How Diet, Exercise, and Sleep May Influence Cell Cleanup Processes in Alzheimer's Disease

According to the World Health Organization (WHO), more than 55 million people worldwide are living with dementia as of 2024, with AD accounting for 60% to 70% of cases. Recent projections estimate that this number will rise sharply, reaching approximately 152.8 million cases by 2050.14 AD is characterized macroscopically by cortical and limbic atrophy, especially in the frontal and temporal lobes, leading to ventricular enlargement and reduced brain weight.15, 16 At the cellular level, AD is characterized by Aβ plaques and tau tangles. Aβ is generated from amyloidogenic cleavage of APP by β‐ and γ‐secretases, producing aggregation‐prone Aβ42 peptides that disrupt cellular homeostasis, trigger oxidative stress, and induce neuronal death. Mutations in γ‐secretase components (presenilin 1 and presenilin 2 [PSEN1/2]) are linked to early‐onset AD.17, 18, 19, 20, 21, 22 Tau, a microtubule‐stabilizing protein, becomes hyperphosphorylated, forming NFTs that impair axonal transport and exacerbate neuronal damage. Aβ and tau pathologies are closely interlinked, contributing synergistically to AD progression.23, 24, 25 Understanding the intricate relationship between autophagy dysfunction and protein aggregation not only deepens our insight into AD pathogenesis but also opens new avenues for therapeutic strategies aimed at restoring autophagic balance and preventing neuronal loss.

Dysregulated autophagy is a key mechanism in neurodegenerative diseases such as AD, amyotrophic lateral sclerosis, Parkinson's disease, and Huntington's disease, where toxic protein starts aggregating over time.26, 27, 28 Autophagy is classified into three main types, depending on the specific pathway used to deliver intracellular components to the lysosome for degradation.10, 13 Macroautophagy, microautophagy, and chaperone‐mediated autophagy (CMA) are the three main autophagy pathways.

Autophagy is vital for maintaining cellular homeostasis.39 Pro‐autophagic signaling activates the autophagy regulated genes (ATG) machinery, including key regulators like ULK1 and the Beclin‐1 complex.10, 12 This activation initiates the four sequential stages of autophagy initiation, nucleation and elongation, maturation, lysosome fusion, and degradation (Figure 1A). Autophagic regulation is mainly carried out by two key nutrient sensors, such as mechanistic target of rapamycin (mTOR) and adenosine monophosphate (AMP)‐activated protein kinase (AMPK).38

mTOR is a serine/threonine kinase belonging to the phosphatidylinositol 3‐kinase‐related kinase (PIKK) family and plays a central role in cellular nutrient sensing and metabolic regulation.41, 42 mTOR acts as a key negative regulator of autophagy by interacting with multiple signaling proteins to inhibit catabolic processes and stimulate protein synthesis.5, 38, 40 mTOR exists in two distinct complexes with different functions and associated proteins. mTOR complex 1 (mTORC1) includes mTOR, Raptor, mLST8, and PRAS40, while mTORC2 is composed of mTOR, Rictor, mLST8, and Sin1.38, 43 mTORC2 primarily regulates kinases such as Akt/protein kinase B (PKB) and protein kinase C (PKC) during autophagy.38 mTORC1 inhibits autophagy initiation by phosphorylating ULK1 and Atg13, two key proteins required for the early stages of autophagosome formation.35, 38 During normal physiological conditions, mTORC1 suppresses autophagy by inhibiting ULK1, a key initiator of the autophagic process, and by phosphorylating transcription factor EB (TFEB), a master regulator of genes involved in autophagy and lysosomal biogenesis.42, 44, 45

mTORC1 also has an important role in protein synthesis by the downstream activation of p70S6 kinase or S6K.38 mTORC1 promotes protein synthesis by activating S6K, which in turn negatively regulates autophagy. Interestingly, S6K activity may also contribute to autophagosome maturation under certain conditions. S6K is one of the negative regulators of autophagy as its main function is ribosomal protein synthesis. Some reports suggest an upregulation of S6K during autophagy, which can be explained by the fact that S6K is primarily involved in protein synthesis, which may be used in the process of autophagy initiation and maturation process.38, 44 As reports suggest, excessive autophagy or self‐eating can lead to cell death. Therefore, a negative regulator like S6K may help maintain autophagic balance by moderating the inhibitory effect of mTORC1. This moderation prevents overactivation of autophagy, protecting cells from autophagy‐induced damage while still allowing necessary cellular clearance and homeostasis.38, 46 While autophagy typically protects against cellular stress, excessive activation/defect can lead to neuronal cell death and aggregate buildup, highlighting the need for precise regulation (Figure 1B).

