Association of Physical Activity with Dementia Risk in Cancer Survivors: A Korean Nationwide Cohort Study.

Introduction

The increasing prevalence of ‘chemo brain’, a term used to describe the cognitive decline experienced by cancer survivors following chemotherapy, underscores the need to focus on cognitive health in this population [ 1 ]. Dementia, including Alzheimer’s disease (AD) and vascular dementia, is commonly reported among cancer patients and may persist for months to decades following treatment [ 2 ]. Such long-term cognitive decline following chemotherapy can profoundly impact the overall quality of life [ 3 ]. Given the clinical importance of dementia, it is crucial to identify and manage associated risk factors. One potential modifiable risk factor is physical activity after a cancer diagnosis. Physical activity has been shown to improve cognitive function and may help prevent dementia in cancer patients [ 4 ]. Along with other well-established traditional and emerging interventions for cancer treatment, physical activity is a crucial public health strategy associated with improved cognitive function in cancer patients [ 5 , 6 ]. The National Comprehensive Cancer Network and other oncology bodies emphasize the importance of physical activity in preventing cognitive impairment or dementia in cancer patients [ 7 ].

A growing body of evidence from observational and clinical studies underscores the cognitive benefits of physical activity in diverse populations, including cancer patients [ 8 - 10 ]. According to an updated review on the relationship between cancer and dementia released in 2023, physical activity can help mitigate cognitive decline by addressing mechanisms such as oxidative stress, inflammation, and neuroplasticity implicated in both cancer and dementia [ 11 ]. A nationwide study using a large Asian cohort found that increased physical activity level was associated with a reduced risk of dementia in older adults [ 12 ]. Specifically, meeting the World Health Organization recommendations for physical activity was associated with a lower risk of AD [ 13 ]. In the context of cancer patients, physical exercise significantly enhances cognitive function in breast cancer survivors, improving self-reported cognitive function (mean difference [MD] 10.12), cognitive fatigue (MD –5.41), and executive function (MD –13.63) [ 5 ]. However, the dementia benefits of physical activity in cancer survivors are more complex, as the potential cognitive effects of chemotherapy must also be considered [ 14 ]. Some studies suggest that chemotherapy may increase the risk of cognitive impairment, often referred to as ‘chemo brain’ [ 15 ]. However, other studies have found that chemotherapy was associated with a reduced risk of developing AD and dementia [ 16 ]. Despite these studies, there is still limited evidence of cognitive benefits, as measured by dementia outcomes, associated with changes in physical activity after cancer diagnosis in cancer patients.

To address this gap in the evidence, we examined the association between increased physical activity after a cancer diagnosis and dementia benefits in a large national cohort study linked to cancer survivor data covering a range of cancer types.

Materials and Methods

1. Data source

The National Health Insurance Service (NHIS) provides mandatory comprehensive health insurance coverage for more than 97% of health services for South Korean citizens [ 17 ]. The NHIS collects and maintains data on insured health services for claims processing. This study was conducted by providing customized data by a system that can use claims data for research. The database of NHIS includes sociodemographic information related to insurance eligibility (sex, age, income level, residence area, etc.), dates of death, claims data from hospitals and pharmacies (diagnosed with the ICD-10 code [10th revision of the International Statistical Classification of Diseases], outpatient and inpatient hospital visits, pharmaceutical prescriptions, etc.) and data from the national health screening examinations. The health check-up is conducted once every 2 years for adults over the age of 40 and consists of physical measurements, blood test results, and questionnaires on health behaviors related to smoking, alcohol consumption, and exercise. The NHIS database used in this study was based on a 50% random sample of eligible individuals due to data provision limitations.

