As humans age, there is often a decline in cognitive function, which significantly increases the risk of developing mild cognitive impairment and eventually dementia (1). In patients with dementia, cognitive impairment severely impacts quality of life and the ability to live independently (2).

Cognitive impairment has become a major public health issue (3). By the middle of the 21st century, it is projected that the number of individuals with cognitive impairment in the United States will exceed 21 million, while the global number of dementia patients will surpass 150 million (3, 4). This growing trend will impose substantial burdens on individuals, society, and the economy (5).

The relationship between obesity and cognitive impairment is particularly significant (6). Obesity increases the risk of developing Alzheimer’s disease, stroke-related dementia (6, 7). Obesity increases cognitive impairment risk via multiple mechanisms: High-fat diets trigger brain inflammation in areas like the hypothalamus and hippocampus, releasing inflammatory factors that damage neural structures (8–10). This process also causes lipid peroxidation, harming the blood-brain barrier (11). Insulin resistance in the brain impairs glucose use and synaptic function, while leptin resistance and ghrelin imbalance disrupt appetite control and reinforce rewards system sensitivity to fatty foods (12, 13). These mechanisms together reduce gray matter volume in key brain regions, degrade white matter integrity, decrease blood flow, and weaken network connectivity, ultimately worsening cognitive decline and dementia risk (14, 15).

As a core factor maintaining the homeostasis of cerebral oxygen supply, hemoglobin (Hb) participates in the regulation of cognitive function by regulating oxygen metabolism (16). When Hb levels decrease, the oxygen delivery through cerebral blood flow fails to match metabolic demands, which can induce functional impairment of brain cells and accelerate the progression of cognitive decline (16, 17). Red blood cell distribution width (RDW) is significantly correlated with systemic inflammatory response and oxidative stress levels, and these mechanisms are the common core pathophysiological pathways driving aging, obesity, and cognitive decline (18, 19). By integrating the oxygen supply regulatory function of Hb and the inflammation and oxidative stress signals reflected by RDW, hemoglobin-to-red blood cell distribution width ratio (HRR) constructs a multi-dimensional association mechanism with aging, obesity, and cognitive function. As a composite biomarker integrating the core physiological functions of Hb and RDW, HRR can more comprehensively reflect the common mechanisms affecting aging, obesity, and cognitive function including inflammation, oxidative stress, abnormal oxygen metabolism, and nerve damage, thereby overcoming the limitation that a single biomarker can only reflect local pathophysiological processes (14). The HRR has shown promise in predicting various diseases, including depression (20), coronary artery disease (21), stroke (22), osteoporosis (23), and metastatic kidney cancer (24) in recent years.

Notably, research on the HRR and cognitive function remains scarce, particularly among obese individuals aged ≥60 years. We hypothesize that in obese populations, higher HRR correlates with better cognitive performance, independent of confounders like age and comorbidities, potentially mediated by improved cerebral oxygenation and reduced systemic inflammation. This study explores HRR’s association with cognitive function in this group, examining whether elevated HRR acts as a cognitive protective factor–offering new insights into cognitive protection for obese older adults.

The study results show that in obese individuals, higher HRR is associated with better DSST performance and reduced likelihood of scoring below the cognitive impairment threshold. The results of the study suggest that HRR may have a positive effect on certain cognitive functions, particularly in areas like reaction time, attention, and working memory. This highlights the potential of HRR as a biomarker for cognitive function and a tool for identifying individuals at risk for cognitive decline.

With the increase of age, obvious declines occur in multiple specific cognitive domains: processing speed continues to decline, affecting the performance of language fluency and other aspects; complex attention tasks such as selective attention and divided attention decline significantly, and working memory is affected by the slowdown of information processing; episodic memory and semantic memory decline; visual naming and verbal fluency decrease; visual construction ability reduces; abilities such as concept formation, abstract reasoning, mental flexibility and response inhibition in executive function decline (31, 32). The neurochemical properties and anatomical structure of the brain exhibit cumulative changes with age, with a significant decline in dopaminergic neuromodulation (32). The volume of gray and white matter gradually decreases, and the atrophy of polymodal cortical regions is particularly prominent, while the atrophy process of the hippocampus is accelerated by vascular factors (32). There are individual differences in the senescent changes of brain structure, especially the significant differences in the degree of age-related contraction in regions such as the lateral prefrontal cortex, prefrontal white matter, and hippocampus (32).

