Alzheimer's disease (AD), the leading cause of dementia, is characterized by irreversible cognitive decline. AD currently affects ~55 million people globally, a number projected to nearly triple by 2050 (1). Despite its prevalence, no effective treatments or preventive measures exist, and a comprehensive understanding of its pathogenesis remains elusive (1-3). The hallmarks of AD include extracellular amyloid β-protein (Aβ) plaques and neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau (p-tau) (4). Aβ plaques disrupt inter-neuronal communication (5) and trigger neuroinflammation, while NFTs impair neuronal function by affecting axoplasmic transport and disrupting the cytoskeleton (6). Therapeutic strategies targeting the amyloid cascade or p-tau have yielded unsatisfactory clinical outcomes, indicating the limitations of single-target therapies (7). AD pathology also involves other critical alterations, including neuronal loss, synaptic dysfunction, oxidative stress and aberrant energy metabolism (8-10), which interact synergistically to drive disease progression. While the exact pathogenesis of AD is not fully understood, emerging evidence implicates impaired autophagic clearance as a key cellular mechanism in AD pathogenesis (11) and as a significant influence on its progression (12,13).

Autophagy, an essential intracellular degradation pathway, plays a critical role in clearing damaged organelles and protein aggregates (14-16). This process is significantly impaired in AD (17), manifesting as defects in autophagosome formation and maturation, dysregulated lysosomal function and inefficient autophagosome-lysosome fusion (18). These disruptions compromise the clearance of Aβ and tau proteins, leading to the accumulation of toxic species both inside and outside neurons, which in turn amplifies neuronal injury and cell death (19,20). Autophagy dysfunction also contributes to mitochondrial deficits, oxidative stress and chronic neuroinflammation; it ultimately blocks energy production, disrupts energy utilization and perturbs metabolic homeostasis, thereby disturbing neuronal energy metabolism, impairing synaptic function and promoting apoptosis (21). Thus, strategies aimed at restoring autophagic activity have become a major focus of AD therapeutic research (22).

Over the past few decades, mounting epidemiological and clinical evidence has unequivocally established that regular physical activity confers substantial benefits for the prevention and management of various chronic diseases, particularly cardiovascular diseases, type 2 diabetes mellitus and certain malignancies (for example, breast, colon and liver cancer) (23-25). This evidence provides a framework for developing non-pharmacological interventions in chronic disease management. Beyond non-modifiable factors such as genetic susceptibility (1), physical inactivity is recognized as a significant modifiable risk factor for AD, accounting for ~13% of cases worldwide (26,27). Clinical and preclinical evidence shows that regular exercise not only reduces the risk of AD incidence (28) but also improves cognitive outcomes in patients with AD (29-32). Mechanistically, dysregulated autophagy serves as a key pathogenic driver in AD, and exercise modulates neurodegeneration by regulating autophagic pathways. Reports have confirmed that physical activity significantly promotes autophagic activation, alleviates cerebral neuroinflammation and mitigates AD-related pathological damage in human and animal models, such as transgenic mouse models of AD (33,34). Thus, clarifying the molecular signaling pathways underlying exercise-regulated autophagy in AD is critical for elucidating the core mechanisms of exercise-based interventions and developing targeted therapeutic strategies. Although existing reviews have independently addressed the role of autophagy in AD or the neuroprotective effects of exercise in AD, a systematic overview of the mechanisms by which exercise modulates autophagic signaling pathways to affect AD is lacking. Clarification of this network pathway is required to translate exercise-based interventions from basic research to clinical practice in AD. The current review systematically explores the recent research progress on how exercise influences the autophagy signaling pathway in AD, emphasizing its core molecular mechanisms. The review also assesses the potential synergy between exercise and natural products in AD intervention, offering a theoretical foundation and research direction for the future development and clinical application of exercise-based AD-targeted interventions.

Neuronal autophagy is an essential intracellular degradation system that mediates the delivery and breakdown of cytoplasmic components within lysosomes (35,36). Autophagy is classified into three forms based on the mechanisms of cargo delivery to lysosomes: Macroautophagy, microautophagy and chaperone-mediated autophagy (CMA) (19) (Fig. 1A). The initial step in macroautophagy (commonly termed autophagy) is the formation of a double-membrane vesicle known as the autophagosome (37). This process is regulated by a set of highly conserved autophagy-associated proteins (ATGs) (36). The initial step involves the activation of the UNC 51-like kinase (ULK) complex, consisting of ULK1/2, ATG13, FAK family kinase-interacting protein of 200 kDa and ATG101 (38,39). Subsequent phagophore nucleation requires the class III PI3K complex, which includes vesicular protein sorting 34 (VPS34), VPS15, beclin-1 and ATG14L (38). Phagophore expansion and autophagosome maturation depend on two ubiquitin-like conjugation systems: One results in the ATG5-ATG12-ATG16L complex that facilitates membrane elongation, and the other conjugates phosphatidylethanolamine to microtubule-associated protein 1 light chain 3 (LC3), generating the lipidated form LC3-II that associates with autophagosomal membranes (40). These steps are critical for autophagosome biogenesis, cargo recognition and eventual fusion with lysosomes to form autolysosomes (38).