The AMPK pathway serves as an energy sensor and acts as a positive regulator of autophagy, especially when mTORC1 is inhibited under energy‐deprived conditions.41 AMPK is a serine/threonine protein kinase that has been conserved throughout evolution, which functions as a cell's energy sensor.47, 48 It is an essential component in upregulating catabolic processes, such as glucose metabolism and uptake, and inactivating anabolic processes, such as carbohydrate, lipid, and protein biosynthesis.49 These effects in turn contribute to the maintenance of homeostasis of the internal environment and energy balance.50 Under cellular energy scarcity, the nutrient sensor AMPK is activated by the decreased levels of ATP/AMP ratio. Additionally, active AMPK inhibits the mTORC activity through Rheb proteins, activating the TSC1/2 complex.38, 41 AMPK also inhibits HMGCoA reductases and prevents cholesterol and fatty acid synthesis by inhibiting Acetyl‐CoA carboxylase (ACC) by phosphorylation.51, 52 AMPK has also been shown to activate ULK1 in fatty acid catabolism by activating adipose triglyceride lipase.52, 53

Under nutrient‐rich conditions, ULK1 is bound to mTOR, which prevents the initiation of the autophagy process.54, 55 Conversely, during nutrient deprivation, mTOR detaches itself from the ULK1 complex, which activates the autophagy process.55 During fasting, AMPK plays a key role in activating autophagy by directly phosphorylating ULK1, a central kinase in the autophagy initiation complex, and concurrently inhibiting mTORC1, a major autophagy suppressor. A pivotal study by Kim et al. revealed that AMPK and mTORC1 exerted opposing regulatory effects on ULK1, highlighting the integration of metabolic signals at the level of autophagy initiation. Specifically, AMPK activates ULK1 by phosphorylating it at Ser317 and Ser777, thereby promoting autophagy under energy‐stressed conditions. In contrast, under nutrient‐rich conditions, elevated mTORC1 activity inhibits autophagy by phosphorylating ULK1 at Ser757, a modification that disrupts the interaction between AMPK and ULK1, effectively suppressing ULK1 activation. Furthermore, the study demonstrated that inhibition of mTORC1 using rapamycin enhances AMPK‐mediated phosphorylation of ULK1, reinforcing the interplay between these nutrient‐sensing pathways. This intricate regulatory network between AMPK, mTORC1, and ULK1 represents a major advancement in our understanding of how cells fine‐tune autophagy in response to metabolic status and stress signals.51, 52, 54

While the core autophagy machinery is primarily regulated by non‐transcriptional nutrient sensors such as mTOR and AMPK, autophagy can also be enhanced through transcriptional regulation, notably via the Forkhead box O3 (FoxO3) transcription factor56, 57 (Figure 1A). Studies on protein breakdown during muscle atrophy led researchers to uncover a transcription‐dependent mechanism for mammalian cells via FoxO3.56, 57 FoxO3 induces numerous autophagy genes, including ATG4B, ATG12, BNIP3, BNIP3L, Beclin‐1, GABARAPL1, LC3B, ULK2, and VPS34.58 Of these genes, gene transcription is induced when FoxO3 binds specifically to the promoters of ATG12, BNIP3, BNIP3L, GABARAPL1, and LC3B.58 TFEB, a basic helix–loop–helix‐leucine‐zipper (bHLH‐Zip) protein, regulates the expression of target genes bearing the Coordinated Lysosomal Expression and Regulation (CLEAR) motif, thereby modulating autophagy and lysosomal biogenesis. In addition to regulating autophagy and lysosomal biogenesis, TFEB plays a role in selective autophagy and lysosomal exocytosis, making it a potential therapeutic target in diseases involving lysosomal dysfunction.59 Together, these insights underscore the complexity and precision of autophagy regulation, which is governed by both nutrient‐sensing kinases like mTOR and AMPK and transcriptional regulators such as FoxO3 and TFEB. The dynamic interplay between these pathways ensures cellular adaptation to metabolic stress and nutrient availability.

