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INCREASED INCIDENT ALZHEIMER’S DISEASE AMONG INDIVIDUALS WITH VARICOSE VEINS: A POPULATION-BASED COHORT STUDY

 

C.-Y. Cheng1,2

 

1. Department of Dermatology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan City 333, Taiwan; 2. Center of tissue engineering, Chang Gung Memorial Hospital, Taoyuan City 333, Taiwan

Corresponding Author: Chun -Yu, Cheng, Chang Gung Memorial Hospital, 199, Tun-Hwa North Road, Taipei 105, Taiwan, Telephone: +886-2-27135211-3397, Email: dermatology99999@gmail.com

J Prev Alz Dis 2022;
Published online February 4, 2022, http://dx.doi.org/10.14283/jpad.2022.23

 


Abstract

Background: Varicose vein may be related to increased risk of comorbidities and decreased cognitive function in the elderly, but little is known about the association between varicose vein and Alzheimer’s disease.
Objectives: To evaluate whether there is an association between varicose veins and Alzheimer’s disease.
Design: The study subjects of this cohort study were selected based on Chang Gung Research Database from January 1, 2003, to December 31, 2012. Follow-up ended December 31, 2017.
Setting: A population-based study
Participants: Patients aged 45 years and older with varicose veins were enrolled, and the participants of control group were selected by matching with gender, age, and index date at a 4:1 ratio.
Measurements: The hazard ratios associated with varicose veins were estimated using Cox regression analysis with competitive risk model. Incidence rates of Alzheimer’s disease, was assessed in people with and without varicose veins.
Results: A total of 9,601 patients with varicose veins and 38,404 matched controls were enrolled in the study. The varicose veins group had higher incidence rates than the control group for Alzheimer’s disease (12.60 vs 6.24 per 10,000 person-years; Hazard ratio, 1.647 [95% confidence interval, 1.326- 2.045, p<0.001]). Patients with complicated varicose veins had increased incidence of Alzheimer’s disease than uncomplicated cases (adjusted HR, 1.474; 95% CI, 1.034-2.101, P=0.032).
Conclusion: The present study demonstrated a positive association between the varicose veins and Alzheimer’s disease. Physicians should be alerted to cognitive function in patients with varicose veins, especially those with presence of inflammation and ulcerations.

Key words: Alzheimer’s disease, dementia, tumor necrosis factor, varicose vein.


 

Introduction

Alzheimer’s disease (AD), the most common cause of dementia, is characterized by progressive impairment of memory and cognition, causing interference in occupational, domestic, or social functioning. Major risk factors for developing AD include advancing age, genetic profile, hearing loss, depression, diabetes, hypertension, and sleep apnea (1-4). Globally, the prevalence of AD and other dementias among people over 65 is estimated to be as high as 7%, and the prevalence is even higher in developed countries due to longer life spans (5). One recent study showed that 6.1 million people in United States (US) had clinical AD or mild cognitive impairment in 2017 (6), and it is the second most burdensome neurological disorder in the US (7).
Varicose vein is a vascular disorder that present with tortuous, lengthened, and/or twisted veins, usually in the lower limbs. The estimated prevalence of varicose veins was between 5% and 30% in the adult population with female predominance (8). The risk factors of varicose veins include advancing age, family history, obesity, smoking, prolonged standing, sedentary lifestyle, lower extremity trauma, prior venous thrombosis, and pregnancy (9-12). The pathogenesis of varicose veins is due to the valvular incompetence of deep or superficial veins, perforator veins, venous tributaries, or venous obstruction, resulting in elevated venous pressure and impaired return of blood. In addition to vascular dysfunction, it is associated with other comorbidities, including COPD, diabetes mellitus, arterial hypertension, and deep vein thrombosis, pulmonary embolism, and peripheral arterial diseases (13, 14). Recently, one cross-sectional study described that varicose veins may be a factor that contributes to decreased cognitive function in the elderly (15). Kujawski et al also demonstrated varicose veins were significantly related to negative changes in Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment scores (16). However, these studies have relatively small sample sizes and lack of long-term follow-up.
The aim of the present study was to evaluate whether there is an increased risk of AD, the most common cause of dementia, among patients with varicose veins. We also try to explore the association between AD and different severity of varicose veins.

