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A LARGE RETROSPECTIVE COHORT STUDY ON THE RISK OF ALZHEIMER’S DISEASE AND RELATED DEMENTIAS IN ASSOCIATION WITH VASCULAR DISEASES AND CANCER THERAPY IN MEN WITH PROSTATE CANCER

 

X.L. Du1, L. Song1,2

 

1. Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; 2. Department of Biostatistics and Data Science, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA

Corresponding Author: Xianglin L. Du, PhD, Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, 1200 Pressler St, Houston, TX 77030, USA; email: Xianglin.L.Du@uth.tmc.edu

J Prev Alz Dis 2023;
Published online January 18, 2023, http://dx.doi.org/10.14283/jpad.2023.8

 


Abstract

Background: No study was conducted on the long-term risk of Alzheimer’s disease (AD) and related dementias (ADRD) in association with vascular diseases in men with prostate cancer.
Objectives: To determine the 26-year risk of ADRD in association with cardiovascular disease (CVD), stroke, hypertension, and diabetes in a nationwide cohort of men with prostate cancer.
Design: Retrospective cohort study.
Setting: Surveillance, Epidemiology, and End Results (SEER) areas of the United States.
Participants: 351,571 men diagnosed with prostate cancer at age ≥65 years.
Measurements: Main exposures were CVD, stroke, hypertension, and diabetes. Main outcome was the incidence of ADRD.
Results: The crude 26-year cumulative incidence of any ADRD was higher in those with versus without CVD (33.80% vs 29.11%), stroke (40.70% vs 28.03%), hypertension (30.88% vs 27.31%), and diabetes (32.23% vs 28.68%). Men with CVD (adjusted hazard ratio: 1.17, 95% CI: 1.15-1.20), stroke (1.59, 1.56-1.61), hypertension (1.13, 1.11-1.14), and diabetes (1.25, 1.23-1.27) were significantly more likely to develop ADRD than those without. Patients with 4 of these vascular diseases were 161% more likely to develop ADRD (2.61, 2.47-2.76) than those without. The risk of AD (0.89, 0.87-0.91) and ADRD (0.91, 0.90-0.93) became significantly lower in men with prostate cancer who received androgen deprivation therapy as compared to those who did not after considering death as a competing risk.
Conclusions: In men with prostate cancer, vascular diseases were associated with significantly higher risks of developing ADRD. Androgen deprivation therapy was associated with a significantly decreased risk of AD in men with prostate cancer.

Key words: Alzheimer’s disease, dementias, vascular diseases, prostate cancer, Medicare.


 

 

Introduction

Alzheimer’s disease (AD) and related dementias (ADRDs) have had an increasing prevalence in the United States and worldwide over the past few decades (1-5). The causes of ADRD remained unknown, but a number of risk factors have been documented by many studies to be associated with an increased risk of ADRD (1-3, 6-20). These potential risk factors include advanced age, lower education, cardiovascular disease (CVD), cerebrovascular disease, hypertension, diabetes, smoking, poorer social and cognitive engagement, comorbid psychiatric disorders, head trauma, and genetic factors (1-3, 6-20). Previous studies on the association between ADRD and vascular diseases were mostly conducted in population-based cohorts of general population (6-20) and a few studies were conducted in long-term cancer survivors (21-25). Based on the findings of previous studies conducted in population without a history of cancer (6-20), similar associations between vascular diseases and a higher risk of ADRD would be expected in patients with a history of cancer. However, the latest research progress on a complex relationship between AD and cancer (22-31) should prompt the research community to explore this complicated question further. Several original research investigations and reviews have suggested an inverse association between AD and cancer (22-31). This inverse association between AD and cancer are not due to a higher mortality in patients with cancer (24) and are not due to selection bias, case ascertainments, or confounding as concluded by a systematic review of several studies that specifically addressed these issues (30). A few potential biological mechanisms have been proposed for this inverse association between AD and cancer (24), but more research is clearly needed to confirm those hypotheses or explore some new links. Furthermore, the side-effects of cancer chemotherapy agents were previously documented to be associated with the risk of decline in memory and cognition (31-38). Similarly, the potential side-effects of androgen deprivation therapy for men with prostate cancer included an increased risk of AD or other types of dementias (39-46), although the findings from various studies were still inconsistent (47-51). Nonetheless, cancer and the side-effects of cancer therapies undoubtedly complicate the associations between vascular diseases and ADRD in long-term cancer survivors.
From a recent original investigation in a large cohort of older women with breast cancer aged 65 or older, we observed a significant association between vascular diseases and AD and ADRD (21). It is still uncertain if these associations may also be observed in older men with prostate cancer and if other tumor factors are associated with the risk of ADRD. Therefore, this study aimed to determine whether the incidence and risk of AD, vascular dementia, other types of dementias and overall ADRD are significantly associated with various vascular diseases, chemotherapy, androgen deprivation therapy, and other factors in a large, nationwide and population-based cohort of long-term prostate cancer survivors.