By contrast, microautophagy involves the direct engulfment of cytoplasmic material through lysosomal membrane invagination (41). CMA, a selective process, recognizes substrate proteins via the chaperone heat shock cognate 70-kDa protein bearing a Kex2-Fer1-Endo U1-Qc-2 motif and translocates them into lysosomes through lysosomal-associated membrane protein 2A (LAMP2A) (19,37,38). CMA deficiency has been linked to exacerbated AD pathology (42). Nutrient deprivation typically induces non-selective autophagy, whereas selective autophagy targets damaged organelles such as mitochondria and peroxisomes, as well as protein aggregates (37,43) (Fig. 1B). Selective autophagy is mediated by receptors such as p62, nuclear dot protein 52, optineurin (OPTN), next to BRCA1 gene 1 and tax1 (human T-cell leukemia virus type I) binding protein 1, which contain a ubiquitin-binding domain and LC3 interaction region that connect ubiquitinated cargo to the autophagic machinery (37,44,45).

Autophagic flux and the expression of lysosome-associated proteins are significantly reduced in both patients with AD and AD animal models (46). This dysregulation is hypothesized to contribute to AD pathogenesis by impairing multiple steps in the autophagy-lysosome pathway, from autophagosome formation to lysosomal degradation (47). In brains affected by AD, neuronal autophagy is disrupted at the initiation phase, partly due to mammalian target of rapamycin (mTOR) hyperactivation, which suppresses the ULK1 complex and impedes autophagosome biogenesis (48,49). Moreover, mutations and the downregulation of autophagy-related genes have been linked to AD. For example, beclin-1 expression is markedly decreased in AD-affected brains (50,51), and beclin-1-deficient microglia in AD models have been reported to exhibit impaired phagocytosis and reduced Aβ clearance (52). LC3, a key autophagosomal membrane protein, shows altered processing in AD, with reduced conversion of LC3-I to LC3-II, thereby inhibiting autophagy initiation (53). Emerging evidence also implicates non-canonical autophagic processes [e.g., LC3-associated phagocytosis (LAP) and LC3-associated endocytosis (LANDO)] in AD pathology, and this pathway has been discovered in microglia of the brain and the central nervous system. LANDO deficiency exacerbates neurodegeneration and cognitive deficits in AD mice (54,55). The mechanisms of LAP and LANDO are distinct from those of autophagy (54). However, no current evidence exists on how exercise affects these pathways. Therefore, the present review will not elaborate further on these processes.

Lysosomal dysfunction further aggravates autophagic impairment in AD. Decreased autolysosomal acidification occurs prior to extracellular Aβ deposition (17), leading to defective proteolysis, increased lysosomal membrane permeability (56,57) and impaired cathepsins, which are lysosomal proteases essential in Aβ and tau clearance (58,59). Notably, Aβ accumulation both results from and exacerbates lysosomal dysfunction, creating a vicious cycle that promotes neurodegeneration (60). Restoring lysosomal function enhances the clearance of Aβ and p-tau (57). The autophagy receptor sequestosome 1 (SQSTM1/p62), which facilitates cargo delivery to LC3, exerts protective effects in AD models by improving memory and modulating autophagic activity (61,62).

Transcription factor EB (TFEB), a master regulator of autophagy-lysosomal biogenesis, plays a critical role in AD (63-65). The activity of TFEB is inhibited by mTOR complex 1 (mTORC1); however, TFEB-mediated endocytosis is essential for mTORC1 activation and autophagy function (57,66). Oxidative stress also contributes to AD progression by promoting the amyloidogenic processing of amyloid precursor protein (APP) and tau hyperphosphorylation (67). Reactive oxygen species (ROS) accumulation damages mitochondria, leading to dysfunction that triggers mitophagy, a selective autophagic process essential for maintaining mitochondrial quality (45,68). Collectively, these disruptions in the autophagy-lysosome pathway significantly exacerbate AD pathology (63,69,70).

Considering the pivotal role that autophagy dysfunction plays in the development of AD, restoring compromised autophagic flux has become a promising approach for therapy. Among the different interventions available, exercise is as a non-pharmacological treatment that is safe, cost-effective and easy to implement. Recent studies have reported the significant potential of exercise to regulate autophagy and ameliorate AD pathology (71,72). The subsequent sections focus on the ways in which exercise serves as a potential modulator to restore autophagic homeostasis in AD.

