The efficacy of a transdiagnostic sleep intervention for outpatients with sleep problems and depression, bipolar disorder, or attention deficit disorder: study protocol for a randomized controlled trial.

BACKGROUND: Patients with mental disorders have a higher prevalence of sleep problems than the general population. Sleep problems may include insomnia, circadian rhythm disorders, or hypersomnia. A transdiagnostic approach combining cognitive behavioral therapy for insomnia (CBT-I) with chronotherapy addressing a broad range of sleep problems has shown promising results in a limited number of studies. The aim of the study is to investigate the efficacy of a transdiagnostic sleep intervention for patients with sleep problems comorbid to bipolar disorder, unipolar depression, or attention deficit disorders. The primary hypothesis is that the intervention improves sleep quality compared with a control group. The secondary hypotheses are that the intervention increases subjective and objective sleep efficiency, reduces sleep onset latency, wake after sleep onset, number of awakenings, and severity of insomnia; and that it improves well-being, personal recovery, work ability, and consumption of sleep medication compared with a control group. METHODS: The study is a randomized controlled trial enrolling 88 outpatients with bipolar disorder, major depression, or attention deficit disorder with symptoms of various sleep problems (insomnia, circadian rhythm disorders, or hypersomnia). Patients are allocated to either an intervention group receiving six sessions of transdiagnostic sleep treatment or to a control group receiving a single session of sleep hygiene education. Assessments are made at baseline, at week two, and after 6 weeks in both groups. Actigraphy is performed continuously throughout the 6-week study period for all patients. The primary outcome is changes in the subjective appraisal of sleep quality (Pittsburgh Sleep Quality Index). The secondary outcomes are changes in sleep efficiency, sleep onset latency, wake after sleep onset, number of nocturnal awakenings (based on actigraph and sleep diary data), changes in insomnia severity (Insomnia Severity Index), well-being (WHO-5 Well-Being Index), personal recovery (INSPIRE-O), work ability (Work Ability Index), and consumption of sleep medication (sleep-diaries). DISCUSSION: The study was initiated in 2022 and the inclusion period will continue until mid-2024. The results may have implications for the development and implementation of additional treatment options for patients with mental disorders and comorbid sleep problems. TRIAL REGISTRATION: ClinicalTrials.gov. NCT05406414. Registered on June 6, 2022.

Pressure Building Against the Clock: The Impact of Circadian Misalignment on Blood Pressure.

PURPOSE OF REVIEW: Misalignment between the endogenous biological timing system and behavioral activities (i.e., sleep/wake, eating, activity) contributes to adverse cardiovascular health. In this review, we discuss the effects of recurring circadian misalignment on blood pressure regulation and the implications for hypertension development. Additionally, we highlight emerging therapeutic approaches designed to mitigate the negative cardiovascular consequences elicited by circadian disruption. RECENT FINDINGS: Circadian misalignment elicited by work schedules that require individuals to be awake during the biological night (i.e., shift work) alters 24-h blood pressure rhythms. Mechanistically, circadian misalignment appears to alter blood pressure via changes in autonomic nervous system balance, variations to sodium retention, dysregulation of endothelial vasodilatory responsiveness, and activation of proinflammatory mechanisms. Recurring circadian misalignment produced by a mismatch in sleep timing on free days vs. work days (i.e., social jetlag) appears to have no direct effects on prevailing blood pressure levels in healthy adults; though, circadian disruptions resulting from social jetlag may increase the risk of hypertension through enhanced sympathetic activation and/or obesity. Furthermore, social jetlag assessment may be a useful metric in shift work populations where the magnitude of circadian misalignment may be greater than in the general population. Circadian misalignment promotes unfavorable changes to 24-h blood pressure rhythms, most notably in shift working populations. While light therapy, melatonin supplementation, and the timing of drug administration may improve cardiovascular outcomes, interventions designed to target the effects of circadian misalignment on blood pressure regulation are warranted.

Recent advances in the study of circadian rhythm disorders that induce diabetic retinopathy.