Autophagy, a key cellular proteostasis mechanism, is closely linked with the pathogenesis of protein misfolding disorders such as AD.60, 61 Early studies identified dysfunction in the endosomal lysosomal system as a critical regulator of amyloid precursor protein (APP) processing, a contributor to AD pathogenesis and Aβ generation. Notably, the endocytic pathway was found to be hyperactive in vulnerable neuronal populations, with early endosomes displaying significant enlargement in the AD brain. Aβ was observed within these enlarged, Rab5‐positive endosomes, implicating early endosomal dysfunction in amyloidogenesis.62, 63 Nixon et al. published one of the first studies demonstrating a clear link between autophagic dysfunction and neurodegeneration, highlighting the critical role of autophagy in maintaining neuronal health.64 Using immunogold staining and electron microscopy, they showed a significant accumulation of autophagosomes in the frontoparietal cortex of AD patients compared to cognitively unimpaired older adults. These findings suggest that enhancing autophagy could be a promising therapeutic strategy for treating AD and other neurodegenerative disorders.64 In line with these findings, Pickford et al. reported significantly reduced levels of Beclin‐1, an essential autophagy‐regulating protein in AD brain tissues at both the transcript and protein levels.65 Other studies expanded this perspective, demonstrating that autophagic dysfunction contributes not only to Aβ pathology but also to tau accumulation and neurofibrillary tangle formation.66, 67, 68 In AD, the impaired clearance of Aβ and hyperphosphorylated tau is closely associated with defects in the autophagy‐lysosomal pathway. Genetic mutations and polymorphisms that affect autophagy‐related components exacerbate this dysfunction. Notably, mutations in PSEN1, a component of the γ‐secretase complex, not only alter APP processing but also disrupt lysosomal acidification and autophagosome clearance.69, 70

Autophagy is tightly interconnected with other pathological mechanisms in AD, including chronic neuroinflammation and oxidative stress. In microglia, autophagy constrains inflammasome activity; targeting NLRP3 shows that enhancing microglial autophagic degradation limits IL‐1β–driven neuroinflammation in AD models.71, 72 Impaired autophagy is associated with increased reactive oxygen species (ROS) and organellar damage; cells and patient‐derived lines from AD display elevated mitochondrial ROS alongside defects in autophagy/lysosomal degradation.73, 74 Conversely, oxidative stress can directly block autophagosome‐lysosome fusion, for example, by disrupting SNARE machinery (VAMP8) or lowering STX17, leading to accumulation of dysfunctional autophagic vesicles.75, 76 Thus, autophagy is both regulated by and protective against inflammatory and oxidative mechanisms, underscoring the importance of restoring autophagic balance in AD.

Mutations in PSEN1 have been implicated not only in aberrant Aβ production but also in autophagic dysfunction. PSEN1 is essential for the proper acidification and maturation of lysosomes. Studies have demonstrated that PSEN1 mutations impair lysosomal proteolysis by disrupting the proper targeting of vacuolar‐type H⁺‐ATPase (v‐ATPase) to lysosomes. This defect leads to impaired autophagosome clearance, independent of PSEN1’s γ‐secretase function, highlighting its multifaceted role in maintaining cellular homeostasis.69, 70 Supporting these findings another study demonstrates that PSEN1 deficiency impairs autophagy in human neural stem cells by reducing extracellular signal‐regulated kinase/cAMP response element‐binding protein (ERK/CREB) signaling, a γ‐secretase‐independent pathway.77 Together, these findings highlight the pivotal role of PSEN1 in regulating autophagy through both lysosomal function and intracellular signaling pathways. Its dysfunction is strongly associated with impaired cellular homeostasis and is a key contributor to the pathogenesis of neurodegenerative diseases such as AD.