Exercise provides a multi-targeted physiological intervention strategy to address the complex autophagy dysfunction aforementioned. Preclinical studies have shown that exercise can improve memory, promote neurogenesis, and enhance hippocampal structure and synaptic plasticity in AD transgenic mouse models [e.g., APP/presenilin 1 (PS1) and proline-301-serine (P301S)] (73,74). Both human and animal studies have shown that a wide range of physical activities, ranging from low-intensity walking to high-intensity training, support cognitive health (75,76). For example, adolescents performing treadmill exercises demonstrated significant cognitive improvements, particularly at moderate to high intensity exercise (28).

In one study, 16 weeks of voluntary running significantly improved autophagy dysfunction in mice with five familial Alzheimer's disease mutations (5xFAD transgenic mice) and exerted neuroprotective effects (77). Notably, more recent studies demonstrated that moderate-intensity exercise was more effective in modulating brain autophagy in AD models than low or high-intensity exercise, whereas low-intensity exercise was associated with higher AD risk, and very high intensity increased oxidative stress (78-82). Aerobic exercise modalities, such as treadmill running, voluntary wheel exercise and swimming, were shown to specifically facilitate the autophagy-mediated clearance of pathogenic proteins (82,83).

Exercise enhances autophagic activity through multiple pathways. In APP/PS1 mice, 12 weeks of aerobic treadmill exercise restored autophagy-lysosomal flux, increased autophagosome numbers in the hippocampus and cortex, promoted Aβ clearance, and improved cognitive performance (71,84,85). Similarly, extended treadmill exercise reduced tau pathology in P301S mice, and autophagy was shown to play a crucial role in tau degradation through a ubiquitin-mediated mechanism (84,86). Exercise also upregulates the expression of core autophagy-related proteins such as LC3-II and beclin-1, as observed following both high intensity interval training (HIIT) and moderate intensity continuous training (MICT) (78). However, a separate animal study reported no significant changes in LC3, p62 or beclin-1 in whole hippocampal lysates after HIIT, suggesting that HIIT has specific effects on brain regions or motor programs (81).

In summary, preclinical studies consistently confirmed that moderate-intensity exercise enhances autophagic flux, particularly in the hippocampus of AD model mice, in a manner associated with spatial memory improvement. These preclinical findings underscore a bidirectional, functionally significant relationship between exercise and autophagy in AD.

Exercise exerts neuroprotective effects against AD primarily by restoring impaired autophagy flux, which serves as a pivotal link between exercise-induced signaling activation and the amelioration of AD-specific pathological phenotypes. A well-orchestrated causal chain underpins this process. Exercise triggers the activation of key signaling pathways [(mTOR, sirtuin 1 (SIRT1) and adiponectin (APN) receptor 1 (AdipoR1)] and the modulation of microRNAs (miRNAs/miRs)/irisin, which in turn corrects defects in autophagosome biogenesis, lysosomal function and autophagosome-lysosome fusion. This restoration of physiological autophagic flux directly enhances the clearance of neurotoxic Aβ aggregates and p-tau, mitigates chronic neuroinflammation, preserves mitochondrial integrity by improving mitophagy and rescues synaptic dysfunction (87). In summary, these effects alleviate neuronal damage and apoptosis, and ultimately improve cognitive function in AD models and patients. Notably, the regulatory effect of exercise on autophagy is not mediated by a single mechanism but is achieved through complex crosstalk between signaling pathways and a cooperative regulatory network. These interactions have not been fully elucidated and analyzing them can be helpful in understanding the overall neuroprotective effect of exercise.

Given the complexity of AD pathology, single-target therapies often fail in clinical trials. AD drug development projects are targeting multiple mechanisms (1). Natural products derived from herbal or dietary sources (e.g., curcumin, catechins and quercetin) have shown favorable safety profiles and multi-target efficacy in clinical studies focused on AD (137). For instance, quercetin and curcumin have entered phase II clinical trials and have significantly demonstrated improvements in cases of mild cognitive impairment (1). These studies highlight the essential role of natural products in treating AD. Additionally, a number of studies have shown the effects of natural products in regulating autophagy in AD (138-140). For instance, Esculentoside A is a kind of triterpene saponin isolated from Phytolacca esculenta that activates the autophagy pathway in an AMPK-dependent manner, thereby promoting the clearance of p-tau and alleviating cognitive decline in 3xTg-AD mice (138). Ginsenoside Rg2, a steroidal glycoside derived from Panax ginseng, activates autophagy via AMPK-dependent but mTOR-independent signaling pathways. This activation facilitates the clearance of Aβ aggregates and enhances cognitive function in 5xFAD transgenic mice (139). Notably, only a few studies have focused on the synergistic effect of exercise and natural products in the autophagy regulation of AD. Consequently, the following review section will focus on representative natural products in AD research. Their synergistic effects and underlying mechanisms in regulating autophagy and alleviating AD pathology upon combination with exercise will be systematically summarized.