 

Methods

Data Sources

This study identified a large cohort of older men with prostate cancer at age of 65 or older from the de-identified Surveillance, Epidemiology, and End Results (SEER) and Medicare-linked database between January 1991 and December 2015 with follow-up from January 1, 1991 to December 31, 2016. This study includes 17 population-based SEER tumor registries: 8 states (Connecticut, Iowa, New Mexico, Utah, Hawaii, Kentucky, Louisiana, and New Jersey), 7 metropolitan/rural areas (San Francisco/Oakland, Detroit, Atlanta, Seattle, Rural-Georgia, Los Angeles County, and the San Jose-Monterey areas), Greater-California, and Greater-Georgia, accounting for 28% of the U.S. total population. The Medicare program provides payments for hospital, physician and outpatient medical services for >97% of persons aged ≥65 (52). The Committee for the Protection of Human Subjects at the University of Texas Health Science Center at Houston approved this study.

Study Design and Population

This is a retrospective cohort study and the study population consisted of 554,646 men who were diagnosed with prostate cancer at age ≥65 years between January 1, 1991 and December 31, 2015 (Supplemental Figure-S1). The study excluded those who did not have a full coverage of both Medicare Part-A and Part-B or who were enrolled with Health Maintenance Organizations or Part-C (Medicare Advantage) from the date of diagnosis to the date of death or the date of last follow-up on December 31, 2016 because their itemized medical claims may not be complete. The study also excluded those who died within 30 days of prostate cancer diagnosis and those who had a history of any diagnosed dementias (ADRD) within 12 months prior to or within 30 days of cancer diagnosis. After exclusions, 351,571 men with prostate cancer who were free of any diagnosed ADRD at the baseline (within 1 year prior to and 30 days after the date of prostate cancer diagnosis) were left in the final analysis.

Study Variables

Main Exposures

Main exposures were CVD (including myocardial infarction, congestive heart failure, or peripheral vascular disease), stroke, hypertension, and diabetes, which were defined as having an ICD-9 or ICD-10 diagnosis for them within 12 months prior to or 30 days after the date of prostate cancer diagnosis (see detailed diagnosis codes for vascular diseases in Supplemental Table-S1).

Main Outcomes

Main outcome was the incidence of ADRD. ADRD was defined when there was a new diagnosis (ICD-9 or ICD-10) for any specific type of dementias (see detailed diagnosis codes for ADRD in Supplemental Table-S2) that occurred after 30 days of cancer diagnosis. ADRD was classified into 6 specific types of dementias: AD, vascular dementia, dementia with Lewy bodies (DLB), Frontotemporal degeneration and dementias (FTD), mild cognitive impairment (MCI), and other dementias. Apart from using any diagnosis code (of total 12 diagnosis codes in Medicare data file), we performed sensitivity analyses by using the primary diagnosis code only (i.e., first diagnosis code out of 12 codes).

Covariates

Covariates included socio-demographics (age, race/ethnicity, and marital status), tumor factors (tumor stage, tumor grade, and receipt of chemotherapy, radiation therapy and hormone therapy), comorbidity, year of diagnosis, and SEER areas by state where SEER registries were located in. Apart from exposures and outcomes of the study interests (ADRD, vascular diseases, and cancer), comorbidities included chronic pulmonary disease, congestive tissue disease, ulcer disease, mild liver disease, hemiplegia, moderate or severe renal disease, leukemia, moderate or severe liver disease, and human immunodeficiency virus (HIV+) or acquired immune deficiency syndrome (AIDS). These co-existing conditions were identified through diagnoses or procedures in Medicare claims made within 1 year prior to and 30 days after the date of cancer diagnosis based on the codes provided by the National Cancer Institute (53). Each comorbid disease was weighted according to its severity and the sum of all scores was analyzed as 0, 1, and ≥2 (53). The methods for defining cancer chemotherapy and radiation therapy were reported elsewhere (54, 55). Hormone therapy for prostate cancer, also known as androgen deprivation therapy (ADT), was defined by procedure codes for goserelin (J9202) or leuprolide (J1950, J9217, or J9218) in Medicare data.