Cathepsin D and PRKAG2 are emerging as important regulators of the autophagy‐lysosomal pathway, with growing evidence linking their dysfunction to neurodegenerative diseases like AD. Cathepsin D, a major lysosomal aspartic protease, plays a critical role in autophagic degradation by breaking down aggregated and misfolded proteins. Genetic polymorphisms or reduced activity of cathepsin D have been associated with impaired lysosomal function and a higher risk of AD.78 In addition, mutations in PRKAG2, a gene encoding the regulatory subunit of AMPK, impair cellular energy sensing and autophagy activation. Studies have also revealed genes that are involved in the autophagy dysfunction observed in AD. Furthermore, findings from our lab demonstrated that the expression of PRKAG2 gene was elevated threefold in the frontal cortex and hippocampus of AD brains compared to controls. Moreover, PRKAG2 protein levels were associated with increased Aβ accumulation in the brain.79 A study in yeast additionally demonstrated that autophagy was activated by Aβ42 expression and co‐expression of the PRKAG2 homolog, SNF4, significantly decreased Aβ42 aggregate levels, and autophagic activity in controls.80 These two studies therefore suggest that elevated levels of Aβ accumulation in the AD brain may result in increased PRKAG2 expression and autophagy activation. Another protein, phosphatidylinositol binding clathrin assembly protein (PICALM) is a crucial protein involved in clathrin‐mediated endocytosis and intracellular trafficking, processes that intersect with autophagy and lysosomal function. Abnormal cleavage of PICALM, whose loss of function has a detrimental effect on autophagy, is increased in AD.81 The loss of function of PICALM on autophagy results in erroneous autophagosome formation and maturation.82 Overall, these findings show that increased autophagy activation and expression of autophagy pathway genes could be a mitigating response to increased Aβ accumulation in the AD brain. Together, these genetic factors underline the critical role of autophagy in the development and progression of AD and other proteinopathies, highlighting the need for therapeutic strategies aimed at restoring autophagic function.

The interaction between mitochondrial dynamics and autophagy, previously viewed as a crucial homeostatic mechanism for preserving cellular integrity, is now increasingly acknowledged as a primary contributor to neurodegenerative pathology in AD.83 A key pathological feature of AD is mitochondrial dysfunction, which is closely related to impaired autophagy.84, 85, 86, 87 Redox homeostasis, calcium regulation, and neuronal energy metabolism all depend on mitochondria. In AD, synaptic failure and neuronal loss are mediated by mitochondria that have altered morphology, decreased oxidative phosphorylation, and excessive ROS production.88 The accumulation of dysfunctional mitochondria is mostly caused by impaired mitophagy, a process that eliminates damaged mitochondria selectively and results in oxidative stress and metabolic dysregulation.83 Studies have shown that changes in the PINK1/Parkin‐mediated mitophagy pathway are important for the development of AD, as ineffective mitochondrial clearance results from decreased Parkin translocation and PINK1 stabilization on damaged mitochondria.89, 90 As a result, abnormal mitochondria build up and release too many ROS and apoptotic factors, which worsen tau hyperphosphorylation and Aβ aggregation.89, 90, 91 Neuronal degeneration is also made worse by impaired mitochondrial dynamics, which are characterized by an imbalance between fusion and fission. There have been reports of protein dysregulation in AD, including dynamin‐related protein 1 (Drp1) and mitofusins (Mfn1/2), which results in mitochondrial fragmentation and synaptic dysfunction.92, 93 Emerging studies suggest that restoration of mitochondrial dynamics and enhancement of mitophagy could serve as a potential therapeutic approach to counteract neurodegeneration in AD. To preserve neuronal homeostasis, autophagy and mitophagy are crucial for mitochondrial quality control, removing faulty or unnecessary organelles.

AD treatment currently involves several US Food and Drug Administration (FDA)‐approved drugs aimed at managing both cognitive symptoms (such as memory loss, impaired thinking, and language deficits) and non‐cognitive symptoms (including behavioral and psychological changes). FDA‐approved drugs includes cholinesterase inhibitors, glutamate regulators, orexin receptor antagonists for treating insomnia, and antipsychotics for managing behavioral disturbances.66, 94, 95, 96, 97 Disease‐modifying therapies focus on Aβ and tau pathologies.98, 99 Aβ is targeted via immunization strategies and secretase inhibitors.100, 101, 102 Recently approved monoclonal antibodies, such as donanemab and lecanemab, reduce Aβ plaques but are associated with adverse effects like amyloid‐related imaging abnormalities.103, 104 Tau‐targeting approaches, including kinase inhibitors and immunotherapy, have not yielded significant clinical benefits.25, 105, 106, 107, 108 Given that impaired autophagy contributes to the aggregation of unwanted proteins like Aβ and tau in AD, its therapeutic activation through mTOR‐dependent (e.g., rapamycin) and mTOR‐independent mechanisms (e.g., nilotinib, GTM‐1, latrepirdine, trehalose) is a promising strategy.26, 51, 109, 110, 111, 112, 113, 114, 115 However, concerns such as immunosuppression, age‐related variability, and potential lysosomal dysfunction remain challenges.79, 105, 106, 107, 108 Emerging evidence also suggests that lifestyle modifications, such as regular dietary interventions, physical activity, cognitive engagement, and sleep, may play a crucial role in preventing or slowing AD progression.116, 117, 118, 119

