The Link Between Circadian Disruption and Alzheimer’s Disease and Related Dementias: Insights from Peripheral Inflammation

Abstract

Circadian rhythms are essential for maintaining physiological homeostasis, influencing biological processes from the sleep-wake cycle to metabolism and immune responses. Disruption of these rhythms is increasingly linked to the pathogenesis of Alzheimer’s Disease and Related Dementias (ADRDs), conditions characterized by cognitive decline and neuropsychiatric symptoms through various pathways including increases in inflammation. While many studies link the effects of circadian disruption on neuroinflammation to ADRDs, this review explores the potential link between the circadian disruption of peripheral inflammation and ADRDs. We discuss the evidence of how circadian misalignment can exacerbate neuroinflammation through the activation of the peripheral immune system. We further examine the role of peripheral factors such as insulin dysregulation, melatonin levels, and gut microbiome imbalances in amplifying these peripheral inflammatory responses. These data underscore the significance of circadian regulation in maintaining immune homeostasis, highlighting potential therapeutic avenues for mitigating ADRDs through the restoration of circadian integrity.

Graphical Abstract

Introduction

Circadian rhythms are a fundamental timing mechanism that plays a vital role in harmonizing genetics and physiology to the Earth’s approximately 24-hour light/dark cycle [1]. The mammalian molecular clock is driven by a transcription-translation negative feedback loop in which activating proteins, circadian locomotor output cycles kaput (CLOCK) and brain and muscle Arnt-like 1 (BMAL1), promote expression of the repressive cryptochrome (CRYs) and period (PERs) proteins [1]. This clock network influences genes involved in metabolism, immunity, hormone secretion, and other essential processes, demonstrating the significance of circadian rhythms in controlling physiology [2] (Figure 1). Large-scale transcriptomic analyses suggest that 20–50% of the genome is rhythmically expressed under circadian control [3][4]. In multicellular organisms, systemic circadian oscillators ensure coordination among cell-autonomous clocks across tissues. In mammals, the central pacemaker resides in the suprachiasmatic nucleus (SCN) of the hypothalamus, which synchronizes peripheral clocks via neural and hormonal cues [5]. Through the SCN, circadian rhythms time gene expression and the organization of major physiological systems, including the sleep-wake cycle, metabolism, and immune function [2], [6]. Hence, circadian rhythms are essential for the regulation of numerous genes and cellular processes, underscoring their pivotal role in maintaining physiological homeostasis in response to the day/night cycle.

Figure 1. The mammalian molecular circadian transcription/translation negative feedback loop drives rhythms in the Suprachiasmatic Nucleus and other tissues.

A. Light signals help to tune the phase of the Suprachiasmatic Nucleus (SCN), the central circadian pacemaker in the brain. The SCN then sends chemical and neuronal messages to peripheral tissues, coordinating timing throughout the body. B. At the molecular level, the circadian pacemaker is comprised of the activating arm complex (green), which initiates the circadian cycle by turning on transcription of the repressive arm complex (red) and clock-controlled genes (ccgs, blue). The repressive arm then goes through a tightly timed lifecycle, setting the period of the clock, until it is removed from the system, the activating arm reactivates, and the cycle begins again.

Given the impact of circadian rhythms on human physiology, disruption to these rhythms can have widespread negative effects on health. One particularly harmful consequence is an increased risk and accelerated progression of neurodegenerative diseases, such as Alzheimer’s Disease and Related Dementias (ADRDs) [7]. Historically, research has focused on how circadian disruption affects the brain itself, with altered protein aggregation, synaptic dysfunction, and neuroinflammation being well-documented mechanisms [8]. However, emerging evidence highlights the contribution of peripheral factors, including systemic inflammation, metabolic signaling, and gut dysbiosis, which are also regulated by the circadian clock [9], [10]. Therefore, in this review, we focus on peripheral inflammation and how circadian dysregulation can elevate inflammatory processes in peripheral systems, potentially amplifying the impact of circadian disruption on ADRD pathophysiology.