 

Methods

Data Source and Collection

The present study was based on the Chang Gung Research Database (CGRD), which is a deidentified database derived from the electronic medical records at the Chang Gung Memorial Hospital (CGMH). CGMH comprises seven medical institutes, which are located from the northeast to southern regions of Taiwan. The outpatient department visits and emergency department visits to CGMH were over 8,500,000 and 500,000, respectively, in 2015 (17). The overall coverage of the CGRD was 21.2% for outpatients and 12.4% for inpatients in Taiwan (17). The CGRD contains clinical epidemiological data, as well as laboratory test data, inpatient and outpatient data, imaging and pathological reports, disease category data, surgery notes, and cancer registry data. Diseases in the CGRD were diagnosed and recorded using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). This study was approved by the Institutional Review Board of Chang Gung Memorial Hospital (CGMHIRB No. 202001554B0). Because the research data employed data anonymization to ensure enrollees’ confidentiality, informed consent was waived.

Study Population

The study subjects were selected based on CGRD data from January 1, 2003, to December 31, 2012. We used ICD-9-CM codes 454 to identify the subjects diagnosed with varicose veins. Individuals were defined as having varicose veins if there were at least two incidences of diagnostic codes in their outpatient clinic records or admission records. The exposed cohort comprised those who were newly diagnosed with varicose veins in 2003 or after; the control group comprised those who had never been diagnosed with varicose veins. The participants of control group were selected by matching with gender, age, and index date at a 4:1 ratio. For the varicose veins group, the index date was set as the date of the first varicose veins diagnosis, and for the control group, the date was the patient first included in the CGRD. We also subdivided varicose veins group into uncomplicated and complicated cases based in the presence of inflammation and ulcers. The diagnosis of varicose veins with inflammation or ulcer (ICD-9-CM codes 454.0, 454.1, and 454.2) was based on at least two incidences of diagnostic codes (either in outpatient visits or hospital admissions). The validation of 454 code corresponding to the diagnosis of varicose veins was performed in our previous study, which demonstrated the positive predictive value of 98% (95% confidence interval [CI], 0.95%-0.99%) and the worst-case positive predictive value was 82% (95% CI, 0.77%-0.87%) (14). We extended the follow-up period to December 31, 2017, to ensure that each patient had sufficient data available.
Although AD often affects older adults, it may occur before the age of 65 years. According to previous studies, early-onset AD mostly develops in 45 to 64 years in age but rarely occurs before the age of 45 (18, 19). Therefore, individuals younger than 45 years were excluded from the present study. We also excluded patients diagnosed with any types of dementia before the index date. In addition, those with incomplete data were also excluded.

Outcomes and Potential Confounders

As documented in physician claims, the outcome of interest in the present study was Alzheimer’s disease (ICD-9-CM code 331.0). We confirmed the endpoints by requiring the records of the diagnosis at least two times (either in outpatient visits or hospital admissions) by board-certified neurologists or psychiatrists. To enhance the accuracy of diagnosis, we only included those receiving cholinesterase inhibitors (i.e., donepezil, rivastigmine, and galantamine) or N-Methyl-D-aspartate receptor inhibitor (i.e., memantine) for treatment of AD. According to the National Health Insurance regulations in Taiwan, these reimbursable therapies for AD were only approved after comprehensive evaluations. All cases should be evaluated with cognitive function examinations, such as MMSE and Clinical Dementia Rating. Besides, all cases should also receive laboratory and imaging examinations to exclude other causes of cognitive impairment, including thyroid dysfunction, vitamin B12 deficiency, syphilis, or cerebrovascular events. These medicines were not approved for the treatment of vascular dementia.
The follow-up duration for subjects with AD was the time between the index date and the date of the first AD diagnosis in either an inpatient or outpatient record, whereas the follow-up duration for subjects without AD was from the index date to the end of 2017.
In addition to gender and age, we also considered following comorbidities as potential confounders, including hypertension (ICD-9-CM codes 401–405), hyperlipidemia (ICD-9-CM code 272), cancer (ICD-9-CM codes 140-208, 290.0-209.3), diabetes (ICD-9-CM code 250), congestive heart failure (ICD-9-CM code 428), coronary artery disease (ICD-9-CM codes 410–414), chronic obstructive pulmonary disease (COPD, ICD-9-CM codes 490-496), chronic liver disease and cirrhosis (ICD-9-CM codes 517), head injury (ICD-9-CM codes 310.2, 800, 801, 803, 804, 850, 851, 853, and 854), hearing loss (ICD-9-CM codes 389), depression (ICD-9-CM codes 296.2, 296.3, 300.4, and 311), cerebrovascular accident (CVA, ICD-9-CM codes 430, 431, 432, 433, 434, 435, 436, 437, and 438), Parkinson’s disease (ICD-9-CM codes 332.0–332.1), chronic renal failure (ICD-9-CM code 585), sleep apnea (ICD-9-CM codes 327.2, 780.53, 780.57), alcohol abuse and dependence syndrome (ICD-9-CM codes 305.0, 303.0m 303.9), tobacco use disorder (ICD-9-CM code 305.1), and obesity (ICD-9-CM code 278) .

