such as impaired mitochondrial performance, elevated reactive oxygen species production, and persistent low-level inflammatory responses. This creates a feedback loop that accelerates neurodegenerative processes. Recent transcriptomic analyses of aged brain tissue revealed a global dampening of circadian gene oscillations in both neurons and glial cells, implicating circadian breakdown as a systemic hallmark of brain aging [68].

In aged human prefrontal cortex tissue, the amplitude and rhythmicity of core clock genes such as BMAL1 and PER2 were shown to decrease significantly. A transcriptomic study involving 146 human samples revealed over 1000 transcripts with age-related changes in circadian patterns, including marked reductions in BMAL1 and PER2 expression. In the SCN and peripheral oscillators, aging was found to impair intracellular coupling and attenuate circadian output [69]. Additionally, bioluminescence imaging of PER2::LUC rhythms revealed a significant reduction in oscillatory strength in aged SCN tissue, indicating impaired synchrony among SCN neurons. Although core molecular oscillations may persist, the reduced coupling efficiency compromises the SCN’s ability to coordinate peripheral clocks, contributing to systemic circadian disruption observed with aging [70].

Given the mounting evidence linking circadian dysregulation with neurological decline, there is growing interest in identifying circadian biomarkers for early detection, disease staging, and therapeutic monitoring in neurodegenerative disorders. Core clock genes, particularly BMAL1, PER2, and REV-ERBα, exhibited disease-specific alterations in expression patterns in both central and peripheral tissues of patients with AD, Parkinson’s disease (PD), and Huntington’s disease (HD) [10,71]. Expression of peripheral clock genes in blood cells or buccal epithelium showed potential as a non-invasive biomarker indicating central circadian disruptions. In AD, diurnal fluctuations in melatonin levels and rest-activity rhythms correlate with cognitive decline and were proposed as prognostic indicators of disease progression [72,73].

Sleep is essential for preserving brain homeostasis, particularly through its facilitation of glymphatic clearance, a process in which cerebrospinal fluid (CSF) flows through perivascular spaces to remove metabolic waste, including neurotoxic proteins such as amyloid-beta (Aβ), tau, and α-synuclein. Sleep disruptions, particularly reductions in slow-wave sleep and fragmentation of the sleep–wake cycle, impair glymphatic function and contribute to the accumulation of these pathological proteins, thereby accelerating neurodegenerative processes [74,75]. Circadian dysfunction often manifests early as REM sleep behavior disorder (RBD), a condition now recognized as a predictive biomarker for neurodegenerative diseases such as PD and Lewy body dementia [76]. Moreover, wearable devices that track actigraphy and body temperature rhythms are emerging as potential digital tools to monitor circadian integrity longitudinally. Advances in machine learning and integrative chronobiomics further enable the characterization of individualized circadian profiles, offering new opportunities for personalized chronotherapeutic interventions [77]. These approaches hold the potential to improve diagnostic accuracy and therapeutic timing, ultimately enhancing outcomes in patients with neurodegenerative diseases.

Emerging evidence highlights the bidirectional relationship between circadian rhythms and the gut microbiota, emphasizing their joint role in neurodegenerative disease pathogenesis. The gut microbiome exhibits diurnal oscillations that are regulated by the host’s internal clock, and in turn, short-chain fatty acids (SCFAs) such as butyrate feed back to modulate host circadian gene expression through histone deacetylase inhibition and epigenetic remodeling [134].

Disruptions in circadian rhythms due to aging, sleep deprivation, or high-fat diets lead to gut dysbiosis, characterized by reduced microbial diversity, loss of rhythmic SCFA production, and impaired intestinal barrier function. These changes have been linked to increased neuroinflammatory responses and cognitive impairment in both preclinical and clinical studies [135,136].

In murine models, chronic jet lag alters the composition and diurnal cycling of key microbial taxa, which in turn impairs glucose homeostasis and inflammatory tone [137]. Furthermore, tryptophan-derived microbial metabolites such as indole derivatives regulate melatonin biosynthesis and gut–brain signaling, forming a key node in the circadian–microbiota axis [138]. Thus, restoring microbial oscillations via chrononutrition, timed feeding, or dietary polyphenols not only improves microbiota rhythmicity but also enhances cognitive resilience in aging and neurodegenerative conditions [139].

Melatonin is abundantly produced in the gastrointestinal system and is essential for maintaining the structural integrity of the intestinal barrier while also modulating host–microbiome communication. The gut microbiota contributes to melatonin biosynthesis via tryptophan metabolism, while melatonin reciprocally influences microbial diversity and intestinal permeability [140].

Specifically, indole derivatives such as indole-3-acetaldehyde and indole-3-propionic acid, produced by Lactobacillus and Clostridium species, serve as key intermediates in melatonin synthesis and have been shown to regulate mucosal immunity and epithelial tight junction integrity [141].