AD poses a growing public health challenge, with rising prevalence due to global aging. Therefore, developing approaches that are effective in lowering the financial and social expenditures, preserving the economic productivity of family carers, and minimizing the impact on the healthcare system will be very beneficial. It has been revealed that most age‐related dementias, especially AD, co‐exist with multiple comorbid conditions, mainly cerebrovascular diseases (CVDs).120, 121 The broader implication is that systemic vascular factors are risk factors for developing AD and related dementias. Major modifiable lifestyle factors for the onset of AD (e.g., diet, level of education, alcohol consumption, leisure, physical, sleep, and social activities), as well as traditional CVD risk factors (e.g., dyslipidemia, type II diabetes, carotid atherosclerosis, hypertension, smoking, and hypercholesterolemia), have therefore been the focus of epidemiological, preclinical, and interventional studies.118, 121, 122, 123, 124, 125, 126 While pharmaceutical treatments offer short‐term relief, lifestyle interventions have shown greater potential for long‐term prevention. Autophagy, a key cellular housekeeping mechanism, is emerging as a critical target in AD prevention. A recent review by Ortega et al. highlights the close relationship between lifestyle factors and autophagy, emphasizing diet, physical activity, sleep patterns, and environmental conditions influence on the regulation of the autophagic process.119 Non‐pharmacological strategies focused on lifestyle, especially diet, physical activity, and sleep, offer promising avenues to delay or prevent AD.127, 128 Yet, few studies explore the molecular mechanisms behind these benefits. Understanding how lifestyle interventions regulate autophagy may enhance prevention strategies and improve clinical trial outcomes through better biomarker use and disease modeling. Autophagy is a complex mechanism, and understanding its pathway for adopting proper preventive strategies is crucial for a successful outcome. A balanced autophagic pathway is essential for cellular homeostasis, preventing the accumulation of toxic aggregates while avoiding excessive self‐digestion (Figure 1B).

Overall, non‐pharmacological intervention and lifestyle changes focusing on diet, physical activity, and sleep could unlock new avenues for prevention and delaying of AD.129, 130, 131 The AD processes start many years before clinical symptoms manifest, so recent attention has been given to delaying or preventing the onset of AD at an earlier stage of life by the introduction of lifestyle interventions. However, only a handful of studies attempted to dissect the molecular pathways underlying the benefits of such interventions.130, 131 It is important to understand the mechanisms in which lifestyle factors regulate homeostasis mechanisms such as autophagy to develop more effective treatment and risk reduction strategies for AD and related neurodegenerative diseases. Research into basic disease mechanisms can have immense benefit for development of strategies to reduce risk or improve prevention. Moreover, clinical trials will have improved rates of success when disease mechanisms and their relevant clinical biomarkers are well defined.

Various dietary interventions, including calorie restriction (CR) and intermittent fasting (IF) and ketogenic, Mediterranean, plant‐based, and polyphenol‐rich diets, modulate key nutrient sensing pathways (e.g., mTOR inhibition; activation of AMPK, SIRT1, and TFEB) to enhance autophagic flux.132, 133, 134, 135 However, clinical translation is challenged by long‐term dietary adherence, individual variability in dietary response, and feasibility in older adults with cognitive impairment. Dietary modulation of autophagy presents a promising non‐pharmacological strategy to delay or prevent AD progression, but further clinical trials are needed to validate long‐term effects and adherence feasibility in older adults.