Sensitivity Analysis

Given the insidious onset of AD, we performed sensitivity analysis to validate the results by minimizing the incipient or sub-diagnostic AD at the time of varicose veins diagnosis. We restricted the inclusion criteria of the follow-up period to at least 1, 2, and 3 years of observation and evaluated the association between the varicose veins and the risk of AD. Besides, we also adjusted the frequency of outpatient visits as a potential confounder.to minimize healthy adherer effect.

Statistical Analysis

The Student t-test and the Chi-squared test were used to compare continuous and categorical data, respectively. The hazard ratios (HRs) associated with varicose veins were estimated using Cox proportional hazard models. To avoid the impact of death competing with risk of AD, Fine-Gray subdistribution competing risk model was performed by considering all competitive causes of death (20). Fine-Gray subdistribution competing risk model is based on a proportional hazards model for the subdistribution of a competing risk, and the covariates in this model can be interpreted as having an effect on the cumulative incidence function (21). Subgroup analysis by age and gender were performed to assess whether the association between varicose veins and dementia varied with age and gender. A two-sided P value of <0.05 was considered statistically significant. Using the SAS software version 9.4 (SAS Institute, Cary, NC), all statistical analyses were conducted.

 

Result

Subject characteristics

In the present study, we identified 696,644 patients older than 45 years out of 2,124,148 cases in the CGRD from January 1, 2003, to December 31, 2012. Subjects with a history of dementia preceding the index date (n = 9,855) were excluded. Thereafter, we identified 9,601 patients who were newly diagnosed with varicose veins and 38,404 matched controls (Figure 1). No missing nor invalid data on age, sex, and vital status were noted in our series.

Figure 1. Flow chart of selection of the study population

 

Table 1 displays the demographic data. The mean ge of participants in both groups was 64.18±9.53 years. Female participants comprised 67.9% of both study cohort. The mean follow-up durations were 10.56±3.30 years for varicose veins group and 10.27±3.47 years for control group. Additionally, compared with the control group, the varicose veins cohort had significantly higher prevalence of coronary artery disease, chronic liver disease, COPD, chronic renal failure, diabetic mellitus, depression, head injury, hearing loss, heat failure, hypertension, hyperlipidemia, obesity, sleep apnea, and stroke. By contrast, no significant difference of prevalence of Parkinson’s disease, alcoholism and tobacco use disorder were found between the two groups. Notably, the prevalence of cancer was higher in control group than in varicose veins group. There were no significant differences of the age at AD diagnosis and the duration from index date to the date of AD diagnosis in each group.

Table 1. Characteristics of the study population

 

Risk of dementia in patients with varicose veins

After up to 15 years of follow-up, 130 patients in the varicose veins cohort (incidence rate, 12.60 /10,000 person-years) and 258 patients in the control cohort (incidence rate, 6.24/10,000 person-years) developed AD (absolute risk difference=6.36/10,000 person-years) (Table 2). The adjusted HR of AD (1.647; 95% CI, 1.326- 2.045, p<0.001) was significantly higher in patients diagnosed with varicose veins than in the control group. In addition, older age, male sex, depression, hearing loss, hyperlipidemia, and Parkinson’s disease were also found to be related to an increased incidence of AD (Table 3). When stratified according to the severity of varicose vein, both the uncomplicated and complicated groups had a significantly higher adjusted HR for AD than matched controls. We also conducted analysis to compare the risk of AD between uncomplicated and complicated cases within varicose veins group, and the result showed complicated cases had higher risk of AD than uncomplicated cases (adjusted HR, 1.474; 95% CI, 1.034-2.101, P=0.032).