Disruption of this bidirectional interaction, such as in gut dysbiosis, was associated with a decline in melatonin production and the onset of neuroinflammatory states, highlighting a potential link between gut health and neurological function. Moreover, melatonin was reported to exert modulatory effects on circadian gene expression in the gut, which, in turn, can influence microbial rhythmicity and metabolic output [134]. Notably, in aged mice exposed to light-at-night conditions, melatonin supplementation not only restored gut microbial rhythm but also reduced intestinal inflammation and blood–brain barrier permeability [142].

This dynamic interplay forms a crucial component of the microbiota–gut–brain axis and may underlie the pathophysiology of several neurodegenerative conditions. These findings offer translational relevance for therapeutic approaches that target both the circadian and microbial components of neurodegeneration.

Nutrition acts as a potent zeitgeber, modulating the rhythmic activity of peripheral clocks through the timing, composition, and frequency of food intake. Unlike light, which primarily entrains the central SCN, feeding behaviors directly influence peripheral oscillators, especially in metabolic organs such as the liver, intestine, pancreas, and adipose tissue. Irregular eating patterns, late-night feeding, and high-fat diets were shown to disrupt circadian synchrony by desynchronizing these peripheral clocks from the central pacemaker. This misalignment leads to impaired metabolic regulation, elevated oxidative stress, and systemic inflammation, all of which are critical contributors to neurodegenerative disease progression [143,144].

In both animal models and clinical settings, chrononutritional interventions such as time-restricted eating, early time-restricted feeding, and intermittent fasting were shown to restore rhythmic gene expression, improve metabolic flexibility, and reduce neuroinflammation. These dietary strategies help reestablish temporal alignment between nutrient intake and the endogenous circadian system, enhancing resilience to cognitive decline and neurodegenerative processes [145,146].

Obesity further amplifies circadian disruption through complex bidirectional mechanisms. As an endocrine organ, adipose tissue exhibits its circadian rhythmicity, secreting hormones such as leptin and adiponectin in a time-dependent manner. In obesity, these rhythms are blunted, contributing to disrupted appetite regulation, increased insulin resistance, and chronic low-grade inflammation [147,148]. Moreover, obesity-associated elevations in pro-inflammatory cytokines can affect hypothalamic function and alter the expression of core clock genes in both central and peripheral tissues, thereby exacerbating circadian misalignment [149,150].

Experimental studies investigated that diet-induced obesity impairs hippocampal synaptic plasticity and reduces the amplitude of circadian oscillations in brain regions responsible for learning and memory [151,152,153]. Additionally, clock gene mutant mice spontaneously developed obesity and metabolic syndrome, even under standard diet conditions, due to the loss of diurnal feeding rhythms and decreased expression of circadian and metabolic regulators such as Per2, orexin, and ghrelin [154]. These findings supported the notion that obesity and circadian disruption interact in a feed-forward loop, promoting neuroinflammatory states, energy imbalance, and increased neurodegenerative vulnerability.

Synthetic melatonin analogs, including ramelteon, agomelatine, and tasimelteon, were developed to overcome the pharmacokinetic limitations of melatonin, such as low bioavailability and short half-life. These agents demonstrated improved receptor selectivity, longer-lasting effects, and greater therapeutic precision in circadian-related disorders.

Agomelatine acts as a high-affinity agonist at MT1 (Ki ≈ 0.1 nM) and MT2 (Ki ≈ 0.12 nM) receptors and as a selective antagonist at 5-HT₂C. This dual mechanism enables both circadian resynchronization and antidepressant activity. The 5-HT₂C antagonism increases dopamine and norepinephrine release in the frontal cortex, a property absent in melatonin [155,156]. Agomelatine is currently approved for major depressive disorder (MDD) in adults under 75 years of age.

Tasimelteon has a higher affinity for MT2 (Ki = 0.069 nM) than MT1 (Ki = 0.304 nM), supporting its role in circadian phase shifting. It is approved for non-24-hour sleep–wake disorder, especially in blind individuals, and exhibits a longer half-life (~1–2 h) than melatonin, with more predictable receptor engagement [156].

Compared to melatonin, these analogs offer greater receptor subtype selectivity, improved bioavailability, and longer pharmacological half-lives, enhancing their clinical utility in specific circadian and psychiatric conditions. Nonetheless, head-to-head trials are needed to evaluate their long-term cognitive and neuroprotective outcomes in neurodegenerative disease populations [156].

While most studies utilized melatonin doses between 40 and 100 mg/day [157], future research should aim at formulation improvements, chronopharmacological timing, and biomarker-guided stratification to fully leverage the therapeutic potential of melatonergic agents.