AD is a devastating neurodegenerative disorder with no curative treatments. Autophagy dysfunction is a key pathogenic driver underlying the accumulation of neurotoxic Aβ aggregates, p-tau, neuronal loss and synaptic impairment. The present review systematically highlights current evidence demonstrating that mild-to-moderate intensity physical exercise represents a safe, cost-effective and multi-targeted non-pharmacological intervention for AD (Table I; Fig. 5). Specifically, exercise restores impaired autophagic flux in AD by modulating core signaling pathways (mTOR, SIRT1 and AdipoR1), regulating miRNAs such as miR-34a and miR-130a, and upregulating irisin. These regulatory effects collectively enhance autophagosome biogenesis, improve lysosomal function and promote autophagosome-lysosome fusion, thereby facilitating the clearance of Aβ and p-tau, alleviating neuroinflammation and mitochondrial dysfunction, and ultimately ameliorating cognitive deficits in both preclinical AD models and clinical settings. Additionally, combining exercise with natural products (e.g., resveratrol and luteolin) exerts synergistic neuroprotective effects by enhancing autophagy-mediated clearance of pathological proteins, highlighting a promising multi-modal intervention strategy for AD.

Despite this valuable insight, this review has several specific limitations that warrant acknowledgment. First, while the roles of key signaling pathways (mTOR, SIRT1 and AdipoR1) in exercise-mediated autophagy regulation are summarized, molecular crosstalk among these pathways (e.g., the AMPK-mTOR-SIRT1 regulatory axis) remains incompletely elucidated, and how exercise coordinates these interconnected networks to fine-tune autophagic flux demands the further integration of multi-omics data. Second, this review did not address the potential regulation of non-canonical autophagic pathways (e.g., LAP and LANDO) through exercise due to limited existing experimental evidence. These pathways have been implicated in AD pathology but remain a critical knowledge gap in the field. Third, the miRNA regulatory network underlying exercise-induced autophagy restoration remains incompletely understood, with only a handful of miRNAs (e.g., miR-34a and miR-130a) characterized, and interactions between miRNAs and irisin/FNDC5 in AD remain largely unvalidated. Fourth, preclinical studies on combinations of exercise and natural products are scope-limited, and data on the optimization of key parameters are lacking, including natural product dosage, exercise intensity and intervention timing (e.g., pre- or post-exercise supplementation), which hinders the translation of these synergistic effects into clinical practice. Finally, the current evidence is predominantly derived from rodent models, and the generalizability of these mechanisms to human AD populations, particularly across different disease stages and genetic backgrounds, remains to be fully established.

Future research should focus on novel, practical and translationally relevant directions to address these gaps and advance the field. Leveraging single-cell RNA sequencing and spatial metabolomics to dissect cell-type-specific mechanisms of exercise-regulated autophagy (e.g., in neurons, microglia and astrocytes) will yield unprecedented insight into cell-cell communication networks underlying neuroprotection. High-throughput CRISPR screening can identify uncharacterized miRNAs or long non-coding RNAs that link exercise and autophagy regulation, facilitating the development of targeted nucleic acid-based therapeutics (e.g., miRNA mimics or inhibitors) for combination with exercise interventions. Large-scale stratified clinical trials are urgently needed to establish personalized exercise prescriptions, using peripheral biomarkers (e.g., serum irisin and TFEB) to tailor exercise intensity, duration and modality for individual patients with AD or high-risk populations. Integrating network pharmacology and in vitro high-throughput assays to identify shared molecular targets of natural products and exercise (e.g., the AMPK-SIRT1-TFEB axis) will expedite the development of combination preclinical strategies with optimized synergistic efficacy. In addition, genetically engineered AD mouse models will clarify the role of non-canonical autophagy (e.g., LAP and LANDO) in exercise-mediated neuroprotection, filling a critical knowledge gap in the current literature. Finally, exploring the long-term sustainability of exercise-induced autophagy restoration and its impact on AD progression (e.g., delaying conversion from mild cognitive impairment to clinical AD) will provide critical evidence to support the integration of exercise into routine clinical care.

In summary, exercise is a potent intervention to counteract autophagy dysfunction in AD, supported by preclinical and clinical evidence of its neuroprotective effects. Addressing the aforementioned limitations and pursuing innovative, translationally focused research directions will further unravel the mechanistic complexity of exercise-autophagy crosstalk and enable the development of more effective, personalized strategies for AD prevention and management. Given the current challenges in AD drug development, integrating exercise alone or its combination with natural products into clinical practice holds considerable theoretical significance and potential for improving patient outcomes.