Table 2. Hazard Ratios of the incidence of Alzheimer’s disease in varicose veins group and control group, including different severities of varicose veins and their matched controls

CI: confidence interval; *Adjust for age, gender, coronary artery disease, cancer, chronic renal failure, chronic liver disease, chronic obstructive pulmonary disease, depression, diabetic mellitus, head injury, heart failure, hearing loss, hypertension, hyperlipidemia, Parkinson’s disease, stroke, alcoholism, tobacco use disorder, sleep apnea, and obesity.

Table 3. Multivariate analysis for prediction of Alzheimer’s disease

CI: confidence interval; *Adjust for age, gender, coronary artery disease, cancer, chronic renal failure, chronic liver disease, chronic obstructive pulmonary disease, depression, diabetic mellitus, head injury, heart failure, hearing loss, hypertension, hyperlipidemia, Parkinson’s disease, stroke, alcoholism, tobacco use disorder, sleep apnea, and obesity.

 

Subgroup analyses

Gender-stratified analysis showed that varicose veins were associated with an increased risk of AD in both gender groups (Table 4). Age-stratified analysis showed varicose veins were only associated with an increased risk of AD in individual older than 65 years.

Table 4. Subgroup analyses of the association of risk of dementia among patients with different severities of varicose veins

CI: confidence interval; * Adjust for age, gender, coronary artery disease, cancer, chronic renal failure, chronic liver disease, chronic obstructive pulmonary disease, depression, diabetic mellitus, head injury, heart failure, hearing loss, hypertension, hyperlipidemia, Parkinson’s disease, stroke, alcoholism, tobacco use disorder, sleep apnea, and obesity.

 

Sensitivity analysis

Table 5 presents the sensitivity analysis results for the association between AD and varicose veins. AD was significantly related to a prior varicose veins diagnosis even after excluding patients diagnosed with varicose veins within the 1, 2, or 3 years preceding the diagnosis of AD (adjusted HRs were 1.659, 1.787, and 1.857, respectively) and adjusting the frequency of outpatient visiting.

Table 5. Sensitivity analysis for excluding patients diagnosed with varicose veins within 1–3 years preceding the diagnosis of dementia

CI: confidence interval; * Comparison of patients had at least 1-year history of varicose veins and control group; † Comparison of patients had at least 2-year history of varicose veins and control group; ‡ Comparison of patients had at least 3-year history of varicose veins and control group; § Further adjust frequency of outpatient visits; || Competitive risk model with adjust for age, gender, coronary artery disease, cancer, chronic renal failure, chronic liver disease, chronic obstructive pulmonary disease, depression, diabetic mellitus, head injury, hearing loss, heart failure, hypertension, hyperlipidemia, Parkinson’s disease, stroke, alcoholism, tobacco use disorder, sleep apnea, and obesity; { Competitive risk model with adjust for age, gender, coronary artery disease, cancer, chronic renal failure, chronic liver disease, chronic obstructive pulmonary disease, depression, diabetic mellitus, head injury, hearing loss, heart failure, hypertension, hyperlipidemia, Parkinson’s disease, stroke, alcoholism, tobacco use disorder, sleep apnea, obesity, and frequency of outpatient visits.

 