Diabetic retinopathy (DR) is a severe microvascular complication of diabetes mellitus and a major cause of blindness in young adults. Multiple potential factors influence DR; however, the exact mechanisms are poorly understood. Advanced treatments for DR, including laser therapy, vitrectomy, and intraocular drug injections, slow the disease's progression but fail to cure or reverse visual impairment. Therefore, additional effective methods to prevent and treat DR are required. The biological clock plays a crucial role in maintaining balance in the circadian rhythm of the body. Poor lifestyle habits, such as irregular routines and high-fat diets, may disrupt central and limbic circadian rhythms. Disrupted circadian rhythms can result in altered glucose metabolism and obesity. Misaligned central and peripheral clocks lead to a disorder of the rhythm of glucose metabolism, and chronically high sugar levels lead to the development of DR. We observed a disturbance in clock function in patients with diabetes, and a misaligned clock could accelerate the development of DR. In the current study, we examine the relationship between circadian rhythm disorders, diabetes, and DR. We conclude that: 1) abnormal function of the central clock and peripheral clock leads to abnormal glucose metabolism, further causing DR and 2) diabetes causes abnormal circadian rhythms, further exacerbating DR. Thus, our study presents new insights into the prevention and treatment of DR.

Chronobiology of Parkinson's disease: Past, present and future.

Parkinson's disease is a neurodegenerative disorder predominately affecting midbrain dopaminergic neurons that results in a broad range of motor and non-motor symptoms. Sleep complaints are among the most common non-motor symptoms, even in the prodromal period. Sleep alterations in Parkinson's disease patients may be associated with dysregulation of circadian rhythms, intrinsic 24-h cycles that control essential physiological functions, or with side effects from levodopa medication and physical and mental health challenges. The impact of circadian dysregulation on sleep disturbances in Parkinson's disease is not fully understood; as such, we review the systems, cellular and molecular mechanisms that may underlie circadian perturbations in Parkinson's disease. We also discuss the potential benefits of chronobiology-based personalized medicine in the management of Parkinson's disease both in terms of behavioural and pharmacological interventions. We propose that a fuller understanding of circadian clock function may shed important new light on the aetiology and symptomatology of the disease and may allow for improvements in the quality of life for the millions of people with Parkinson's disease.

[Chronobiological aspects of bipolar disorder]. / Chronobiologische Aspekte der bipolaren Störung.

BACKGROUND: Numerous symptoms of bipolar disorder are regulated by the circadian rhythm. Because of this association it is assumed that disruption of the circadian rhythm may be part of the pathomechanism of bipolar disorder. OBJECTIVES: A comparison and subsequent critical discussion of the current data situation on chronobiological aspects of bipolar disorder are presented. METHODS: A narrative literature search was carried out and the main findings are presented in a summarized form. RESULTS: There are a large number of animal and human studies investigating the connection between disorders of the circadian rhythm and bipolar disorder. Especially chronotype, the environmental factor light and sleep disorders seem to be associated with the development of bipolar disorder. CONCLUSIONS: The neurobiology of bipolar disorder shows numerous chronobiological aspects. There is evidence for a direct connection of disruption of the circadian rhythm and development and progression of bipolar disorder; however, at present there is no proof for the specificity of these findings for bipolar disorder. Future studies should consolidate the evidence on the impact of disorders of the circadian rhythm on the pathomechanism of bipolar disorder.

Beneficial effects of voluntary wheel running on activity rhythms, metabolic state, and affect in a diurnal model of circadian disruption.