Analysis

Differences in the distribution of baseline characteristics among prostate cancer patients by CVD, stroke, hypertension, and diabetes were tested using the chi-square statistic for categorical variables or using the Kruskal-Wallis test for median age comparisons. Cumulative incidence of ADRD is defined as the ratio of the number of cases with a new diagnosed dementia over the number of population-at risk who were free of dementia at the baseline when a prostate cancer diagnosis was made. Incidence density is defined as the ratio of the number of cases with a new diagnosed dementia over the total number of person-years by taking into consideration the differential follow-up times of study participants. Person-years are calculated as the number of people multiplied by the number of years from the time of prostate cancer diagnosis to the date of first dementia, date of death, or date of last follow-up (December 31, 2016), whichever occurred first. Cox regression models were utilized to perform the time to event analysis to determine the hazard ratio of developing dementia by vascular diseases or cancer therapies while adjusting for potential confounders. The proportionality assumption was assessed by checking whether the log-log Kaplan-Meier curves were parallel and did not intersect and also by adding an interaction term between exposures and time variables to the Cox models (56, 57). Fine and Gray competing risk proportional hazards regression was performed accounting for death as a competing risk (57).

 

Results

The distributions of baseline characteristics by the status of vascular diseases (CVD, stroke, hypertension and diabetes) among men diagnosed with prostate cancer are presented in Supplemental Table-S3. Of older men aged >=65, about 50% of those with a history of CVD and stroke were 75 years or older, while 40% of those with hypertension and diabetes were over 75 years. NH-white and Hispanic men accounted for 74%-79% and 5%-6% of cases with CVD, stroke and hypertension were, but accounted for 67.83% and 8.67% of cases with diabetes, respectively. The distributions of marital status, tumor characteristics, year of diagnosis and SEER areas differed slightly by the status of vascular diseases.
Table-1 presents the cumulative incidence rates of specific types of ADRD and total dementias by CVD, stroke, hypertension, diabetes, age, cancer therapies, and other factors. The crude 26-year cumulative incidence of any ADRD was higher in those with versus without CVD (33.80% vs 29.11%, p<0.01), stroke (40.70% vs 28.03%, p<0.01), hypertension (30.88% vs 27.31%, p<0.01), and diabetes (32.23% vs 28.68%, p<0.01). The cumulative incidence of ADRD increased substantially by age, from 18.46% for age 65-69 to 36.61% for age 75-79 and 44.39% for age 85 or older. The crude cumulative incidence rates varied slightly by race/ethnicity, marital status, tumor characteristics, and SEER areas.

Table 1. Cumulative incidence of dementias by vascular diseases in men with prostate cancer with up to 26 years of follow-up

* ADRD (Alzheimer’s disease and related dementias), AD (Alzheimer’s disease), Vascular (vascular dementia), DLB (dementia with Lewy bodies), FTD (Frontotemporal degeneration and dementias), MCI (Mild cognitive impairment), others (other dementias), and total (any of above ADRD).

 

The incidence density of specific and total ADRD by taking into consideration differential follow-up times of men with prostate cancer is presented in Supplemental Table-S4. The number of ADRD cases per 1,000 person-years were higher in those with CVD (57.95 vs. 38.39, p<0.01), stroke (69.14 vs. 36.73, P<0.01), hypertension (44.28 vs. 33.43, p<0.01), and diabetes (50.26 vs. 37.03, p<0.01) than their counterparts. The incidence density rates of AD and other specific types of dementias were also higher in patients with vascular diseases and increased substantially by age. Table-1 and Supplemental Table-S4 also present variations in the unadjusted cumulative incidence and incidence density rates of ADRD by race/ethnicity, tumor characteristics, comorbidity scores, chemotherapy, radiation therapy, androgen deprivation therapy, and SEER areas. For instance, patients who received chemotherapy had a higher incidence density rate of ADRD (48.40 vs. 35.36 cases per 1,000 person-years, p<0.01)) and AD (16.25 vs. 12.01, p<0.01) than those who did not.
Table-2 presents the time to event Cox regression analyses on the risk of ADRD in men with prostate cancer after adjusting for potential confounders. Men with CVD (adjusted hazard ratio: 1.17, 95% CI: 1.15-1.20), stroke (1.59, 1.56-1.61), hypertension (1.13, 1.11-1.14), and diabetes (1.25, 1.23-1.27) were significantly more likely to develop any ADRD than their counterparts. Patients with vascular diseases were also significantly more likely to develop AD, vascular dementia, or other dementias than those without. Patients with stroke and hypertension had a significantly elevated risk of dementia with Lewy bodies, FTD, or MCI, and patients with diabetes had a significantly elevated risk of FTD and MCI. However, patients with CVD did not have a significantly higher risk of developing dementia with Lewy bodies, FTD or MCI, and patients with diabetes did not have a significantly higher risk of dementia with Lewy bodies. Table-2 also presents the effects of specific components of CVD (including myocardial infarction, congestive heart failure, or peripheral vascular disease) on the risk of ADRD. Overall results were similar to those of CVD as a whole, except that peripheral vascular disease was not significantly associated with the risk of AD and vascular dementia, likely due to small sample size with wide confidence internals.