This study found that the protective effect of HRR on cognitive function was more pronounced in individuals with higher educational attainment, a result that can be theoretically explained by the mediating mechanism of cognitive reserve (33). In studies by Clare et al., educational level has been explicitly identified as a core component of cognitive reserve (33). Cognitive reserve buffers the impact of neuropathological changes on cognitive function by optimizing brain network recruitment strategies or activating alternative cognitive pathways (34). Higher educational attainment is often associated with greater cognitive reserve, which amplifies the protective effects of physiological processes reflected by HRR–such as oxygen supply status and inflammation–on cognition through enhancing neurovascular coupling efficiency or metabolic compensatory capacity (35).

In our study, a positive association between higher HRR and better cognitive performance was observed in obese individuals, but no such relationship was found in non-obese counterparts. This discrepancy may be attributed to the role of obesity in cognitive decline. Obesity is closely linked to various chronic diseases, and its negative impact on the brain is increasingly gaining attention (36). Obesity affects brain function and leads to cognitive decline through mechanisms such as neuroinflammation, oxidative stress, and alterations in the gut-brain axis (9, 36, 37). Anfal Al-Dalaeen et al. pointed out that neuroinflammation, oxidative stress, and reduced local blood flow induced by obesity jointly affect the brain (36). These factors disrupt the metabolic functions of the hypothalamus and the hippocampus, ultimately leading to cognitive impairment (36, 38). Alyson A. Miller et al. further emphasized that systemic inflammation and increased free fatty acids caused by obesity can lead to local inflammation in the hypothalamus, which then affects cognitive-related brain regions, such as the hippocampus and amygdala, thereby exacerbating cognitive decline (38, 39). Sarah-Jane Leigh et al. reviewed the relationship between obesity, high-fat diets, and cognitive impairment, finding that changes in the gut microbiome, systemic and central nervous system inflammation, and alterations in the blood-brain barrier are key mechanisms in this process (10, 37).

In our study, Model 3–adjusted for multiple covariates–still showed that higher HRR was positively associated with better cognitive performance, including higher DSST scores and reduced low cognitive function assessed by DSST, suggesting HRR could act as a biomarker for cognitive function in obese individuals. An increasing number of studies have shown a significant association between hemoglobin levels and cognitive function (40–44). Low hemoglobin levels have been identified as a potential risk factor for cognitive decline (42–48). Yi-Xuan Qiang et al. revealed that anemia is connected to a risk increase of more than 50% for all-cause dementia, with brain structure changes being a potential contributing factor that affects cognitive abilities (49). Laura M. Winchester et al. pointed out that lower hemoglobin levels were significantly associated with cognitive decline, particularly in the domains of reaction time and reasoning abilities (48). Andrea L. C. Schneider et al. also found that lower hemoglobin levels were negatively correlated with cognitive domains such as processing speed, attention, and working memory, as assessed by the DSST (16). In patients suffering from stroke, lower hemoglobin levels have been correlated with a higher likelihood of post-stroke cognitive impairment (50). Some studies have also found that higher hemoglobin levels in stroke patients are positively correlated with the maintenance of cognitive function (51). However, Raj C. Shah et al. highlighted that both very low and very high hemoglobin levels were associated with lower cognitive function, particularly in areas such as semantic memory and perceptual speed (52, 53). This suggests that hemoglobin may have a bidirectional effect on cognitive function. Despite these findings, some studies have not found a direct relationship between hemoglobin levels and cognitive function (16, 54, 55). Beydoun et al. found that in individuals with anemia, no significant association was observed between RDW and cognitive performance (54). By contrast, in non-anemic populations, the association between RDW and cognition was more consistent (54). This lack of association with anemia may be attributed to the elevated RDW in anemic individuals within the sample, which potentially masked the independent effect of hemoglobin (54). Chen et al.’s study recruited healthy old men from Taiwan, China, and used the Cognitive Abilities Screening Instrument Chinese version and the Wechsler Digit Span Task test for cognitive assessment (55). The study’s conclusions indicated that the association between hemoglobin levels and cognitive function was influenced by differences in study populations and cognitive assessment methods (55). Schneider et al. found in their study on different hemoglobin concentrations that the sample size of individuals with high hemoglobin was relatively small (21 men and 56 women), a limitation that compromised the statistical power of analyses examining associations between this group and cognitive function (16). In the prospective follow-up with a mean duration of 6 years, the study further revealed no significant associations between overall anemia or its subtypes and declines in cognitive function (16). This result may be attributed to multiple factors: the relatively young baseline age of the study participants (mean age 57 years), the relatively short follow-up period, and the presence of attrition bias–those who were lost to follow-up were predominantly older individuals with lower educational attainment and multiple vascular risk factors (16).

