Given the accelerating aging of the population, mortality attributable to cardiovascular and cerebrovascular diseases among older adults has increased [1]. Cardiovascular and cerebrovascular diseases—including heart failure, hypertension, coronary heart disease, and stroke—remain a major global health challenge and impose a substantial burden on healthcare systems [2, 3]. Although age, obesity, smoking, alcohol misuse, physical inactivity, cognitive dysfunction, and diabetes are well-documented risk factors for cardiovascular and cerebrovascular mortality, specific biomarkers that reliably predict these risks in older adults remain limited [4, 5, 6].

The albumin-to-alkaline phosphatase ratio (AAPR), an emerging and promising biomarker, is increasingly used in clinical practice and scientific research [7]. Accumulating evidence indicates that AAPR may serve as a valuable predictor of prognosis for several malignancies, including hepatocellular carcinoma, lung cancer, and renal cell carcinoma [8, 9, 10]. Albumin (ALB), primarily synthesized in the liver, is a significant component of serum proteins. It is crucial for maintaining physiological homeostasis and is frequently depleted during infection, inflammation, or systemic stress [11, 12]. Alkaline phosphatase (ALP) is a ubiquitous enzyme involved in cellular phosphorus metabolism and signal transduction pathways [13]. Clinically, ALP levels are commonly used in the diagnosis and monitoring of disorders affecting the skeletal and hepatobiliary systems.

Prior work has shown that the alkaline phosphatase–to–albumin ratio predicts prolonged harmful results of coronary artery disease with percutaneous coronary intervention (PCI) [14]. Furthermore, emerging data suggest that AAPR has superior predictive performance for cardiovascular mortality and fracture risk compared with traditional bone turnover markers, with higher AAPR levels correlating with improved survival [15, 16]. Notably, Li et al. [17] reported that preoperative AAPR combined with an inflammatory burden index effectively predicted overall survival in patients with rectal cancer.

Studies suggest that AAPR is a potential biomarker for cardiovascular and cerebrovascular mortality [18, 19]. However, evidence supporting this association remains insufficient. Given prior research on AAPR, its ease of accessibility, and computability, we hypothesized that it is related with all-cause and cardiovascular and cerebrovascular mortalities among the elderly people. Therefore, we investigated relationship between AAPR and cardiovascular and cerebrovascular prognosis in individuals aged 60 years and above, as well as potential underlying mechanisms, to provide insight into the utility of AAPR as a risk-stratification tool.

AAPR, a novel biomarker, is a prognostic factor for many malignancies [20, 21, 22]. Previous studies indicate that AAPR is related to bone metabolism and serves as a prognostic biomarker for spinal fusion in patients with lumbar degenerative disease undergoing lumbar spinal fusion [16, 23]. Mathold et al. [15] reported that AAPR influences the prognosis of cardiovascular diseases. However, few studies have systematically assessed the association between AAPR and cardiovascular and cerebrovascular mortality.

No prior literature, to our knowledge, has specifically evaluated the relation between AAPR and all-cause mortality and cardiovascular and cerebrovascular mortality among adults aged 60 years and above, indicating that AAPR is a robust predictor of these outcomes. A negative linear relationship was observed between AAPR and cardiovascular and cerebrovascular mortality (p for nonlinearity = 0.176), suggesting that cardiovascular and cerebrovascular mortality risk consistently decreases with increasing AAPR levels.

Conversely, the link between AAPR and all-cause mortality exhibited an L-shaped curve (p for nonlinearity 0.001). Before the inflection point, the risk of all-cause mortality declined by 16% with every 0.1-unit increase in AAPR. Beyond this threshold, a plateau effect was observed, with no further significant decline in mortality risk despite continued increases in AAPR. These findings were consistently replicated in both male and female subgroups.

Subgroup analysis showed no statistically significant relations between AAPR and most subgroups. However, the interaction effect of AAPR was stronger in males, individuals with lower BMI (24 kg/m²), and patients with liver disease. Regarding gender differences, compared with men, women typically have higher baseline albumin levels (reflecting differences in muscle mass and hormone regulation) and lower alkaline phosphatase levels (reduced bone turnover in women due to postmenopausal hormonal changes) [24, 25]. Alterations in hepatic protein synthesis that reduce albumin are more common in individuals with obesity; thus, AAPR may serve as a more sensitive marker of systemic dysregulation in this population, enhancing its prognostic value [26]. In patients with liver disease, hepatic dysfunction directly impairs albumin synthesis (reducing albumin) and disrupts bile acid metabolism (increasing ALP), making AAPR a direct indicator of liver function in this subgroup [27]. Sensitivity analysis showed that AAPR was an independent risk factor for cardiovascular mortality (p = 0.005), and AAPR was more efficient in predicting all-cause mortality and cardiovascular and cerebrovascular mortality compared with ALB and ALP. We further examined the link of AAPR with all-cause mortality and cardiovascular and cerebrovascular mortality by mediation analysis and found that AAPR influenced these outcomes through effects on BUN, eGFR, MI, heart failure, and stroke. The data originated from the NHANES database (2003–2018), and 13,603 cases were included. Therefore, we believe that applying AAPR to predict the prognosis of all-cause and cardiovascular and cerebrovascular mortality in adults aged 60 years and above is highly credible.