Emerging evidence suggests that disruption of circadian rhythmicity contributes to development of comorbid depression, cardiovascular diseases (CVD), and type 2 diabetes mellitus (T2DM). Physical exercise synchronizes the circadian system and has ameliorating effects on the depression- and anxiety-like phenotype induced by circadian disruption in mice and sand rats. We explored the beneficial effects of voluntary wheel running on daily rhythms, and the development of depression, T2DM, and CVD in a diurnal animal model, the fat sand rat (Psammomys obesus). Voluntary exercise strengthened general activity rhythms, improved memory and lowered anxiety- and depressive-like behaviors, enhanced oral glucose tolerance, and decreased plasma insulin levels and liver weight. Animals with access to a running wheel had larger heart weight and heart/body weight ratio, and thicker left ventricular wall. Our results demonstrate that exercising ameliorates pathological-like daily rhythms in activity and blood glucose levels, glucose tolerance and depressive- and anxiety-like behaviors in the sand rat model, supporting the important role of physical activity in modulating the "circadian syndrome" and circadian rhythm-related diseases. We suggest that the utilization of a diurnal rodent animal model may offer an effective way to further explore metabolic, cardiovascular, and affective-like behavioral changes related to chronodisruption and their underlying mechanisms.

Strategies for circadian rhythm disturbances and related psychiatric disorders: a new cue based on plant polysaccharides and intestinal microbiota.

Circadian rhythm is essential to human physiological homeostasis and health. The oscillation of host circadian rhythm affects the composition and function of intestinal microbiota, meanwhile, the normal operation of host circadian rhythm depends on the diurnal changes of intestinal microbiota. The imbalance of intestinal micro-ecology or the disorder of host circadian rhythm may lead to psychiatric disorders, while the intervention of plant polysaccharides is a possible way to alleviate circadian rhythm disturbance and the related psychiatric diseases. This review discusses the interaction between host circadian rhythm and intestinal microbiota and their effects on psychiatric disorders, and proposes a possible strategy of plant polysaccharides to alleviate circadian rhythm disorders and related psychiatric disorders by regulating intestinal micro-ecology.

[Sleep disorders in patients with a neurocognitive disorder]. / Les troubles du sommeil chez les patients atteints d'un trouble neurocognitif.

INTRODUCTION: Sleep disorders are prevalent in patients with a neurocognitive disorder, and diagnosis and treatment in these patients remain challenging in clinical practice. METHODS: This narrative review offers a systematic approach to diagnose and treat sleep disorders in neurocognitive disorders. RESULTS: Alzheimer's disease is often associated with circadian rhythm disorders, chronic insomnia, and sleep apnea-hypopnea syndrome. Alpha-synucleinopathies (e.g., Parkinson's disease and Lewy body dementia) are often associated with a rapid eye movement sleep behavior disorder, restless legs syndrome, chronic insomnia, and sleep apnea-hypopnea syndrome. A focused history allows to diagnose most sleep disorders. Clinicians should ensure to gather the following information in all patients with a neurocognitive disorder: (1) the presence of difficulties falling asleep or staying asleep, (2) the impact of sleep disturbances on daily functioning (fatigue, sleepiness and other daytime consequences), and (3) abnormal movements in sleep. Sleep diaries and questionnaires can assist clinicians in screening for specific sleep disorders. Polysomnography is recommended if a rapid eye movement sleep behavior disorder or a sleep apnea-hypopnea syndrome are suspected. Sleep complaints should prompt clinicians to ensure that comorbidities interfering with sleep are properly managed. The main treatment for moderate to severe obstructive sleep apnea-hypopnea syndrome remains continuous positive airway pressure, as its efficacy has been demonstrated in patients with neurocognitive disorders. Medications should also be reviewed, and time of administration should be optimized (diuretics and stimulating medications in the morning, sedating medications in the evening). Importantly, cholinesterase inhibitors (especially donepezil) may trigger insomnia. Switching to morning dosing or to an alternative drug may help. Cognitive-behavioral therapy for insomnia is indicated to treat chronic insomnia in neurocognitive disorders. False beliefs regarding sleep should be addressed with the patient and their caregiver. The sleep environment should be optimized (decrease light exposure at night, minimize noise, avoid taking vital signs, etc.). Sleep restriction can be considered as patients with a neurocognitive disorder often spend too much time in bed. The need for naps should be assessed case by case as naps may contribute to insomnia in some patients but allow others to complete their diurnal activities. Trazodone (50mg) may also be used under certain circumstances in chronic insomnia. Recent evidence does not support a role for exogenous melatonin in patients with a neucognitive disorder and insomnia. Patients in long-term care facilities are often deprived of an adequate diurnal exposure to light. Increasing daytime exposure to light may improve sleep and mood. Patients with circadian rhythm disorders can also benefit from light therapy (morning bright light therapy in case of phase delay and evening bright light therapy in case of phase advance). Rapid eye movement sleep behavior disorder can lead to violent behaviors, and the sleeping environment should be secured (e.g., mattress on the floor, remove surrounding objects). Medication exacerbating this disorder should be stopped if possible. High dose melatonin (6 to 18mg) or low dose clonazepam (0.125-0.25mg) at bedtime may be used to reduce symptoms. Melatonin is preferred in first-line as it is generally well tolerated with few side effects. Patients with restless legs syndrome should be investigated for iron deficiency. Medication decreasing dopaminergic activity should be reduced or stopped if possible. Behavioral strategies such as exercise and leg massages may be beneficial. Low-dose dopamine agonists (such as pramipexole 0.125mg two hours before bedtime) can be used to treat the condition, but a prolonged treatment may paradoxically worsen the symptoms. Alpha-2-delta calcium channel ligands can also be used while monitoring for the risk of falls. CONCLUSION: Multiple and sustained nonpharmacological approaches are recommended for the treatment of sleep disturbances in patients with neurocognitive disorder. Pharmacological indications remain limited, and further randomized clinical trials integrating a multimodal approach are warranted to evaluate the treatment of sleep disorders in specific neurocognitive disorders.

