Cyclooxygenase (COX) plays a key role in the synthesis of prostaglandin E2 (PGE2) from arachidonic acid (Zhu et al., 2025). COX has three isoforms: COX-1, COX-2, and COX-3. COX-2 is a potent enzyme that, upon stimulation by various inflammatory factors such as cytokines and bacteria, can trigger inflammation and promote prostaglandin synthesis (Yang et al., 2020). Its elevated levels are closely associated with the onset of AD (Moussa and Dayoub, 2023). Research indicates that its dysregulation may lead to abnormal cleavage of the APP (Qin et al., 2003; Guan and Wang, 2019), even creating a vicious cycle (Quadros et al., 2003). Exercise can inhibit the COX-2 pro-inflammatory pathway. Studies indicate that exercise significantly reduces COX-2 activity, potentially exerting therapeutic effects on vestibular migraine by suppressing COX-2-mediated inflammation (Lee et al., 2015). Moreover, moderate-intensity exercise can also reduce levels of COX-2 and APP (Pahlavani, 2023). This provides a theoretical basis for the potential therapeutic effect of exercise on AD by inhibiting COX-2, thereby preventing abnormal cleavage and the level of the APP. It also offers a direction for future research. Investigating whether exercise can indeed inhibit COX-2 in AD models, effectively prevent abnormal cleavage of APP, and reduce pathological products such as Aβ plaques may become a key focus for future research.

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has long been recognized as a crucial enzyme in energy metabolism, generating ATP and pyruvate through anaerobic glycolysis in the cytoplasm (Nicholls et al., 2012). Recent studies have progressively elucidated the crucial role of GAPDH in non-metabolic processes. Whether it is promoting the antitumor immune activity of CD8 T cells (Wang X. et al., 2024), acting as a housekeeping gene with oncogenic effects across various cancers (Wang J. et al., 2023), or participating in the heme maturation of myoglobin and hemoglobin, these findings reveal its significant biological importance beyond metabolic functions. In the pathogenesis of AD, GAPDH also plays a pivotal role (El Kadmiri et al., 2014). Research indicates that GAPDH can form high-affinity interactions with APP, which may be responsible for impaired glycolytic function in AD and could ultimately lead to cell death (El Kadmiri et al., 2014; Ahmad et al., 2023). However, limited research indicates that exercise can prevent the upregulation of GAPDH (Zhao et al., 2012). However, whether this mechanism can reduce the interaction between GAPDH and APP, thereby delaying the progression of AD, remains to be further investigated. Metabolism is a complex, multi-pathway biological process. To determine whether exercise can regulate APP by inhibiting GAPDH upregulation, it is necessary to observe whether GAPDH-APP interactions are weakened post-exercise, assess downstream GAPDH responses, and examine whether related metabolic processes like glycolysis regain function. Concurrently, monitoring changes in APP processing and assembly into Aβ is also essential.

β-amyloid precursor protein-cleaving enzyme 1 (BACE-1) is a novel type I transmembrane aspartic protease essential for the generation of Aβ peptides in AD (Venugopal et al., 2008; Singh et al., 2022a). BACE-1 is widely distributed throughout the central nervous system (CNS) and exhibits all functional characteristics of a β-secretase, acting as the key enzyme initiating Aβ formation (Luo et al., 2016) Increased neuronal BACE-1 activity is believed to promote the production of Aβ and the formation of amyloid plaques in the brains of AD patients (Singh et al., 2022b). BACE-1 cleaves the APP into soluble APP and the membrane-bound C-terminal fragment C99, a rate-limiting step. C99 is further cleaved by γ-secretase to produce Aβ (Gehlot et al., 2022). The beneficial effects of exercise on AD likely also stem from its regulation of BACE-1. Studies indicate that treadmill exercise (TE) prevents PS2 mutation-induced memory deficits and reduces Aβ-42 deposition by inhibiting β-secretase and its product C-99 in the cortex and/or hippocampus of aged PS2 mutant mice (Kang et al., 2013). This partially explains exercise’s inhibitory effect on BACE-1, indirectly suggesting that exercise may effectively regulate the processing changes of APP. However, current research evidence remains insufficient and requires further clarification and validation. For instance, experimental investigation into whether the non-amyloidogenic pathway is activated and experiments such as measuring APP content and APP gene transcription expression levels would enhance our understanding of the underlying mechanisms.