The Causative Mechanisms of ADRDs

ADRDs are a suite of neurodegenerative disorders projected to reach 152 million cases worldwide by 2050 [11]. Clinically, ADRDs are characterized by declining cognitive functions and neuropsychiatric symptoms [12]. The classic model of pathogenesis centers on the abnormal accumulation of hyperphosphorylated tau tangles and amyloid-β (Aβ) plaques [12]. Under normal conditions, soluble Aβ is a byproduct of neuronal metabolism [13], [14]. Tau protein, in its physiological state, stabilizes microtubules that support intracellular transport and communication [15], [16]. In ADRDs, Aβ peptides misfold and aggregate into extracellular plaques that interfere with synaptic signaling, while tau becomes hyperphosphorylated, forming neurofibrillary tangles that destabilize the microtubule network [12], [15], [16]. Collectively, these pathological changes interfere with synaptic transmission, disrupt intracellular trafficking, and compromise neuronal connectivity [15], [16]. Over time, these molecular insults induce neuronal loss and network-level dysfunction, which manifest as the progressive cognitive and behavioral impairments observed in patients with ADRDs [11], [12].

In addition to the roles of tau tangles and Aβ plaques, immune dysregulation and inflammation are increasingly recognized as significant contributors to the progression of ADRDs. In rodents, astrocytes and microglia become activated in response to protein aggregates, releasing pro-inflammatory cytokines (TNF-α, IL-6, IL-1β), chemokines, and reactive oxygen species (ROS), which collectively amplify neuroinflammation [17]. Chronic neuroinflammation has been experimentally demonstrated to disrupt the integrity of the blood-brain barrier (BBB), thereby allowing peripheral immune cells to infiltrate the central nervous system (CNS), which further exacerbates inflammation and accelerates neurodegeneration [18], [19]. These infiltrating cells release additional pro-inflammatory signals, creating an environment that directly impairs microglial clearance of Aβ and tau [18], [20], [21]. As a result, misfolded proteins can accumulate to further stimulate neuroinflammation and neuronal damage, establishing a self-reinforcing cycle that drives the progression of neurodegeneration.

Beyond neuronal inflammation, recent evidence suggests that peripheral inflammation may also have a significant impact on ADRD progression. Clinical studies demonstrate that acute respiratory infections correlate with increased levels of systemic pro-inflammatory markers that cross the BBB and amplify neuroinflammation [22], [23]. Further, as ADRDs develop, Aβ plaques and phosphorylated tau can be found beyond the brain in peripheral tissues, where they trigger inflammatory signals that activate immune cells capable of infiltrating the BBB [23]. Taken together, these findings support a bidirectional relationship between peripheral and neuronal immune activity that drives the development and progression of ADRDs.

Circadian Timing of the Progenitors of ADRDs

While genetic factors contribute to ADRDs, the sporadic form, responsible for most cases, involves complex interactions among various genetic predispositions and environmental influences, including chronic disruptions of the circadian clock [7], [8], [24]. This link between circadian dysregulation and ADRDs is supported by evidence that key molecular processes underlying disease pathogenesis are tightly regulated by daily rhythmicity under homeostatic conditions. In the brain, both Aβ and tau exhibit diurnal oscillations, with their abundance in interstitial fluid fluctuating across the day-night cycle. In humans, cerebrospinal fluid Aβ levels display these daily rhythms [13], whereas in mice, tau levels fluctuate in parallel with light-dark cycles [24]. Studies using genetic knockout models, such as global Bmal1-deficient mice, demonstrate that loss of core clock components abolishes these daily oscillations and accelerates Aβ accumulation in the hippocampus [14]. Similarly, disrupted PER2 rhythmicity in the hypothalamus of mice has been associated with increased tau pathology [25]. Environmental and behavioral circadian disruption models, including altered light-dark cycles or chronic sleep deprivation, also impair circadian rhythmicity and have been shown to exacerbate Aβ and tau pathology [14], [24], [26]. Microglia, the brain’s resident immune cells responsible for clearing accumulated Aβ and tau, exhibit strong circadian oscillations in immune activity, which influence neuronal function, protein clearance, and neuroinflammation in mice [27], [28]. Circadian regulation also affects cerebral blood flow, glymphatic system function, and the permeability of the BBB, all of which influence the clearance of Aβ and tau [25], [29], [30], [31]. The above highlights the importance of a robust circadian clock in maintaining neuronal homeostasis and the immune response.