Circadian Rhythm Disruption Influenced Hepatic Lipid Metabolism, Gut Microbiota and Promoted Cholesterol Gallstone Formation in Mice.

Background: Hepatic lipid metabolism regulates biliary composition and influences the formation of cholesterol gallstones. The genes Hmgcr and Cyp7a1, which encode key liver enzymes, are regulated by circadian rhythm-related transcription factors. We aimed to investigate the effect of circadian rhythm disruption on hepatic cholesterol and bile acid metabolism and the incidence of cholesterol stone formation. Methods: Adult male C57BL/6J mice were fed either a lithogenic diet (LD) only during the sleep phase (time-restricted lithogenic diet feeding, TRF) or an LD ad libitum (non-time-restricted lithogenic diet feeding, nTRF) for 4 weeks. Food consumption, body mass gain, and the incidence of gallstones were assessed. Circulating metabolic parameters, lipid accumulation in the liver, the circadian expression of hepatic clock and metabolic genes, and the gut microbiota were analyzed. Results: TRF caused a dysregulation of the circadian rhythm in the mice, characterized by significant differences in the circadian expression patterns of clock-related genes. In TRF mice, the circadian rhythms in the expression of genes involved in bile acid and cholesterol metabolism were disrupted, as was the circadian rhythm of the gut microbiota. These changes were associated with high biliary cholesterol content, which promoted gallstone formation in the TRF mice. Conclusion: Disordered circadian rhythm is associated with abnormal hepatic bile acid and cholesterol metabolism in mice, which promotes gallstone formation.

Circadian misalignment promotes vascular smooth muscle cell apoptosis via defective autophagy.