Cathepsins are a class of proteases found within cells of various animal tissues and constitute major members of the cysteine protease family. Approximately 11 cathepsin isoforms are primarily present in the human body, with cathepsins B, D, E, and others having been demonstrated to be closely associated with AD pathogenesis. Cathepsins B, D, and E are all capable of metabolically degrading Aβ peptides. Among these, cathepsin D has been observed to cleave APP100-FLAG near the C-terminal end of the Aβ peptide. Meanwhile, cathepsin B exhibits high carboxypeptidase activity under low pH conditions. Therefore, the possibility that cathepsins D and B participate in the amyloid processing of APP cannot be ruled out (Mackay et al., 1997). Numerous studies have demonstrated that exercise can increase peripheral tissue protease B levels and improve cognitive function (Gökçe and Gün, 2023). However, whether cathepsins are involved in the process by which exercise improves cognitive function requires further research to elucidate.

Extracellular signal-regulated kinase (ERK) is a member of the mitogen-activated protein kinase (MAPK) family. CAMP response element-binding protein (CREB), which selectively binds to cAMP response elements (CRE) and regulates gene transcription in various cells, including dopaminergic neurons (Zhen et al., 2023). The ERK/CREB pathway has been increasingly elucidated to play a crucial role in the nervous system. Its function in mediating neurotrophic factors and exerting neuroprotective effects has been widely recognized (Grimes et al., 2015). ERK/CREB signaling regulates synaptic protein expression and learning and memory functions (Peng et al., 2010; Wang J. et al., 2023). The progression of AD is often accompanied by memory decline. A study on treadmill exercise has also demonstrated that it can effectively activate the ERK/CREB pathway (Seo et al., 2021). Although this study is limited to investigating signaling pathways and does not further clarify whether exercise can improve memory by activating the ERK/CREB pathway, it strongly suggests that exercise may enhance memory through this pathway. ERK is closely associated with APP, which was discovered long ago to potentially regulate ERK signaling (Venezia et al., 2006). Subsequent studies have further revealed that Ginsenoside Rg1 promotes non-amyloidgenic cleavage of APP via estrogen receptor signaling to MAPK/ERK (Shi et al., 2012). Additionally, studies have revealed that presenilin not only influences the processing of APP and the generation of Abeta, but also modulates the activity of the ERK through a protein kinase C alpha-dependent mechanism (Dehvari et al., 2008). This further adds to the complexity of the relationship between ERK and APP. Meanwhile, CREB has been found to exert transcriptional regulation over PEN-2, a key component of the γ-secretase complex (Wang et al., 2006). Not only ERK protein, but also the activation of the ERK/CREB pathway has been elucidated in studies as a crucial intermediate step in the non-amyloid cleavage and metabolism of APP (Guo et al., 2017). Therefore, exercise may exert potential therapeutic effects on AD by promoting the non-amyloid cleavage and processing of APP through effective activation of the ERK/CREB pathway. This warrants further investigation and validation by researchers in their studies.

Fractures rank among the most common sports injuries. An intriguing question arises: Could sports-related fractures alter the assembly of APP, leading to abnormalities in learning, memory, and cognitive function and potentially even AD? This curiosity drives researchers and may concern fracture patients. While current research remains limited, existing studies offer some preliminary insights into this question, that it may affect cognitive function (Guo et al., 2014). Clinical studies directly reveal that among hip fracture patients without dementia, 88.6% of cognitively normal individuals exhibit partial or complete abnormalities in indicators such as the Aβ42/40 ratio, p-tau, and t-tau (Oh et al., 2018). Moreover, more in-depth research has focused on APP, revealing a potential shared molecular pathway in disease progression between femoral neck fractures, osteoporosis, and AD by investigating the close relationship between APP genes and bone remodeling genes such as TRAP and RANKL (Stapledon et al., 2021). Of course, current research has not revealed whether changes in the APP processing and assembly process occur during the injury itself or during the subsequent repair process. This research question presents numerous challenges awaiting breakthrough solutions. Among these, how to eliminate other influencing factors and determine whether fracture injury is one of the primary factors causing changes in APP assembly is a key issue requiring resolution. Additionally, the process of APP assembly changes as injury occurs and recovery progresses is a fascinating topic equally worthy of in-depth investigation.