Circadian rhythms also shape peripheral inflammatory responses, extending their influence beyond brain-specific ADRD progenitors. These rhythms balance pro-inflammatory and anti-inflammatory states, with wakefulness associated with heightened glycolytic activity and increased expression of inflammatory signaling compared to rest periods [6], [32], [33]. Circadian regulation affects various aspects of immune function, including cytokine production, immune cell distribution, and phagocytic activity. For example, the secretion of pro-inflammatory cytokines, such as TNF-α and IL-6, fluctuates throughout the day, impacting the magnitude and timing of inflammatory responses [6], [34]. These cytokine signals coordinate the migration of immune cells to specific sites at optimal times, thereby enhancing immune surveillance and response efficiency [33], [35]. Peripheral immune cells also adjust their trafficking in response to signals related to Aβ clearance in the brain, clear Aβ at different rates over the circadian day, and demonstrate a greater capacity than microglia to phagocytose and degrade Aβ [36], [37]. Thus, circadian rhythms widely drive factors that regulate ADRDs via the timing of both neuronal and peripheral immune regulators that influence inflammation.

The Effect of Circadian Disruption on the Peripheral Immune System and Its Potential Role in ADRDs Pathophysiology

Short-term disruptions of circadian rhythms caused by shift work, jet lag, time-restricted feeding, and other environmental factors can misalign the temporal regulation of the immune system, resulting in systemic mistiming of inflammatory states [6], [38], [39]. For example, mice subjected to light cycle inversion show increased expression of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β during rest phases, when the immune system is normally biased toward anti-inflammatory activity [38], [39]. Chronic circadian misalignment in these models induces a persistent pro-inflammatory phenotype, characterized by elevated cytokines, chemokines, and ROS [40]. Complementary data from genetic models support these findings as Bmal1-null mice reveal that intrinsic circadian clocks regulate immune and oxidative pathways, with increases in mitochondrial ROS, inflammasome activation, and neuroinflammation-like phenotypes [41], [42]. Together, these studies indicate that circadian rhythm disruption dysregulates immune signaling and promotes sustained inflammatory states.

Environmental circadian disruption also alters immune cell dynamics, leading to mistimed cytokine release and abnormal distribution of peripheral immune cells such as monocytes and NK cells [35]. These disruptions increase inflammatory cell activity during rest phases, which, particularly under conditions of compromised BBB integrity, increases the likelihood of peripheral immune cell infiltration into the brain [22], [43]. In addition, circadian misalignment has been associated with upregulation of vascular adhesion molecules, including ICAM1 and VCAM1, in brain endothelial cells, facilitating leukocyte trafficking across the BBB [43]. Once within the CNS, infiltrating immune cells release pro-inflammatory cytokines that impair microglial clearance of Aβ and tau, further exacerbating protein accumulation [22], [44]. Elevated chemokine expression and other peripheral inflammatory markers have also been demonstrated in rodents and humans during environmental circadian disruption, linking peripheral immune alterations to neuroinflammatory outcomes [22], [43]. Collectively, these findings suggest that environmental circadian disruption mistimes immune cell dynamics and promotes peripheral immune cell trafficking into the brain.

Beyond immune timing, environmental circadian misalignment reduces cellular resilience. Simulated circadian disruption in mice suppresses cell proliferation, increases apoptosis, and weakens stress response pathways [35]. These effects impair the clearance of Aβ and tau proteins, promoting neuroinflammation [22], [43]. Evidence from both environmental circadian disruption models (e.g., light cycle inversion, sleep fragmentation) and genetic clock gene knockout mice consistently demonstrates that circadian rhythms are essential for maintaining immune regulation and brain homeostasis [35], [43]. Overall, these data suggest that circadian misalignment, particularly through peripheral inflammatory pathways, may serve as a key upstream driver of chronic neuroinflammation, contributing to the onset and progression of ADRDs.