Defective autophagy in vascular smooth muscle cells (VSMCs) in response to oxidative stress can lead to cellular apoptosis and plaque instability. Previous studies have revealed that the circadian clock system is involved in autophagic regulation and plaque progression. However, the mechanism by which circadian rhythmicity influences VSMC autophagy and plaque stability remains unclear. Our study described the circadian profiles in atheromatous plaques and verified the role of circadian misalignment in VSMC autophagy and apoptosis. We found that the mRNA expression levels of circadian locomotor output cycles protein kaput (CLOCK) and Beclin 1 were significantly decreased in unstable plaques compared with stable plaques. No significant differences were observed in other circadian rhythm genes. VSMCs treated with oxidized low-density lipoprotein (ox-LDL, 80 µg/ml) exhibited abnormal circadian rhythmicity and impaired autophagy, as evidenced by consistent decreases in CLOCK and Beclin 1 expression, suggesting a correlation between CLOCK and autophagy. CLOCK protein expression was inhibited by ox-LDL, accompanied by defective autophagy and an increased apoptosis rates (P < 0.05). Administration of rapamycin (10 nM) reversed the effect of ox-LDL on VSMC autophagy and apoptosis. Finally, CLOCK silencing led to a considerable decrease in autophagy. VSMCs with stable CLOCK silencing also showed an increased apoptosis rate. In addition, gene silencing of CLOCK in VSMCs counteracted the effects of moderate rapamycin concentrations on autophagy and apoptosis. In conclusion, these findings suggested that the CLOCK-dependent rapamycin signaling pathway is a critical mediator in ox-LDL-induced VSMCs with defective autophagy that exacerbates plaque destabilization.

Sleep and Circadian Rhythm Disorder in Bipolar Affective Disorder.

Symptoms of affective disorders encompass a range of changes to biological processes such as sleep and appetite. These processes are regulated over a 24-h cycle known as the circadian rhythm. Sleep is a particularly useful marker of this rhythm as it is readily measurable and functionally significant. Sleep disturbance is common in bipolar affective disorder and may act as a marker, and precipitant, of relapse. Circadian rhythms are modulated by environmental and social cues and have been shown to be influenced by treatment in BPAD. As such understanding of circadian rhythms may lead to a better understanding of the pathophysiology of BPAD and its treatment. This chapter will explore the neurobiology of the circadian clock and the putative role of circadian rhythm dysregulation in the pathophysiology and treatment of bipolar affective disorder (BPAD).

Association between circadian disruption and diseases: A narrative review.

Circadian rhythms play an important role in a wide range of human physiology and pathology. Individuals increasingly experience situations such as night-shift work schedules, likely leading to circadian disruption. Recent studies have also demonstrated that patients with other diseases often show symptoms of circadian disruption as manifested by the sleep-wake cycle and other biological rhythms. Circadian disruption often results in changes to the phase, period, and amplitude of the sleep-wake cycle, melatonin rhythm, and core body temperature. Several cardiometabolic, psychiatric, and neurodegenerative diseases are closely related to circadian disruption. Several interventions are also available, including phototherapy, exogenous melatonin, and exercise. The cumulative findings suggest that circadian disruption can increase risk for some cardiometabolic diseases. Circadian disruption also acts as a concomitant symptom of several psychiatric and neurodegenerative diseases. More attention should be paid to evaluating the impact of circadian disruption on these related diseases, as well as the benefits of the mitigation interventions for both circadian disruption and related diseases.

Impact of circadian and diurnal rhythms on cellular metabolic function and neurodegenerative diseases.

The 24-h rotational period of the earth has driven evolution of biological systems that serve to synchronize organismal physiology and behavior to this predictable environmental event. In mammals, the circadian (circa, "about" and dia, "a day") clock keeps 24-h time at the organismal and cellular level, optimizing biological function for a given time of day. The most obvious circadian output is the sleep-wake cycle, though countless bodily functions, ranging from hormone levels to cognitive function, are influenced by the circadian clock. Here we discuss the regulation of metabolic pathways by the circadian clock, discuss the evidence implicating circadian and sleep disruption in neurodegenerative diseases, and suggest some possible connections between the clock, metabolism, and neurodegenerative disease.

Chronic circadian disruption modulates breast cancer stemness and immune microenvironment to drive metastasis in mice.