2. Study population and design

A total of 798,770 patients newly diagnosed with cancer (having ICD-10 codes C00-C97 and critical condition code V193, V194, V027) [ 18 ] from January 1, 2009 to December 31, 2015 were enrolled in this study. To identify 3-year cancer survivors among these eligible subjects, patients who died (n=158,285) within 3 years of their cancer diagnosis were excluded from the analysis. We identified 363,168 cancer survivors who had a health screening examination between 1 and 3 years after diagnosis. We excluded 4,822 individuals due to missing or erroneous data in these examinations. To measure the incidence of dementia, individuals with any diagnosis of dementia at any time prior to the index date were excluded from the study (n=14,194). A final cohort of 344,152 cancer survivors was identified and included in our analyses. We defined the index date as 3 years after the date of the new cancer diagnosis ( Fig. 1 ).

Physical activity was evaluated using a modified International Physical Activity Questionnaire during each health examination. We utilized health examination results conducted between 1 and 3 years after a cancer diagnosis to extract weekly frequencies of light (≥ 30 min/day; e.g., leisure walking), moderate (≥ 30 min/day; e.g., brisk walking, tennis), and vigorous (≥ 20 min/day; e.g., running, aerobics) physical activity (PA). Metabolic equivalents of task (MET) values of 2.9, 4.0, and 7.0 were assigned to light, moderate, and vigorous PA, respectively, based on prior research [ 19 , 20 ]. The aggregate weekly energy expenditure was then estimated by summing these values across all levels of PA intensity. Patients were divided into four PA groups; (1) inactive group; (2) insufficiently active group, 1 to < 500 MET-min/wk; (3) active group, 500 to < 1,000 MET-min/wk; (4) highly active group, over 1,000 MET-min/wk.

3. Outcome and covariates

A diagnosis of dementia was based on the ICD-10 codes for dementia. The primary outcome was defined as the occurrence of overall dementia (F00-F03 and G30). Secondary outcomes were the development of dementia subtypes, including AD (F00 or G30) and vascular dementia (VaD; F01) [ 19 ].

To evaluate dementia risk by exercise levels among cancer survivors, we collected dementia-related variables from the 1 year before the index date to minimize confounding. These covariates include demographic variables such as sex, age, and income level, as well as clinical indicators such as the Charlson comorbidity index (CCI) for assessing comorbidities [ 20 ], body mass index (BMI) from physical measurements, and laboratory results including systolic blood pressure (SBP), fasting blood glucose (FBS), total cholesterol, and treatment of cancer [ 21 , 22 ]. We categorized income levels into four groups based on the insurance premium quartiles, merging the Medicaid group with the lowest income group. Smoking status was categorized as nonsmokers, past smokers, and current smokers. Alcohol consumption was categorized into non-drinkers, those drinking 1-2 days per week, 3-4 days per week, and those consuming alcohol on 5 or more days per week. Cancer treatments were categorized into chemotherapy and radiation therapy [ 22 ].

4. Statistical analyses

Basic characteristics of the study population were compared using the t test for continuous variables and the chi-square test for categorical variables. In addition to the age and sex-adjusted multivariable model 1, income level and CCI were adjusted in multivariable model 2. Multivariable model 3 was additionally adjusted for smoking status, alcohol consumption, BMI, FBS, SBP and total cholesterol. Multivariable model 4 was constructed by adjusting for types of cancer treatment, including chemotherapy and radiation therapy in addition to the variables included in the multivariable model 3.

We used the Cox proportional hazards model to examine the association between fitness and the risk of incidence of dementia among 3-year cancer survivors without a diagnosis of dementia ever. It was determined by the adjusted hazard ratio (HR) and 95% confidence interval (CI). Survival time was defined as the number of days from the 3-year survival date (index date) to the outcome incident date or the date of death or December 31, 2021 (end of the dataset). We evaluated the risk of dementia with increasing exercise by cancer type, including cancer risk related. Alcohol-related cancer includes the oral cavity, pharynx, esophagus, colon, rectum, liver, larynx, and breast in women [ 23 ]. Obesity-related cancer includes esophageal cancer, gastric cancer, colorectal cancer, liver cancer, kidney cancer, multiple myeloma, meningioma, pancreatic cancer, and gallbladder cancer (U.S. National Cancer Institute). Smoking-related cancer includes cancers of the head and neck, esophagus, stomach, colorectum, liver, pancreas, larynx, trachea, lung, bladder, kidney, kidney pelvis, or ureter, and acute myeloid leukemia (U.S. Surgeon General’s Report, 2014). Finally, we conducted a subgroup analysis for the overall dementia stratified by follow-up time and baseline covariates.