Table 2. Hazard ratio of dementias by vascular diseases in men with prostate cancer with up to 26 years of follow-up from 1991 to 2016

*Hazard ratios were adjusted for age, race/ethnicity, marital status, tumor stage, tumor grade, comorbidity score, chemotherapy, radiation therapy, androgen deprivation therapy, year of diagnosis, and SEER areas; **see Methods section or footnote in Table-1 for the description of abbreviations.

 

The adjusted risks of all types of ADRD were significantly associated with patient age. As compared to patients aged 65-69, those aged 75-79 were 3 times more likely to develop AD (3.26, 3.16-3.37) and those aged 85 or older were nearly 7 times more like to develop AD (6.98, 6.67-7.31). As compared to NH-white men, NH-black and Hispanic men were 26% and 7% more likely to develop AD, respectively, while Asian men were 20% less likely to develop AD. Unmarried men appeared more likely to develop AD, vascular dementia, other dementias, and overall ADRD, but less likely to develop dementia with Lewy bodies, FTD and MCI than married men. Higher tumor stage appeared to be associated with a higher risk of ADRD but poorer tumor grade was associated with a lower risk of ADRD. The receipt of chemotherapy was associated with a significantly increased risk of AD (1.14, 1.08-1.21) and ADRD (1.16, 1.13-1.20), whereas the receipt of radiation therapy was associated with a significantly lower risk of AD (0.85, 0.83-0.87) and ADRD (0.87, 0.86-0.88), but there was no significant association between androgen deprivation therapy and ADRD. Patients with higher comorbidity scores had a significantly higher risk of AD, vascular dementia, other dementias, or total ADRD. There were some significant geographical variations in the risk of AD and other types of ADRD among patients from SEER areas by state where the registries located.
Table-3 presents the risk of various types of ADRD in association with the number of vascular diseases (CVD, stroke, hypertension, and diabetes) that were present. There was a significant and consistent association between the risk of AD and ADRD and the increasing number of vascular diseases present. As compared to patients without any of these diseases, those with 1, 2, 3, 4 of these diseases were significantly more likely to develop all types of dementias, including AD, vascular dementia, and total ADRD. For example, patients with 4 of these vascular diseases were 85% more likely to develop AD (1.85, 1.66-2.05), 250% more likely to develop vascular dementia (3.50, 3.09-3.97), and 161% more likely to develop any ADRD (2.61, 2.47-2.76) as compared to those without any of these diseases, after adjusting for patient socio-demographics and tumor factors. The hazard ratio of FTD in association with 4 of these risk factors was the only hazard ratio that was not statistically significant, likely due to small number of events for FTD with wide confidence intervals. The patterns of associations between the risk of various types of ADRD and other factors (such as age, race/ethnicity, tumor characteristics, cancer treatments, comorbidity, and SEER areas) after adjusting for a combination of vascular diseases (Table 5) were similar to the results that adjusted for individual vascular diseases in Table 4.

Table 3. Hazard ratio of dementias by combination of risk factors (CVD, stroke, hypertension and diabetes) in men with prostate cancer

*Hazard ratios were adjusted for age, race/ethnicity, marital status, tumor stage, tumor grade, comorbidity score, chemotherapy, radiation therapy, hormone therapy, year of diagnosis, and SEER areas; **see Methods section or footnote in Table-1 for the description of abbreviations.