Circadian Regulation of Inflammation in Peripheral Systems Beyond Immune Cells and Its Effect on ADRDs Pathophysiology

While the immune system is the primary driver of inflammation, there are many alternative ways to heighten inflammatory states. Beyond the effects of the circadian clock on the immune system, circadian disruption also interferes with other peripheral systems, including hormonal rhythms, metabolism, and gut microbial activity, that can amplify inflammatory signals and modulate neuronal health. Below, we will examine the roles of the clock in the regulation of insulin, the gut microbiome, and melatonin, highlighting pathways by which circadian disruption may promote peripheral inflammation and influence ADRD pathology (Figure 2).

Figure 2. Disruption of circadian rhythms and its effect on peripheral inflammation in pathways that can exacerbate ADRDs development and phenotypes.

Aligned circadian rhythms (left) maintain timed hormonal, immune, and metabolic processes, whereas circadian disruption (right) is associated with increased systemic and neuroinflammation, potentially accelerating the progression of Alzheimer’s disease and related dementias (ADRDs). Brain: Normal circadian rhythms support microglial and astrocyte quiescence, IDE (Insulin-Degrading Enzyme)/ LRP1 (Low-Density Lipoprotein Receptor-Related Protein 1)-mediated amyloid-β (Aβ) and tau clearance, and an intact blood–brain barrier. Disruption of circadian rhythms leads to microglial/astrocyte activation, reduced IDE/LRP1 clearance of Aβ and tau, blood-brain barrier breakdown, increased ROS (reactive oxygen species), and NF-κB/NLRP3 (nuclear factor kappa B / NLRP3 inflammasome) signaling. Immune cells & cytokines: Rhythmic cytokine release and immune cell trafficking optimize surveillance and limit inflammation. Disruption causes mistimed cytokine release with increased TNF-α, IL-6, IL-1β, and ROS accumulation, NF-κB/NLRP3 hyperactivation, and chronic low-grade inflammation. Insulin & melatonin: Circadian rhythms maintain rhythmic insulin secretion, PI3K/Akt (Phosphoinositide 3-Kinase/Protein Kinase B)-mediated IDE activity, and melatonin signaling via MT₁/MT₂ (melatonin receptors 1 and 2) to regulate metabolic and immune homeostasis. Disruption of circadian rhythms causes insulin resistance, reduced IDE/LRP1 clearance, blunted melatonin rhythms, and peripheral metabolic stress. Gut/microbiome: Rhythmic microbial oscillations and production of short-chain fatty acids or tryptophan preserves gut barrier integrity and limits lipopolysaccharide (LPS) translocation. Disruption leads to gut dysbiosis, leaky barrier, elevated LPS, and peripheral inflammation, reinforcing neuroinflammatory pathways.

Disruption of the Daily Oscillation of Insulin Affects Inflammation and Aβ levels

The hormone insulin, a key regulator in glucose metabolism, plays a crucial role in processes implicated in ADRDs and inflammation. In the brain, reduced insulin receptor signaling has been associated with increased Aβ plaque deposition and tau hyperphosphorylation, as demonstrated by postmortem analyses [45] and neuroimaging studies [46]. However, insulin resistance is not limited to the brain. In peripheral tissues such as the liver, adipose tissue, and muscle, chronic hyperinsulinemia and insulin resistance drive systemic inflammation and metabolic dysfunction, factors that are proposed to impair peripheral Aβ clearance and influence central Aβ burden [47]. A key mechanistic connection in this pathway is Insulin-Degrading Enzyme (IDE), which cleaves both insulin and Aβ [48]. In vitro, excess insulin competitively inhibits IDE-mediated Aβ degradation [49] and in vivo, IDE knockout mice accumulate both insulin and Aβ in the brain and peripheral tissues [48]. These findings support the hypothesis that chronic peripheral hyperinsulinemia may saturate IDE capacity, thereby reducing systemic Aβ clearance and contributing to its accumulation in the CNS.