All statistical analyses were conducted using SAS 9.3 (SAS Institute Inc.), and 2-sided p-values < 0.05 were considered statistically significant.

Results

1. Participant characteristics at baseline

In total, 344,152 participants (male, 43.7%; female, 56.3%) with a mean±standard deviation age of 58.68±12.17 years were included in this analysis. Participants’ demographic data, comorbidities, and laboratory findings according to leisure-time PA level are summarized in Table 1 . In this study, 19.4% of participants belonged to the inactive group; 28.2%, to the insufficiently active group (mean, 292.97 MET-min/wk); 30.2%, to the active group (mean, 690.32 MET-min/wk); and 22.2%, to the highly active group (mean, 1,489.09 MET-min/wk).

2. PA level and dementia in cancer survivors by sex

The mean follow-up time for the total population was 5.81 years, and the maximum follow-up period was 10 years. A total of 24,363 patients (7.1%) developed dementia, 19,407 patients (5.6%) developed AD, and 4,238 patients (1.2%) developed VaD. When stratified by PA level, the incidence was 1.76 per 100 person-years in the inactive group, 1.11 per 100 person-years in the insufficiently active group, 1.13 per 100 person-years in the active group, and 0.97 per 100 person-years in the highly active group ( Table 2 ). Compared to the inactive group, the risk of overall dementia significantly reduced among the insufficiently active (HR, 0.89; 95% CI, 0.86 to 0.92), active (HR, 0.85; 95% CI, 0.83 to 0.88), and highly active (HR, 0.79; 95% CI, 0.76 to 0.82) groups after adjusting for potential confounders including chemotherapy and radiation therapy (multivariable model 4). The risk associations between AD and VaD were found to be similar. When analyzed by sex, men exhibited a higher incidence of dementia compared to women. However, higher levels of PA were consistently associated with reduced risks of overall dementia, AD, and VaD.

3. PA level and dementia in cancer survivors by cancer types

Table 3 presents the cancer-type specific analysis of the risk of overall dementia among cancer survivors based on exercise levels, shown as HR values from the fully adjusted multivariate model 4, which accounts for all variables, including chemotherapy and radiation therapy. This inverse relationship between exercise and dementia risk was statistically significant for stomach, colon, lung, breast, prostate, bladder, and thyroid cancers. The most prevalent cancer type was thyroid cancer, with a total of 3,232 cases of dementia observed among 103,076 patients. The active and highly active group of thyroid cancers had 13% (HR, 0.87; 95% CI, 0.79 to 0.96 and HR, 0.87; 95% CI, 0.79 to 0.97) reduction in risk of overall dementia, respectively. Among the insufficiently active, the risk reduction for overall dementia did not reach statistical significance (HR, 0.94; 95% CI, 0.86 to 1.03). Furthermore, when analyzing the data based on combined cancer risk factors, a significant association was consistently observed, indicating that increased exercise is significantly linked to a reduced risk of dementia across various cancer risk profiles.

In subgroup analysis, associations between PA level and risk of dementia were consistent regardless of age, CCI, whether excluding the first 1, 2 years, and comorbidities ( S1 Table ). After excluding the first 2 years, 335,297 participants developed dementia, with an overall incidence of 0.87 per 100 person-years during follow-up. Out of 148,613 individuals (43.2% of the total) who underwent chemotherapy, 15,761 developed overall dementia. The risk of overall dementia decreased sequentially across the exercise groups compared to the group with no exercise: insufficient group (HR, 0.86; 95% CI, 0.83 to 0.90), active group (HR, 0.81; 95% CI, 0.78 to 0.85), and highly active group (HR, 0.74; 95% CI, 0.70 to 0.77). Subgroup analyses for AD and VaD also showed similar trends ( S2 and S3 Tables ).