The influence of hemoglobin on cognitive function may be related to several mechanisms, such as chronic hypoxia, β-amyloid deposition, and neuroinflammation (52, 56). When hemoglobin levels are too low, cerebral blood flow cannot meet the oxygen demands, leading to impaired brain cell function and exacerbating cognitive decline (16, 17). Additionally, a reduction in erythropoietin receptor expression may worsen neural damage, further increasing the risk of cognitive decline (52). Different types of anemia may affect brain function through different mechanisms. For example, iron-deficiency anemia may impair cognitive function by interfering with key enzymes in brain cell metabolism (57), while vitamin B12 and folate deficiencies may exacerbate cognitive impairment by affecting the metabolism of homocysteine and acetylcholine (58).

As a core component of HRR, RDW serves as an indicator of red blood cell volume heterogeneity (18). Studies have demonstrated that RDW is associated with inflammation, oxidative stress, and other factors, which play critical roles in cognitive decline (18, 19). Elevated RDW has been associated with various health conditions, and studies suggest it may also serve as a marker for cognitive dysfunction (54, 59, 60). Yi-Xuan Qiang et al. identified a link between RDW levels and the risk of developing Alzheimer’s disease, suggesting that RDW could serve as a valuable biomarker for monitoring cognitive decline (49). Laura M. Winchester et al. found that lower RDW was associated with poorer language reasoning and memory abilities (48). Kyoung Min Kim et al. pointed out that individuals with higher RDW had worse cognitive function and slower gait (61).

The relationship between increased RDW and cognitive decline may be closely related to inflammatory responses (60). Chronic inflammation is one of the key mechanisms of cognitive decline. Systemic inflammation triggers amyloid deposition, activates microglia and astrocytes in the central nervous system, leading to neuroinflammation that damages neuronal structure and function, ultimately affecting cognitive function (62). Yuan Fang et al. found that peripheral inflammation, by disrupting the blood-brain barrier, activates inflammatory responses in the nervous system, further exacerbating cognitive impairment (59, 63).

In summary, an increase in HRR reflects the body’s ability to resist factors such as systemic inflammation and oxidative stress. These mechanisms, acting together, contribute to the protection of cognitive function.

This study provides evidence of HRR as a potential biomarker for cognitive health in obese populations. However, due to the cross-sectional design, longitudinal clinical trials are needed to further clarify the causal relationship. While multi-ethnic groups were included, Southeast Asian and other Asian populations were underrepresented. Using BMI to classify obesity has inherent limitations: it relies solely on height and weight, failing to distinguish muscle from fat, and cannot reflect true fat distribution in metabolically obese but normal weight individuals. BMI obesity thresholds also vary by ethnicity. Moreover, the failure to comprehensively assess obesity by integrating multi-dimensional indicators such as body fat percentage, waist circumference, and visceral fat area weakens the accuracy and generalizability of the research conclusions (64, 65).

This study suggest that HRR may serve as a potential biomarker for reflecting cognitive function status: individuals with higher HRR levels demonstrated better performance in cognitive assessments. This discovery indicates that maintaining a higher HRR could be a potential intervention strategy for protecting the cognitive abilities of obese populations. However, this conclusion still requires further validation through longitudinal studies with larger sample sizes, multicenter clinical trials, and exploration of action mechanisms to clarify the clinical application value of HRR as a target for cognitive protection.