Osteoporosis is a common disease that contributes to sports injuries. Previously, we often believed that this condition primarily affected the elderly or postmenopausal women (Johnston and Dagar, 2020; Walker and Shane, 2023). However, with the continuous evolution of lifestyle habits, osteoporosis has shown a trend toward younger onset, and the management of younger patients has become a difficult challenge to address (Herath et al., 2022; Ishimoto and Shah, 2024). We note that previous studies have found significantly elevated levels of Aβ in bone tissue affected by osteoporosis (Downey et al., 2017; Duan et al., 2023). Osteoporosis may also affect cognitive function (Zhao et al., 2023). This establishes a link between osteoporosis and Aβ, thereby paving the way for further investigation into the potential relationship between osteoporosis and AD (Wang H. S. et al., 2024; Nasme et al., 2025). However, this potential link remains uncertain unless elevated levels of Aβ are simultaneously detected in brain tissue from individuals with osteoporosis. This finding also suggests that osteoporosis may influence Aβ levels by affecting the assembly process of APP. While current research has not elucidated the underlying mechanisms, it points the way for future investigations.

Muscle injuries rank among the most common conditions resulting from sports-related trauma. This category encompasses numerous distinct types of injuries. Among them, muscle strains are relatively more prevalent and generally easier to recover from. This group also includes more severe conditions like rhabdomyolysis, which can cause multi-organ involvement. Many such cases involve irreversible damage and tend to have a relatively slow recovery process (Guerrero-Hue et al., 2023; Nathan, 2023). Research indicates that muscle strains may lead to cognitive impairment (Guéniot et al., 2020). The connection between muscle mass and Aβ is strong. From a clinical research perspective, greater thigh muscle mass is associated with a lower risk of Aβ positivity in women (Kang et al., 2022). From a basic research perspective, intracellular accumulation of Aβ leads to Ca²⁺ dysregulation in skeletal muscle (Lopez and Shtifman, 2010). Moderate exercise can aid skeletal muscle energy metabolism, but inappropriate exercise may lead to certain traumatic injuries (Baumert et al., 2016; Yook and Cho, 2017). During this process, certain metabolic pathways may be disrupted. Recent research has focused intensely on the close association between exercise-induced myopathy and Aβ deposition. Findings suggest a potential strong link between severe exercise-induced myopathy and tissue infiltration by amyloid deposits in skeletal muscle (Appelman et al., 2024). APP, as the precursor of Aβ, is located at the base of the postsynaptic folds of the neuromuscular junction and is regulated by the neurotrophic factor neurotrophic factor-1 (NRG1). NRG1 causes a reduction in APP mRNA levels while simultaneously decreasing steady-state protein levels (Rosen et al., 2003). In skeletal muscle, the absence of NRG1 leads to the loss of neuromuscular synapses (Liu et al., 2019). Interestingly, NRG1 expression increases within the first 48 h after muscle injury, aiding in the remodeling and recovery of both presynaptic and postsynaptic regions (Pimentel Neto et al., 2025). This implies that during the initial phase of muscle injury, APP expression is likely influenced by increased NRG1 expression, resulting in a decrease in its levels. Whether APP levels rebound after 48 hours and whether Aβ deposition increases remains to be further investigated and discovered. For severe exercise-related muscle injury diseases such as rhabdomyolysis, the connection between these conditions and Aβ deposition represents an intriguing research direction; however, currently reported studies in this area remain limited.

The variety of diseases caused by exercise injuries is extensive, making it difficult to list them all in detail. Among these, some diseases may exhibit alterations in the APP processing pathway during their progression. Currently, most research on these diseases lacks findings that directly clarify the relationship between APP processing, Aβ generation and deposition, and disease progression. However, we can still discern a close connection between these diseases and cognitive impairment from a few studies, such as those on lumbar disk herniation (Luo et al., 2025). This underscores the value and significance of investigating mechanisms related to APP and Aβ (Figure 3).