The concept of chronopharmacology examines how the timing of drug administration affects pharmacokinetics, pharmacodynamics, and therapeutic efficacy. Biological processes demonstrate circadian rhythms, pharmacokinetic phases, target receptor sensitivity, and downstream signaling pathways [158]. Therefore, aligning medication timing with endogenous circadian rhythms can optimize efficacy and minimize adverse effects.

Several classes of neuroactive drugs demonstrated time-dependent efficacy. For instance, the administration of acetylcholinesterase inhibitors such as donepezil in the morning was associated with improved behavioral outcomes and reduced sleep disturbances in AD patients [159]. Similarly, the timing of monoamine oxidase-B inhibitors like selegiline may influence dopaminergic tone and motor symptom control in PD [160]. Corticosteroids, often used in MS, showed enhanced anti-inflammatory activity and reduced toxicity when dosed in alignment with circadian cortisol rhythms [161].

Chronopharmacology also plays a role in melatoninergic treatments. Melatonin’s efficacy is highly timing-dependent, with administration in the evening or at dim-light melatonin onset (DLMO) producing the greatest phase-shifting effects. Mistimed administration may lead to phase delays or reduced therapeutic impact [162]. Moreover, circadian timing of drug administration influences gene expression profiles; for instance, clock-controlled transcription factors modulate the expression of metabolic enzymes and membrane transporters involved in drug metabolism [163].

In addition to time-of-day-dependent efficacy, potential pharmacokinetic and pharmacodynamic interactions between melatonin and neuroactive agents must be considered. For example, in PD, co-administration of melatonin with L-dopa enhanced dopaminergic response and motor coordination while mitigating oxidative stress, as demonstrated in MPTP-induced parkinsonian mice. This effect was attributed to melatonin’s antioxidant activity and its capacity to preserve striatal dopamine levels by reducing lipid peroxidation and enhancing glutathione peroxidase activity [164]. In AD and mild cognitive impairment, melatonin given alongside cholinesterase inhibitors such as donepezil improved cognitive performance, sleep quality, and reduced depressive symptoms, supporting its use as an adjunctive chronotherapeutic agent [165].

Furthermore, melatonin hybrids were explored in preclinical models as multitarget agents combining antioxidant, cholinesterase-inhibitory, and monoamine oxidase-inhibitory effects, demonstrating promising interactions with donepezil and other agents for synergistic modulation of AD pathophysiology [166].

Recent advances in chronobiology and neurodegenerative research identified nuclear receptors and epigenetic regulators as promising targets for therapeutic modulation. Among these, RORα, REV-ERBα, and SIRT1 garnered attention for their pivotal roles in linking circadian timing to cellular metabolism, neuroinflammation, and mitochondrial homeostasis [167].

RORα functions as a transcriptional activator within the auxiliary loop of the circadian clock, positively regulating BMAL1 expression and enhancing circadian amplitude. In neurodegenerative disease models, RORα activation was investigated to suppress microglial activation, promote anti-inflammatory phenotypes, and protect synaptic integrity. Pharmacological agonists of RORα, such as SR1078, demonstrated efficacy in reducing neuroinflammation and improving behavioral performance in preclinical models of PD and AD [168].

Conversely, REV-ERBα serves as a transcriptional repressor of BMAL1, balancing circadian oscillations and contributing to metabolic regulation. Its dysfunction was associated with mitochondrial impairment, elevated oxidative stress, and glial overactivation—key pathomechanisms in AD [169]. Pharmacological activation of REV-ERBα using synthetic ligands such as SR9009 yielded promising results in attenuating neuroinflammatory cascades and restoring circadian rhythmicity [170].

Furthermore, SIRT1 represents a key node between metabolic sensing and epigenetic regulation of circadian genes. SIRT1 deacetylates BMAL1 and PER2, influencing circadian period length and amplitude. It also modulates cellular stress responses, autophagy, and mitochondrial biogenesis [171]. In some models of neurodegeneration, SIRT1 activation via resveratrol or SRT1720 was also linked to enhanced neuronal survival, reduced tau pathology, and improved cognitive outcomes [172]. Collectively, the pharmacological modulation of these molecular targets offers a novel chronotherapeutic axis with the potential to recalibrate disrupted molecular clocks and mitigate disease progression.

Music therapy (MT) had considerable efficacy in improving the quality of life in individuals affected by neurodegenerative conditions, including AD and PD. A study by Sharma et al. proposed that rhythm-based interventions can exert neuroprotective effects by stabilizing circadian rhythms, potentially mitigating disease progression. MT was investigated to influence not only cognitive and emotional domains but also neural circuitry involved in circadian regulation, thus representing a multifaceted non-pharmacological intervention [173]. Nonetheless, there is a need for longitudinal studies that examine the direct effects of MT on sleep architecture and circadian entrainment.