Although extensively reviewed elsewhere, dietary patterns such as the Mediterranean, DASH, and Mediterranean‐DASH Intervention for Neurodegenerative Delay (MIND) diet are consistently associated with reduced AD risk, potentially through modulation of autophagy‐related pathways.128, 185, 186, 187 Beyond CR and ketogenic strategies, several nutritional components modulate autophagy and cognitive health. Omega‐3 fatty acids, particularly DHA, enhance neuronal resilience by activating AMPK and suppressing mTOR signaling and promoting autophagic flux.188, 189 Vitamins and micronutrients, including vitamin D, vitamin E, selenium, zinc, and B‐complex vitamins, support redox balance, limit tau hyperphosphorylation, and improve cognitive health.190 Polyphenols such as resveratrol (found in red grapes), EGCG (from green tea), curcumin (from turmeric), and oleuropein aglycone (from extra virgin olive oil) regulate autophagy through SIRT1, AMPK, and mTOR pathways, as well as histone acetylation and upregulation of autophagy‐related genes, enhancing clearance of misfolded proteins, supporting neuroprotection, and reducing oxidative and inflammatory injury.191, 192, 193, 194 These compounds likely contribute to the observed benefits of Mediterranean‐style dietary patterns in reducing AD risk. These mechanistic links suggest that autophagy may be a key mediator of the cognitive benefits observed with these diets, though human data confirming this relationship remain limited.

Physical activity is well known to promote better health. Being physically active can improve heart and lung functions, promote brain health, help manage weight, reduce the risk of disease, strengthen bones and muscles, and improve the ability to do everyday activities. Exercise is a structured form of physical activity, and all exercises can be considered physical activity. Extensive reviews have discussed the benefits of physical activity in AD and the multiple biochemical pathways that mediate its protective effects.202, 203, 204

Several meta‐analyses showed that physical activity promoted cognitive function and ameliorated brain volume loss in individuals undergoing various exercise interventions, primarily aerobic exercises.205, 206, 207, 208, 209, 210 Of these studies, three meta‐analyses involved individuals who either had AD or MCI or were at risk of AD with a sample size ranging from 673 to 1145. Aerobic exercise significantly enhanced cognition, often measured by Mini‐Mental State Examination score, and increased cardiorespiratory fitness and hippocampal volume, correlating with better memory performance.205, 206, 208, 211 Resistance training also improved cognition, altered brain structure, and reduced white matter hyperintensities in older adults with MCI and early‐stage dementia.212, 213, 214 Both exercise types are beneficial, though no additive cognitive advantage has been observed from combining them.205 AD is a highly comorbid disease and generally co‐exists with multiple chronic conditions such as heart disease, stroke, type 2 diabetes, and high blood pressure. Because physical activity has a profound impact on overall health and helps to prevent and manage several chronic conditions, it is still yet to be determined whether cognitive benefits of different exercise regimes are dependent on the type of comorbidities observed in AD. Moreover, the etiologic role of physical activity in AD pathogenesis and fundamental mechanisms that reduce the risk of neurodegeneration remains to be fully understood.

Animal models of exercise are commonly used in research studies to investigate the beneficial effects of acute and chronic exercise conditioning on the brain and neurodegenerative diseases. In animal studies, particularly transgenic AD mouse models, it is now well recognized that exercise has substantial pro‐cognitive and pro‐neurogenic benefits.215 Using two main modes of exercise, treadmill running and voluntary wheel running protocols, studies have shown to significantly reduce AD pathology in transgenic mice brains by reduction in tau phosphorylation, soluble Aβ protein, and Aβ plaque levels.216, 217, 218 While the vast majority of the studies show the profound benefits of physical activity in AD, some studies have shown no significant effect of exercise on amyloid pathology.219 This, therefore, highlights a need for further research in understanding the mechanisms involved in which exercise lowers AD and amyloid pathology. In the next section, we summarize the experimental evidence of physical activity and its impact on autophagy in AD models and further discuss the possible mechanisms of action based on recent advances.

Sleep is a highly conserved biological process essential for metabolic homeostasis, cognitive function, and overall health. Sleep undergoes changes with aging and lifestyle factors,243, 244 and its poor sleep quality is linked to neurodegenerative diseases and other chronic illnesses, including hypertension, diabetes, and stroke.245, 246, 247 Research indicates that sleep quality, including continuity, efficiency, and depth, is an important predictor of neurological health and AD risk.248 Poor sleep quality, even without total sleep loss, has been linked to impaired cognition and decreased glymphatic clearance of metabolic waste.249 Recent research has also shown that poor sleep quality increases the risk of AD,248 implying that fragmented or non‐restorative sleep may be just as harmful as short sleep duration. A common feature of many sleep disorders is decreased sleep quality, which reflects not only total sleep time but also the consistency of sleep continuity, sleep depth, and the integrity of rapid eye movement (REM) and non‐REM cycles. Insomnia and sleep fragmentation primarily disrupt sleep continuity, while circadian rhythm disorders impair sleep timing and architecture, all of which contribute to poor restorative sleep quality. These disturbances degrade sleep quality by impairing memory consolidation, altering neurotransmitter balance, and decreasing the efficiency of glymphatic and autophagy‐mediated clearance pathways.249, 250, 251 Thus, sleep quality serves as a unifying concept that connects various sleep disorders to shared mechanisms of brain disorders, providing a coherent foundation for understanding how sleep disruption, whether through deprivation, fragmentation, or REM loss, compromises proteostasis and increases the risk of AD.