Discussion

In this cohort of cancer survivors, increased PA was consistently associated with a significantly lower risk of dementia. The protective effect of PA against dementia was found to be intensity and frequency-dependent and remained broadly consistent across different types of cancer, sexes, and both AD and VaD. This is the first study to use national-level data to demonstrate the protective effect of increased PA after cancer diagnosis on preventing dementia, covering a wide range of cancer types.

1. Protective effects of PA against dementia

Our observation of dementia risk reduction among cancer survivors who increased their PA post-diagnosis aligns with the established benefits of PA in reducing dementia risk. A large cohort study of 62,286 older adults demonstrated that increased PA levels were associated with a reduced risk of dementia (HR, 0.84; 95% CI, 0.74 to 0.95) compared to those with lower activity levels [ 12 ]. Similarly, a meta-analysis of 58 studies involving 257,983 participants also confirmed that PA reduced the risk of all-cause dementia by 20% (pooled relative risk [RR], 0.80; 95% CI, 0.77 to 0.84), AD by 14% (RR, 0.86; 95% CI, 0.80 to 0.93), and VaD by 21% (RR, 0.79; 95% CI, 0.66 to 0.95), with significant dose-response trends for all-cause dementia [ 24 ]. Our study extends these findings by showing that the protective effects of PA are significant in cancer survivors, who are often underrepresented in research.

Additionally, a large cohort study involving 197,685 participants found that midlife PA was particularly linked to a lower incidence of VaD but not AD [ 25 , 26 ]. This suggests that the timing and type of PA might influence its protective effects. Our study shows that increased PA after a cancer diagnosis helps prevent both AD and VaD, consistent with findings from large cohort studies [ 27 ]. Our study adds value by showing these associations hold true across different cancer types and are consistent by sex.

2. Potential benefits of PA for cancer survivors

Our results align with previous research highlighting the benefits of PA for cancer survivors. The updated consensus statement from the International Multidisciplinary Roundtable for Exercise Guidelines for Cancer Survivors underlines that cancer survivors could safely engage in exercise to improve physical fitness, restore physical functioning, enhance quality of life, and mitigate cancer-related fatigue [ 28 ]. A randomized controlled trial involving 181 chemotherapy-exposed breast cancer patients found that although PA did not notably enhance memory performance in breast cancer patients, it did positively impact self-reported cognitive function, fatigue, quality of life, and depression [ 4 ]. This suggests that PA impacts cognitive function indirectly. Our study demonstrates a direct link between PA and reduced dementia risk in cancer survivors, adding to the body of knowledge in this area, especially given the rising prevalence of both cancer and dementia in aging populations [ 16 ].

3. Mechanisms of dementia benefits of PA in cancer survivors

Currently, evidence of the cognitive benefits of PA is supported by experimental and observational studies on dementia-related biomarkers. A study involving 768 elderly patients found that men with a higher fat-to-muscle mass ratio, particularly those with chronic conditions like type 2 diabetes, had a 31.1% increased risk of cognitive impairment [ 29 ]. This ratio reflects the balance between fat and muscle in the body, where higher fat mass can lead to increased inflammatory cytokines and insulin resistance, both of which negatively impact cognitive health [ 30 ]. Conversely, maintaining low muscle mass has been associated with a decline in cognitive function over time [ 31 ]. Ehlers et al. [ 32 ] used a structural equation modeling approach to explore the connection between PA and fatigue and then cognitive performance. They inferred that the impact of exercise on cognitive performance could be partially attributed to its effect on symptoms related to cancer, including fatigue. Further supporting this, investigators from the British examined the effects of PA on cancer survivors and found that exercise elicited beneficial changes in insulin-related pathways, down-regulated inflammation, and enhanced oxidative, immune, and cellular repair pathways [ 33 ]. These molecular and biomarker changes suggest that PA may attenuate neuroinflammation and oxidative stress, which are key contributors to the development of dementia. While these observational studies demonstrated biologically plausible mechanisms of cognitive benefits of PA in patients with dementia, the evidence is limited to the patient population undergoing chemotherapy.