Breast cancer is the most common type of cancer worldwide and one of the major causes of cancer death in women. Epidemiological studies have established a link between night-shift work and increased cancer risk, suggesting that circadian disruption may play a role in carcinogenesis. Here, we aim to shed light on the effect of chronic jetlag (JL) on mammary tumour development. To do this, we use a mouse model of spontaneous mammary tumourigenesis and subject it to chronic circadian disruption. We observe that circadian disruption significantly increases cancer-cell dissemination and lung metastasis. It also enhances the stemness and tumour-initiating potential of tumour cells and creates an immunosuppressive shift in the tumour microenvironment. Finally, our results suggest that the use of a CXCR2 inhibitor could correct the effect of JL on cancer-cell dissemination and metastasis. Altogether, our data provide a conceptual framework to better understand and manage the effects of chronic circadian disruption on breast cancer progression.

Diurnal Rhythmicity of Autophagy Is Impaired in the Diabetic Retina.

Retinal homeostasis is under both diurnal and circadian regulation. We sought to investigate the diurnal expression of autophagy proteins in normal rodent retina and to determine if this is impaired in diabetic retinopathy. C57BL/6J mice and Bio-Breeding Zucker (BBZ) rats were maintained under a 12h/12h light/dark cycle and eyes, enucleated over a 24 h period. Eyes were also collected from diabetic mice with two or nine-months duration of type 1 diabetes (T1D) and Bio-Breeding Zucker diabetic rat (BBZDR/wor rats with 4-months duration of type 2 diabetes (T2D). Immunohistochemistry was performed for the autophagy proteins Atg7, Atg9, LC3 and Beclin1. These autophagy proteins (Atgs) were abundantly expressed in neural retina and endothelial cells in both mice and rats. A differential staining pattern was observed across the retinas which demonstrated a distinctive diurnal rhythmicity. All Atgs showed localization to retinal blood vessels with Atg7 being the most highly expressed. Analysis of the immunostaining demonstrated distinctive diurnal rhythmicity, of which Atg9 and LC3 shared a biphasic expression cycle with the highest level at 8:15 am and 8:15 pm. In contrast, Beclin1 revealed a 24-h cycle with the highest level observed at midnight. Atg7 was also on a 24-h cycle with peak expression at 8:15am, coinciding with the first peak expression of Atg9 and LC3. In diabetic animals, there was a dramatic reduction in all four Atgs and the distinctive diurnal rhythmicity of these autophagy proteins was significantly impaired and phase shifted in both T1D and T2D animals. Restoration of diurnal rhythmicity and facilitation of autophagy protein expression may provide new treatment strategies for diabetic retinopathy.

Saliva cortisol, melatonin levels and circadian rhythm alterations in Chinese primary school children with dyslexia.

Cortisol is the main end product of hypothalamic-pituitary-adrenal gland (HPA axis), and melatonin (MT) has a regulating effect on HPA axis, and both are closely related to individual behavior and cognitive function. We aimed to evaluate cortisol and MT roles on children dyslexia in this study.A total of 72 dyslexic children and 72 controls were recruited in this study. Saliva samples were collected in the morning, afternoon, and night, respectively. The levels of saliva cortisol and MT were measured by enzyme-linked immunosorbent assay method. Differences of cortisol and MT levels between dyslexic and normal children were compared, and the variation trend was also analyzed by dynamic monitoring in 3 time points.The levels of salivary cortisol and MT in children with dyslexia were all lower than those in normal children whether in the morning (7:30-8:30 AM ), at afternoon (15:30-16:30 PM ) or at night (21:30-22:30 PM ) (all P < .001). Compared with normal children, the circadian rhythm variations of salivary cortisol and MT in dyslexic children disappeared and became disordered. The salivary cortisol and MT levels in children with dyslexia were declined throughout the day; and the circadian rhythm was disordered or disappeared.The results suggest that cortisol and MT levels and their circadian rhythm may affect children dyslexia, but the mechanisms need further exploration.

Impact of circadian disruption on glucose metabolism: implications for type 2 diabetes.