Another critical link between insulin signaling and Aβ metabolism is low-density lipoprotein receptor-related protein-1 (LRP-1), a multifunctional receptor expressed in both the brain and peripheral tissues [50]. LRP1 facilitates insulin transport across the BBB and, in murine neurons, stabilizes insulin receptor expression while activating the Phosphoinositide 3-Kinase/Protein Kinase B (PI3K/Akt) pathway, a key intracellular signaling cascade involved in glucose uptake and cell survival [51]. Activation of PI3K/Akt inhibits the transcription factor FOXO1, promoting IDE transcription [52], thus linking insulin signaling with brain Aβ clearance capacity. Peripherally, LRP1 also mediates Aβ uptake and degradation, and the loss of LRP1 impairs Aβ clearance and elevates inflammatory cytokines [53],[54]. Together, IDE and LRP1 represent key molecular links through which insulin signaling may exacerbate inflammation and impair systemic Aβ.

Timing of insulin and the insulin-regulating pathways described above is governed by the circadian clock. Insulin secretion follows a circadian rhythm, and disruption of these rhythms can lead to systemic impairments in insulin levels [55]. LRP1 transcription is upregulated by peroxisome proliferator-activated receptor gamma (PPARγ), which itself oscillates rhythmically in metabolic tissues [56]. IDE transcription is modulated by the PI3K/Akt-FOXO1 pathway, which itself exhibits circadian-dependent oscillations [52]. Together, these data show that insulin secretion, LRP1 expression, and IDE are timed by the circadian clock to coordinate peripheral metabolic and immune function with daily behavioral cycles.

Circadian disruption alters insulin signaling, affecting downstream inflammation and systemic Aβ accumulation. Chronic circadian misalignment in shift workers impairs glucose tolerance and reduces insulin sensitivity, promoting systemic inflammation [47]. In mice, environmental circadian misalignment disrupts peripheral insulin signaling, elevates TNF-α, IL-6, and IL-1β, and accelerates immune aging [38], [57]. Genetic models of circadian disruption support this relationship. In brain endothelial cell-specific Bmal1 knockout mice, reduced expression of LRP1 slows Aβ transport out of the brain [14]. Global Bmal1 knockout mice exhibit decreased insulin secretion and, under certain conditions, increased insulin sensitivity, alongside elevated peripheral TNF-α and IL-β [58], [59]. Similarly, mutations in the Clock gene impair insulin signaling and exacerbate inflammatory responses during metabolic stress [60]. Taken together, these observations suggest disruption of the circadian regulation of insulin components such as IDE and LRP-1 likely impairs systemic Aβ clearance and promotes inflammation.

Circadian Disruption Affects the Microbiome Content to Increase Inflammation

Inflammation in the brain-gut axis is closely linked to the development of ADRDs. Gut dysbiosis, characterized by an elevated ratio of pro-inflammatory to anti-inflammatory bacterial taxa, has been associated with increased systemic inflammation in individuals with ADRDs [10]. This link is likely caused by the compromising effects of microbial imbalance on intestinal barrier integrity, facilitating the translocation of lipopolysaccharide (LPS), an endotoxin derived from the outer membrane of Gram-negative bacteria, into the bloodstream [61]. Once in circulation, LPS binds Toll-like receptor 4 (TLR4) on peripheral immune cells, triggering the activation of the nuclear factor kappa B (NF-κB) signaling pathway and driving the release of pro-inflammatory cytokines [61], [62], [63]. These circulating cytokines, together with LPS, can cross the BBB, where they activate microglia [64], and trigger tau hyperphosphorylation via kinase activation in APP/PS1 mouse models [20]. Postmortem studies have reported significantly higher concentrations of LPS in the hippocampus and cortex of ADRD patient brains compared to healthy controls, often concentrated near microglial perinuclear regions, indicating active engagement of brain immune cells with microbial endotoxins [61]. These observations underscore that LPS translocation resulting from gut microbial dysbiosis drives peripheral inflammation that can propagate to the brain.