According to the International Classification of Sleep Disorders, sleep disorders include insomnia, hypersomnolence, circadian rhythm disorders, parasomnias, and sleep‐related movement disorders.252 Sleep deprivation and sleep fragmentation are important components of sleep disorders and are associated with anxiety, poor cognition, and impaired brain performance.28, 143, 253 Sleep plays a crucial role in memory processing and neurological health, primarily by regulating a wide array of neuroanatomical and neurochemical systems, including acetylcholine, dopamine, noradrenaline, serotonin, histamine, and hypocretin.254, 255

Sleep is a key component for better brain maintenance and health, and sleep disturbances are associated with an increased risk of developing AD. A meta‐analysis of 27 observational studies found a 1.68‐fold increased risk of AD and cognitive impairment in individuals with sleep difficulties.256 Multiple studies have demonstrated the effect of sleep deprivations on AD pathologies like Aβ and tau accumulations in both animal models and humans.257, 258, 259 Both sleep deprivation and sleep fragmentation have been shown to increase Aβ and tau accumulations by dysregulating autophagy mechanisms in AD mouse models.260, 261, 262, 263, 264 Approximately 45% of AD patients report sleep disturbances, suggesting a bidirectional relationship between sleep and AD.265, 266 Sleep deprivation often occurs before cognitive decline, making it a potential early biomarker and therapeutic target.267, 268, 269, 270, 271

A cross‐sectional study on 4425 cognitively unimpaired participants showed an increased risk of Aβ deposition with reduced night‐time sleep.272 Even one night of sleep deprivation raises chronic sleep deprivation Aβ levels by over 30%,222, 273 and partial chronic sleep deprivation elevates cerebrospinal fluid orexin, a regulator of sleep–wake cycles.274, 275 Other systematic reviews further confirm sleep disturbances significantly raise dementia risk.276, 277

Animal models demonstrate that sleep deprivation exacerbates memory loss, synaptic damage, and tau pathology while also increasing insoluble tau and glial activation markers.258 More recent evidence has shown that sleep has a direct role in regulating the clearance of metabolic waste, including Aβ, from mice brains.278 The close link between AD pathogenesis and sleep deprivation is further supported by findings showing that Aβ and tau commonly accumulate in the suprachiasmatic nucleus and lateral hypothalamic areas of brain regions critically involved in the regulation of sleep–wake cycles.279 While mounting evidence implicates disturbed sleep or lack of sleep as a risk factor for AD, the etiologic role of sleep in AD pathogenesis and neuroprotective pathways associated with sleep intervention remains to be fully understood.

Building upon the established association between sleep quality and AD risk, emerging evidence highlights that sleep also directly regulates autophagic activity and protein homeostasis in the brain. Like autophagy, a cellular clearance pathway, sleep serves as a physiological process that clears unwanted and accumulated proteins from the brain and other parts of the body, thereby maintaining protein homeostasis.3, 280 Sleep cycles or circadian rhythms play a prominent role in regulating clearance and the protein homeostasis mechanism.280, 281 Mammalian sleep comes in two electrophysiological and metabolic states. REM sleep is observed in mammals and birds and associated with high brain‐metabolic demands, nearly indistinguishable from wakefulness.264, 282 REM sleep is key for new memory formation and a healthy brain. REM sleep is known to be altered in most of the neurodegenerative diseases.264, 283 Furthermore, REM sleep deprivation is known to affect brain excitability, neurogenesis, synaptic pruning, and memory consolidation264 (Figure 4).