Discussion

In this population-based study, we found that patients diagnosed with varicose veins had an increased incidence of AD, especially those older than 65 years. We also found patients with complicated varicose veins had higher incidence of AD than uncomplicated cases.
The present study showed that patients diagnosed with varicose veins have a female predominance and a higher prevalence of coronary artery disease, chronic liver disease, COPD, chronic renal failure, depression, heart failure, hypertension, hyperlipidemia, and stroke. The demographic data was similar to one previous large study in Taiwan (14). Several studies have shown that patients diagnosed with varicose veins have higher levels of inflammatory markers than healthy controls, such as monocyte chemoattractant protein-1, interleukin (IL) -6, intercellular adhesion molecule 1, vascular cell adhesion protein 1 (VCAM-1), and P-selectin (22, 23). In addition, one recent study demonstrated the expression of pro-inflammatory cytokines, such as IL-1αand tumor necrosis factor (TNF)-α in peripheral blood mononuclear cells were higher in patients with venous leg ulcers than control individuals (24). Another cohort study also showed patients with the chronic inflammation caused by high grade of varicose veins may be related to increasing mortality and major adverse cardiovascular events (25). These findings suggested varicose veins may potentiate endothelial cell dysfunction as well as local and systemic proinflammatory environment, which may be associated with the development of other systemic comorbidities, especially those with complicated varicose veins.
Several studies have reported that inflammation may play a role in the pathogenesis of AD (26-31). In AD, the pathogenesis is due to the accumulation of abnormally folded amyloid-β and tau proteins forming tangles within neurons. The amyloid-β (Aβ) plaques trigger cerebral neuroinflammation by activating microglia and eventually cause damage and death of neurons (28). Additionally, inflammatory molecules of chronic peripheral inflammation may also be related to microglial activation and expansion within distinct anatomical brain regions (32). Some studies showed that serum proinflammatory cytokines and molecules, such as TNF-α, IL-1, IL-6, IL-12, and C-reactive protein (CRP) were elevated in patients with AD (27). A longitudinal study demonstrated elevated IL-6 level predicted subsequent mild cognitive impairment and both IL-6 and CRP levels predicted greater change in global and regional Aβ deposition.(33) Another study also showed the baseline inflammatory factors, including TNF-α, myeloperoxidase, and IL-8, significantly predicted a decline in executive function in AD patients over 12 months.(34) Additionally, other studies also reported that the serum VCAM-1 level was higher in patients with AD than in the control group (35). The level of VCAM-1 was associated with the severity of AD, macro- and micro-white matter changes, poor short-term memory, and visuospatial function (36). The results suggested that endothelial dysfunction may also play a role in the development of AD.
Taken together, we postulated the potential mechanism for the relationship between the varicose veins and AD might be related to the chronic inflammatory process and endothelial dysfunction. Noteworthy, the present study showed patients with complicated varicose veins had higher risk of AD than uncomplicated cases. The result may be that varicose veins with presence of inflammation or ulcer can induce greater inflammatory reaction, thereby increasing the risk of cognitive impairment subsequently. During the recent years, many studies have demonstrated TNF-α inhibitors may be beneficial to wound healing in chronic venous legs ulcers as well as improving cognitive function in AD patients (37, 38). These results indicated that TNF-α-related inflammatory pathway may be associated with the pathogenesis of both diseases.
In contrast, we did not find an association between varicose veins and AD in the group of 45-65 years old. This phenomenon may be due to the relatively low prevalence of AD before the age of 65 and the cognitive deficit in AD may be mild in the very early stage that is difficult to diagnose. Nevertheless, further studies are required to address this issue.
There are some limitations of the present study. First, although there may be coding errors in the diagnosis of AD, all the cases included in this study had been confirmed by cognitive assessment, laboratory examination, and imaging studies, thus improving the accuracy of the diagnosis. Second, the study only included patients in a single hospital system and most of the cases are Taiwanese; it is unclear whether these results can be generalized to nationwide populations and other ethnicities. Third, claims data only included patients seek medical assistance for treatment of varicose veins. Some patients with early stage of varicose veins may regard the disease as an esthetic problem and do not seek medical help. Therefore, we may underestimate the actual number of patients with varicose veins and the result of the present study may reflect the risk of AD in patients with relatively severe varicose veins requiring medical treatment. Forth, the information of some potential confounders, such as education, family history of AD, smoking status, alcohol consumption, over-weight, and life activities, were not available in the claims data. Fifth, because the incidence of AD increases with age, we may have underestimated the true risks of AD because of the limited follow-up duration. Moreover, we cannot analyze the association between the development of AD and inflammatory markers in patients with varicose veins because the biochemical data is not available in the retrospective database.

 

Conclusion

The present study demonstrated a positive association between the varicose veins and AD. Physicians should be alerted to cognitive function in patients with varicose vein, especially those with presence of inflammation and ulcerations. Early diagnosis and intervention of AD may be helpful for preventing progressive deterioration of cognitive function. However, further explorations of the underlying mechanism between varicose veins and dementia were warranted.

 

Funding: The author has no conflicts of interest to declare.

Conflict of interest disclosure: The author has no funding source to declare.

Ethical standard: CGMHIRB No. 202001554B0.

 

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