AAPR, the ratio of ALB to ALP, plays a crucial role in cardiovascular and cerebrovascular mortality. On one hand, ALB, the most abundant protein in blood, has multiple physiological functions to maintain osmotic pressure and is involved in oxidative stress responses, anticoagulation, and antiplatelet aggregation [28, 29, 30]. Low ALB reflects malnutrition, liver dysfunction, or inflammatory status [11, 31]. Low ALB reduces fibrinolytic and antioxidant capacities, damages endothelial cells, activates inflammatory responses, and increases the risk of thrombosis, leading to adverse cardiovascular and cerebrovascular events [32, 33]. Some studies suggest that low ALB is significantly related with poor long-term prognosis in patients undergoing PCI, and that preoperative ALB can serve as a clinical predictor of future cardiovascular events in patients with stable coronary heart disease and preserved renal function [34].

On the other hand, ALP is an enzyme widely present in many tissues and is associated with pathological processes, including inflammation, metabolic disorders, and atherosclerosis [35, 36, 37]. High ALP may promote inflammation, affect mineral metabolism, and accelerate atherosclerosis, ultimately leading to cardiovascular and cerebrovascular atherosclerosis [38]. Additionally, Dai et al. [14] reported that ALP was associated with mortality in coronary heart disease, recurrent infarction, and thromboembolic events after PCI. Wang et al. [39] found that ALP was associated with slow flow in patients with coronary heart disease; patients with high ALP were more susceptible to coronary slow flow. High ALP also affected pyrophosphate metabolism, promoted vascular calcification, compromised vascular integrity, and worsened atherosclerosis [40, 41]. Erez et al. [42] reported that ALP, combined with intracranial artery calcification, served as a prognostic predictor in patients with nephropathy undergoing hemodialysis, suggesting that high ALP levels were associated with mortality in chronic kidney disease. Haarhaus et al. [43] characterized ALP as a clinically actionable target for cardiovascular and mineral–bone pathology in the context of chronic kidney disease. Therefore, AAPR comprehensively reflects the levels of albumin and alkaline phosphatase. Low AAPR may indicate a pathological condition associated with aging-related chronic diseases such as heart failure, liver disease, and renal failure, and suggests that chronic inflammation inhibits albumin synthesis, promotes ALP release, and accelerates vascular endothelial injury and atherosclerosis. Consequently, AAPR may serve as a novel prognostic indicator for patients with cardiovascular and cerebrovascular diseases. Clinicians should assess AAPR alongside the overall clinical condition of the patient and rule out reversible factors affecting ALB or ALP to avoid reliance on a single indicator.

The study findings suggest that AAPR can be applied in clinical practice. First, as an easily obtainable prognostic indicator for routine health evaluations and chronic disease management in older adults—derived from standard laboratory tests—it enables risk stratification. Second, as an adjunct to existing risk tools, it can capture concealed nutritional impairments and mild inflammation that traditional scores may overlook, thereby improving predictive accuracy.

One constraint of this study is the reliance on a single initial assessment of AAPR to forecast long-term mortality outcomes. Biological markers such as ALB and ALP can vary over time—for example, with changes in nutritional status or inflammatory processes—and a solitary measurement may not reflect the overall health. A further limitation involves the intrinsic selection bias associated with the NHANES database. Nonresponse bias remains a concern, as individuals who choose to participate are typically more attentive to health, including being more likely to follow medical advice and provide accurate accounts of health-related behaviors, than those who decline participation. Despite comprehensive adjustments for factors influencing outcomes, residual confounding may persist, including genetic predispositions and underreported comorbidities.

Therefore, multicenter, large-scale studies must be performed to further confirm the prognostic value of AAPR in cardiovascular and cerebrovascular diseases, with endpoint events that include MI, heart failure, arrhythmia, stroke, hemorrhagic stroke, and transient ischemic attack. AAPR should be dynamically monitored in accordance with the health status of older adults during routine physical examinations or hospitalizations at community healthcare facilities. Further research must aim to reveal the mechanisms linking AAPR to cardiovascular and cerebrovascular diseases.

AAPR effectively predicts the risks of all-cause mortality and cardiovascular and cerebrovascular mortality in individuals older than 60 years. It could act as a novel prognostic indicator in this population. Clinicians may utilize AAPR to inform treatment planning and follow-up for older patients, thereby improving quality of life.

The datasets that were used and evaluated in this study can be obtained from the corresponding author upon making a reasonable request.

HR and YL: conceptualization, methodology, designed the research study, and wrote the first draft. ZT and MZ: data curation, writing-original draft preparation. LL: analyzed the data by using software, visualization, created figures, and revised the manuscript. SL: supervision, validation, project administration, formal analysis, designed the manuscript and critically revised it. XX: investigation, writing-reviewing and editing, edited part of the paper and reviewed some literature. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

The National Center for Health Statistics and Ethics Review Board approved the protocol for NHANES, and all participants provided written informed Consent. According to Article 32 of the “Ethical Review Measures for Life Sciences and Medical Research Involving Human Beings”, research using legally obtained public data or data generated through observation without interfering with public behavior, as well as research using anonymous information data, does not require ethical approval. Our research meets these exemption conditions as we use legally obtained public data. Our research utilizes anonymous information data, was carried out in accordance with the guidelines of the Declaration of Helsinki and the Ethics Committee of Suining Central Hospital has approved this study for exemption from review, with the ethics number KYLLMC20250032.

The authors express their gratitude to the participants and staff of the NHANES for their invaluable contributions to this study.

This research received no external funding.

The authors declare no conflict of interest.

Supplementary material associated with this article can be found, in the online version, at https://doi.org/10.31083/RCM45049.