Our study observed a higher incidence of dementia in men compared to women, contrary to the global trend of higher dementia prevalence in women, largely attributed to their longer life expectancy and greater susceptibility to AD. This finding may be attributed to higher vascular risk factors, such as smoking and alcohol consumption, which are more prevalent in men and are strongly associated with VaD [ 19 , 25 ]. Men are also more likely to experience vascular comorbidities, including hypertension and diabetes, which elevate dementia risk [ 34 , 35 ]. Additionally, sex differences in the neurocognitive effects of cancer treatments, such as chemotherapy, may contribute to disparities, as evidence suggests male cancer survivors experience greater impairments in role (–9.9; 95% CI, –11.2 to –8.6) and social functioning (–7.7; 95% CI, –9.6 to –7.6) compared to age-matched reference populations, potentially reflecting broader treatment-related cognitive impacts [ 36 ]. Prostate cancer survivors undergoing hormonal therapy have reported cognitive difficulties, including fatigue and slower processing speed, potentially linked to treatment [ 37 ]. However, evidence remains inconsistent, with some studies suggesting that female survivors may report more cognitive symptoms and psychological distress following treatment [ 38 ]. These findings underscore the complexity of sex-specific responses to cancer treatments, highlighting the need for further research to clarify the mechanisms underlying these differences.

The sex-stratified analysis in our study revealed that the protective effects of PA are significant for both men and women. This is in line with findings, which reported sex-varying associations between PA intensity and mental quality of life in older cancer survivors [ 39 ]. Our study further supports the notion that both men and women can benefit from increased PA post-cancer diagnosis in terms of dementia prevention. However, it’s important to note that radiotherapy would be directly associated with dementia for head and neck cancers such as brain, oral, and pharyngeal cancer [ 40 , 41 ]. Our study did not find a significant association between PA and the risk of dementia in head and neck cancers. This suggests that the relationship between these specific cancers, their treatments, and dementia is complex and warrants further investigation. Further large-scale studies are needed to determine the extent to which there are differences in the effects of exercise across various types of cancer.

The observational nature of our study prevents any definitive conclusion on the causality of this protective association. Therefore, the evidence on the safety and efficacy of PA to mitigate the risk of dementia should be further supported by controlled, randomized studies.

One of the key strengths of our study is the use of national-level data, which provides a robust and comprehensive analysis of the association between PA and dementia prevention in cancer survivors. This approach addresses the limitations of smaller, localized studies and offers a broader perspective on the potential public health benefits of promoting PA among cancer survivors. The Lancet Commission report on dementia prevention, intervention, and care emphasized the importance of large-scale data in understanding and addressing dementia risk factors [ 42 ]. Our study aligns with this recommendation and adds valuable insights into the role of PA in dementia prevention for cancer survivors at a national level. Moreover, we were able to account for a wide range of confounders in sociodemographic factors, health status, health behavior, and clinical characteristics for adjustment and stratified analyses to minimize potential bias in the analyses.