Circadian rhythms are critical for regulating bacterial abundance and function within the gastrointestinal tract and bloodstream, and the microbiome displays rhythmic patterns in gene expression, localization, and metabolite production. Certain gut bacteria, such as Enterobacter aerogenes, display melatonin-sensitive rhythmic gene expression and motility aligned with host feeding–fasting cycles, which supports barrier integrity and reduces LPS translocation [65], [66]. These microbial rhythms also govern the production of key metabolites, including short-chain fatty acids and tryptophan derivatives, which modulate immune signaling pathways, such as NF-κB activation [66], [67]. The coordination of gut microbial homeostasis and immune balance by the circadian clock, therefore, plays a significant part in the dynamic interface between host and microbiota.

Disruption of circadian rhythms has the potential to affect widespread immune and inflammatory disturbances. Studies in mice have shown that disruption of these rhythms by altered light–dark cycles, simulated jet lag, or phase-shift paradigms has a concordant effect on the diurnal rhythms of the gut microbiome [67], [68] and can lead to an increased abundance of Proteobacteria, a phylum containing many LPS-producing species [68]. Additionally, genetic models demonstrate that intestinal epithelial cell-specific deletion of Bmal1 impairs epithelial function and promotes mucosal inflammation consistent with compromised barrier integrity [69]. This compromised barrier integrity facilitates increased translocation of LPS entering the bloodstream [61], driving systemic inflammation [62], and contributing to a neuroinflammatory environment similar to that found in ADRDs [21]. Collectively, these findings support the hypothesis that circadian disruption promotes disturbances in the gut-microbiota-brain axis in the periphery, driving LPS-mediated systemic inflammation.

Circadian Control of Peripherally Produced Melatonin Regulates Inflammation

Melatonin is involved in regulating circadian rhythms, sleep, antioxidant defenses, and immune function [70]. It is synthesized primarily in the pineal gland under the control of the SCN [71], but is also produced in large amounts in peripheral tissues, particularly the gastrointestinal tract, where it can be found at concentrations up to 400 times greater than in the pineal gland [72]. Melatonin, acting through MT₁ and MT₂ G-protein–coupled receptors expressed in neurons, immune cells, and gut tissues [73], enhances antioxidant defenses, stabilizes mitochondrial function, and suppresses NF-κB–mediated pro-inflammatory signaling [74]. In a pharmacologically induced murine model of sporadic Alzheimer’s disease, melatonin reduces levels of TNF-α, IL-6, and IL-1β, decreases microglial activation, and promotes the clearance of Aβ and tau in the brain [75]. In the periphery, systemic melatonin administration in mice preserves intestinal barrier integrity, reduces overall inflammation, and in some cases lowers pro-inflammatory cytokines, including TNF-α and IL-6 [76]. Experimental depletion of peripheral melatonin promotes gut dysbiosis and exacerbates cognitive deficits and Aβ pathology [77], supporting a role for peripheral melatonin loss in driving ADRD-relevant outcomes. Together, these findings indicate that peripheral melatonin is a key regulator of both inflammation and gut barrier function, making it critical in the gut/brain axis.

The circadian timing of melatonin synthesis is critical for coordinating physiological processes both in the brain and periphery. In the pineal gland, production peaks at night in synchrony with SCN signals, whereas in peripheral tissues, local clocks interact with central cues to modulate melatonin synthesis [71]. Peripherally, MT₁ and MT₂ exhibit circadian variation in expression [74], suggesting that tissue-specific clocks regulate sensitivity to melatonin. These rhythmic signals influence gut microbial activity like bacterial growth, gene expression, and metabolism [66], which may, in turn, modulate host immune and barrier function. Through these combined effects on microbial composition, immune modulation, and epithelial integrity, gut-derived melatonin acts as a key mediator linking circadian regulation to brain health and protection against ADRD-related inflammation.