The circadian system generates endogenous rhythms of approximately 24 h, the synchronisation of which are vital for healthy bodily function. The timing of many physiological processes, including glucose metabolism, are coordinated by the circadian system, and circadian disruptions that desynchronise or misalign these rhythms can result in adverse health outcomes. In this review, we cover the role of the circadian system and its disruption in glucose metabolism in healthy individuals and individuals with type 2 diabetes mellitus. We begin by defining circadian rhythms and circadian disruption and then we provide an overview of circadian regulation of glucose metabolism. We next discuss the impact of circadian disruptions on glucose control and type 2 diabetes. Given the concurrent high prevalence of type 2 diabetes and circadian disruption, understanding the mechanisms underlying the impact of circadian disruption on glucose metabolism may aid in improving glycaemic control.

[Relationship between Circadian Rhythm Disorder of Blood Pressure and Ischemic Stroke].

Hypertension plays an important role in the pathogenesis of stroke,which,however,is only known at the blood pressure level.The relationship between circadian rhythm of blood pressure(especially the circadian rhythm disorder of blood pressure)and stroke has been a hot research topic.This article reviews the concept of circadian rhythm of blood pressure,classification of circadian rhythm disorder of blood pressure,and the relationship of circadian rhythm disorder of blood pressure with ischemic stroke.

Circadian disturbances in Alzheimer's disease progression: a prospective observational cohort study of community-based older adults.

BACKGROUND: Circadian disturbances are commonly seen in people with Alzheimer's disease and have been reported in individuals without symptoms of dementia but with Alzheimer's pathology. We aimed to assess the temporal relationship between circadian disturbances and Alzheimer's progression. METHODS: We did a prospective cohort study of 1401 healthy older adults (aged >59 years) enrolled in the Rush Memory and Aging Project (Rush University Medical Center, Chicago, IL, USA) who had been followed up for up to 15 years. Participants underwent annual assessments of cognition (with a battery of 21 cognitive performance tests) and motor activities (with actigraphy). Four measures were extracted from actigraphy to quantify daily and circadian rhythmicity, which were amplitude of 24-h activity rhythm, acrophase (representing peak activity time), interdaily stability of 24-h activity rhythm, and intradaily variability for hourly fragmentation of activity rhythm. We used Cox proportional hazards models and logistic regressions to assess whether circadian disturbances predict an increased risk of incident Alzheimer's dementia and conversion of mild cognitive impairment to Alzheimer's dementia. We used linear mixed-effects models to investigate how circadian rhythms changed longitudinally and how the change integrated to Alzheimer's progression. FINDINGS: Participants had a median age of 81·8 (IQR 76·3-85·7) years. Risk of developing Alzheimer's dementia was increased with lower amplitude (1 SD decrease, hazard ratio [HR] 1·39, 95% CI 1·19-1·62) and higher intradaily variability (1 SD increase, 1·22, 1·04-1·43). In participants with mild cognitive impairment, increased risk of Alzheimer's dementia was predicted by lower amplitude (1 SD decrease, HR 1·46, 95% CI 1·24-1·72), higher intradaily variability (1 SD increase, 1·36, 1·15-1·60), and lower interdaily stability (1 SD decrease, 1·21, 1·02-1·44). A faster transition to Alzheimer's dementia in participants with mild cognitive impairment was predicted by lower amplitude (1 SD decrease, odds ratio [OR] 2·08, 95% CI 1·53-2·93), increased intradaily variability (1 SD increase, 1·97, 1·43-2·79), and decreased interdaily stability (1 SD decrease, 1·35, 1·01-1·84). Circadian amplitude, acrophase, and interdaily stability progressively decreased over time, and intradaily variability progressively increased over time. Alzheimer's progression accelerated these aging effects by doubling or more than doubling the annual changes in these measures after the diagnosis of mild cognitive impairment, and further doubled them after the diagnosis of Alzheimer's dementia. The longitudinal change of global cognition positively correlated with the longitudinal changes in amplitude and interdaily stability and negatively correlated with the longitudinal change in intradaily variability. INTERPRETATION: Our results indicate a link between circadian dysregulation and Alzheimer's progression, implying either a bidirectional relation or shared common underlying pathophysiological mechanisms. FUNDING: National Institutes of Health, and the BrightFocus Foundation.