Animal studies show that REM sleep is necessary for maintaining protein homeostasis and promoting autophagy via AMPK phosphorylation, which activates the TSC1/TSC2 complex and inhibits mTOR activity to initiate autophagosome formation.262, 264 Disturbances in REM sleep disrupt Ca²⁺‐dependent CaMKKβ‐AMPK signaling, dysregulating autophagy and increasing vulnerability to neurodegeneration.247, 264, 284 Because sleep and circadian rhythms are closely linked, autophagy shows significant diurnal variation: Circadian genes peak during the sleep phase and upregulate autophagy‐related transcription, enhancing metabolic waste clearance and maintaining proteostasis.143, 147, 232 Disrupted sleep thus influences both the activation of autophagy pathways and the timing of their circadian regulation.

In animal models, poor sleep quality, including sleep fragmentation and sleep deprivation, consistently impairs autophagic flux and lysosomal function.285 Fragmented sleep disrupts the endosome—autophagosome–lysosome axis, alters LC3 cycling (Table 3), and suppresses normal circadian oscillations of autophagy proteins in the hippocampus, indicating early neurodegenerative dysfunction.260, 263, 286 Mitochondrial quality control is also impacted, with mitophagy pathways such as PINK1/Parkin shifting based on metabolic demand between sleep and wake states,287 linking sleep disruption to impaired proteostasis. Furthermore, two‐photon imaging has revealed that autophagosome formation follows a circadian pattern independent of feeding behavior, confirming sleep's regulatory control over neuronal autophagy.138 Sleep deprivation has far‐reaching consequences for the body (Table 3). Sleep deprivation activates AKT/mTOR signaling in the liver and suppresses autophagy,288 whereas obstructive sleep apnea causes oxidative stress, endothelial dysfunction, hypoxia, and ER stress, all of which can lead to maladaptive autophagy responses.289, 290, 291, 292 Sleep‐deprivation‐induced thyroid injury has also been linked to imbalanced autophagy and apoptosis,288 though whether these peripheral autophagy abnormalities contribute to AD pathology is unknown.

Pharmacological sleep modulators provide additional mechanistic insight. Melatonin, a key circadian regulator, promotes autophagy by activating AMPK and mTOR‐dependent pathways, providing neuroprotection in AD models.293, 294 Pinocembrin promotes BNIP3‐mediated mitophagy during intermittent hypoxia,295, 296 whereas propofol appears to suppress excessive autophagy and mitophagy during sleep deprivation stress, improving cognitive outcomes.297 However, propofol's effects are likely to involve both autophagy modulation and restoration of GABAergic excitatory/inhibitory balance, emphasizing the difficulty of interpreting its mechanisms.298 Nonetheless, considering that propofol predominantly functions as a GABA receptor agonist and that the concentrations necessary for GABAergic activation are significantly lower than those affecting autophagy, its cognitive advantages may also pertain to the reestablishment of the excitatory/inhibitory (E/I) equilibrium. Recent evidence indicates that the GABAergic system, the principal inhibitory neurotransmitter network and a crucial regulator of excitatory/inhibitory balance, is significantly disrupted in AD, exacerbating synaptic dysfunction and disease advancement.299 Thus, the beneficial effects of propofol may result from a combination of autophagy regulation and correction of GABAergic dysfunction underlying E/I imbalance in AD. Additional modulators, including hydrogen sulfide, suppress pathological autophagy and improve cognitive function in sleep‐deprived animals.300 Notably, autophagy responses to sleep modulation appear to be state‐dependent: Sleep induction promotes autophagic flux in physiological conditions, whereas sleep deprivation has varying effects depending on circadian timing and cellular stress.301 Although these studies show neuroprotective actions of sleep modulators, their mechanisms of action and specific targets need to be validated, and, more importantly, how they modulate autophagy to protect against AD neurodegeneration still needs to be elucidated.

These findings suggest that sleep, specifically sleep quality and REM integrity, plays an important role in regulating autophagy, mitophagy, and protein clearance. Although, these studies show neuroprotective actions of sleep modulators, their mechanisms of action and specific targets need to be validated and more importantly how they modulate autophagy to protect against AD neurodegeneration still needs to be elucidated. However, significant knowledge gaps exist regarding the relative contributions of different sleep stages, the directionality of sleep–autophagy interactions in early AD, and the extent to which peripheral autophagy alterations influence CNS pathology. These uncertainties highlight the need for additional mechanistic studies, ideally combining circadian biology, autophagy flux measurements, and AD‐relevant models, to better understand how improving sleep quality can restore proteostasis and reduce neurodegeneration.