4. Limitations

While our study has provided valuable insights into the association between PA and the risk of dementia among cancer survivors, it is important to acknowledge certain limitations. Our study has several limitations. First, we lacked individual-level data on PA from personal monitoring equipment. Instead, we were only able to use the data derived from self-reported questionnaires. Nonetheless, well-established population-based studies, including the NHIS cohort study, have shown that self-reported PA data can serve as a reliable alternative to personal monitoring equipment [ 43 ]. Second, we used self-reported data for PA, collected at a single time point. Conditions at the time of questionnaire completion may not reflect PA conditions prior to cancer diagnosis or represent actual lifetime PA levels. Behavioral changes during the follow-up period were also unmeasurable. Third, there is the possibility of reverse causality bias. Subclinical neuropathological changes that precede the diagnosis of dementia can gradually affect behavior, reducing physical activities as much as 9 years before the diagnosis of dementia. This could lead to an overestimation of the protective effects of PA on dementia risk. Fourth, our study lacked direct data on cancer staging and progression, which could influence PA levels and confound the observed associations. Cancer severity and progression may significantly influence PA levels, which in turn could impact dementia risk. Studies have shown that PA can reduce the risk of cancer progression and mortality [ 44 ]. However, the severity and progression of cancer can lead to decreased PA levels due to increased fatigue, pain, and other symptoms [ 45 , 46 ]. While we adjusted for treatment types as proxies for disease severity, we acknowledge that the absence of direct cancer staging data remains a limitation. Future studies should incorporate detailed staging information to refine these analyses further. Moreover, by including only individuals who survived at least 3 years post-diagnosis, our study population likely represents a subset of cancer survivors with better prognoses and greater resilience to severe disease effects. This design choice aimed to reduce confounding effects related to acute illness but may limit the generalizability of our findings to those with more advanced cancer. Future research with a broader cancer population, including individuals with varying survival durations, could provide additional insights into how PA impacts dementia risk across different cancer severities. Fifth, while our study focuses on cancer survivors, it is important to consider how these findings compare to those observed in the general population. A direct comparison with non-cancer individuals would provide additional context for the magnitude of dementia risk reduction associated with PA. However, our study was specifically designed to investigate post-diagnosis PA within the unique context of cancer survivors, given their distinct risk factors such as oxidative stress, systemic inflammation, and neurotoxic effects of treatment. Additionally, the NHIS database does not include comparable PA data for non-cancer populations, limiting our ability to conduct direct comparisons. Future studies should integrate both cancer and non-cancer populations to better understand the role of cancer-related factors in modifying the protective effects of PA against dementia. Nonetheless, our analyses showed a significant dose-response relationship between PA and dementia risk reduction. This association is also supported by previous studies documenting cognitive benefits among patients with high compliance to PA recommendations. However, the observational nature of our study prevents any definitive conclusion on the causality of this protective association. Therefore, the evidence on the safety and efficacy of PA to mitigate the risk of dementia should be further supported by controlled, randomized studies.

In conclusion, our study provides strong evidence that increasing PA after a cancer diagnosis can significantly reduce the risk of dementia. This consistent association underscores the importance of integrating PA into post-diagnosis care protocols to optimize cognitive health and prevent dementia in cancer survivors.

Footnotes

Ethical Statement

This study was approved by the Institutional Review Board of Seoul National University Hospital (IRB No. E-2204-038-1314). The requirement for informed consent was waived because the study was conducted using de-identified cohort data and posed minimal risk to participants.

Author Contributions

Conceived and designed the analysis: Lee SK, Han M, Park SM.

Collected the data: Park S, Park SJ, Song J, Kim HJ, Kim J, Lee H.

Contributed data or analysis tools: Lee SK, Han M, Park SM.

Performed the analysis: Lee SK, Han M.

Wrote the paper: Lee SK, Han M.

Critical review of the manuscript for important intellectual content: Lee SK, Han M, Park S, Park SJ, Song J, Kim HJ, Kim J, Lee H, Shin HY, Kim KH, Park SM.

Conflicts of Interest

Conflict of interest relevant to this article was not reported.

Funding

The Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (RS-2023-00244084); Sangwoo Park received a BK21 FOUR education program scholarship. It was offered by the National Research Foundation of Korea (2021R1F1A1063346).

Electronic Supplementary Material

Supplementary materials are available at Cancer Research and Treatment website ( https://www.e-crt.org ).

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