In line with the essential role of melatonin in the clock, circadian disruption of melatonin signaling impairs immune homeostasis across the brain and peripheral tissues. In vitro, siRNA-mediated knockdown of Bmal1 in chicken pinacocytes led to the loss of circadian rhythms in arylalkylamine N-acetyltransferase (AANAT), the rate-limiting enzyme in melatonin synthesis, and melatonin production [78]. Cry1/Cry2 double knockout mice exhibit blunted pineal melatonin levels and altered light-induced suppression of melatonin [79]. Similarly, peripheral circadian disruption and melatonin deficiency exacerbate neuroinflammation in murine models [9]. Consistent with these mechanistic findings, individuals with ADRDs frequently exhibit disrupted sleep-wake cycles, reduced nocturnal melatonin secretion, and blunted circadian amplitude [8], [80]. Although directionality and causality are not clear in these clinical observations, they align with the experimental evidence, suggesting that the effects of circadian disruption on melatonin may contribute to inflammation and Aβ levels.

Conclusion

Circadian disruption promotes ADRD progression by simultaneously dysregulating multiple peripheral systems that converge on the brain. Environmental and genetic misalignment impairs temporal coordination of immune signaling, producing mistimed cytokine release, altered immune cell trafficking, and priming of the NLRP3 inflammasome in myeloid cells [33], [38], [41]. Elevated circulating cytokines compromise BBB integrity, facilitate leukocyte infiltration, and activate microglia, directly linking peripheral inflammation to central neuroinflammatory processes [10], [19], [44]. When disrupted, clock components such as BMAL1 and CLOCK, which normally restrain NF-κB–driven transcription, amplify pro-inflammatory signaling, creating a sustained inflammatory environment [33], [38], [41], [42]. Together, these intersecting immune disruptions drive inflammation, impair proteostasis, and accelerate ADRD progression.

Circadian misalignment also perturbs metabolic and proteostasis pathways essential for Aβ and tau clearance. By disrupting insulin sensitivity and promoting hyperinsulinemia, circadian disruption can indirectly reduce IDE-mediated Aβ degradation, while its associated pro-inflammatory cytokine release may suppress LRP1 expression, impairing both peripheral and central clearance of Aβ and tau [48], [53], [61]. Altered gut microbial rhythms contribute further, as increased LPS translocation activates TLR4 signaling in peripheral immune cells, indirectly amplifying microglial activation [10], [62]. These metabolic, microbial, and immune disruptions interact to reinforce neuroinflammation and proteinopathy.

Hormonal dysregulation, particularly the loss of peripheral melatonin, integrates these pathways and magnifies downstream pathology. Reduced MT₁/MT₂ signaling impairs epithelial and vascular barrier function, exacerbates mitochondrial stress, and promotes pro-inflammatory cytokine release, while also modulating insulin/IDE/LRP1–mediated Aβ clearance [75], [76], [77]. By simultaneously impacting immune, metabolic, microbial, and hormonal systems, circadian misalignment establishes converging peripheral drivers that heighten inflammation, impair protein clearance, and accelerate neuronal damage. This positions circadian disruption of peripheral inflammatory factors as a central player in ADRD pathophysiology.

In total, the data suggests the circadian-related progression of ADRDs arises from the interplay of central and peripheral circadian mechanisms. Disruption of clock function not only perturbs Aβ and tau dynamics within the brain, but also amplifies systemic drivers, including heightened inflammatory levels, impaired metabolic clearance, and hormonal and gut dysregulation. Because these mechanisms are inherently rhythmic, interventions that restore circadian alignment hold promise for dampening peripheral inflammation, restoring homeostasis, and slowing neurodegeneration.

Highlights:

• Circadian Rhythms broadly affect essential physiological pathways, including those involved in inflammation, and disruption of Circadian Rhythms is known to increase inflammation.

• Alzheimer’s Disease and Related Dementias have three key hallmarks, one of which is an increased level of inflammation.

• Insulin dysregulation, gut microbiome imbalances, and melatonin fluxes all arise from the disruption of Circadian Rhythms, increase peripheral inflammation, and have been associated with Alzheimer’s Disease and Related Dementias.

• The increase in peripheral inflammation may play a role in the effect of Circadian Disruption on Alzheimer’s Disease and Related Dementias.