 

Table-4 presents the risk of ADRD by vascular diseases and other factors after taking into consideration death as a competing risk for ADRD in the Fine and Gray regression models. Associations between the vascular diseases and the risk of AD and ADRD remained statistically significant after considering death as a competing risk in the regression models. For instance, the risk of AD significantly increased for patients with CVD (1.09, 1.06-1.14), stroke (1.30, 1.28-1.32), hypertension (1.04, 1.03-1.05), and diabetes (1.24, 1.23-1.25), whereas the risk of vascular dementia significantly increased for patients with CVD (1.17, 1.11-1.23), stroke (1.31, 1.29-1.33), hypertension (1.05, 1.04-1.06), and diabetes (1.25, 1.24-1.27). The patterns for the risks of AD and other types of ADRD in association with patient socio-demographics and tumor factors were also similar overall after considering death as a competing risk in the regression models. Chemotherapy was still significantly associated with a higher risk of AD (1.29, 1.26-1.32) and ADRD (1.25, 1.22-1.28). However, the reduced risk of AD (0.89, 0.87-0.91), vascular dementia (0.89, 0.87-0.91), total ADRD (0.91, 0.90-0.93), and other types of dementias became statistically significant in men with prostate cancer who received androgen deprivation therapy as compared to those who did not.

Table 4. Hazard ratio of developing ADRD by a history of CVD, stroke, hypertension and diabetes in men with prostate cancer with up to 26-year follow-up from 1991 to 2016 considering death as competing risk

*Hazard ratios were adjusted for age, race/ethnicity, marital status, tumor stage, tumor grade, comorbidity score, chemotherapy, radiation therapy, androgen deprivation therapy, year of diagnosis, and SEER areas; **see Methods section or footnote in Table-1 for the description of abbreviations.

 

Table-5 presents the risk of AD and ADRD by excluding incident cases that occurred during the first 1 year and 5 years after the date of cancer diagnosis, which aimed to control for potential reverse causation bias that could be resulted from the effects of preclinical or prodromal dementia on susceptibility to vascular diseases. The magnitude and direction of the adjusted hazard ratios of developing AD or ADRD were similar to those in Table 2 that did not exclude those cases within 1 or 5 years, after adjusting for confounding factors. For example, after excluding any ADRD cases that occurred during the first 5 years, men with CVD (adjusted hazard ratio: 1.18, 95% CI: 1.15-1.21), stroke (1.42, 1.39-1.45), hypertension (1.21, 1.19-1.23), and diabetes (1.34, 1.32-1.36) had significantly higher risks of developing ADRD than those who did not have these conditions. The patterns of cumulative incidence (Supplementary Table-S5) and the adjusted hazard ratios of developing AD or ADRD (Table 5) by history of vascular diseases, age, gender, and race/ethnicity were similar to the results that did not exclude those cases (Tables 1 and 2). Table-5 also presents the effects of specific components of CVD (i.e., myocardial infarction, congestive heart failure, or peripheral vascular disease) on the risk of ADRD. Overall results were similar to those of CVD as a whole, except that peripheral vascular disease was not significantly associated with the risk of AD.

Table 5. Adjusted hazard ratio of AD and ADRD after excluding dementia cases that occurred within 1 or 5 years, by history of vascular diseases

*Hazard ratios were adjusted for age, race/ethnicity, marital status, tumor stage, tumor grade, comorbidity score, chemotherapy, radiation therapy, androgen deprivation therapy, year of diagnosis, and SEER areas; **see Methods section or footnote in Table-1 for the description of abbreviations.

 

The cumulative incidences, incidence density rates, and the adjusted risk of AD, other types of dementias, and total ADRD that were defined by primary diagnosis only (see Supplemental Tables-S6, S7, S8, S9, and S10) had the similar patterns by CVD, stroke, hypertension, diabetes, and other sociodemographic and tumor characteristics as compared to the above results in Tables 1-5 using any diagnosis code for ADRD, although overall incidence rates of ADRD were lower due to a more stringent definition of ADRD using primary diagnosis only. Because of some differences in the distribution of comorbidities scores, chemotherapy and androgen deprivation therapy between the exposed (vascular diseases) and the unexposed groups, there could be a certain degree of residual confounding. Hence, analyses on the association between vascular diseases and the risk of ADRD were stratified by comorbidities scores, chemotherapy and androgen deprivation therapy (See Supplemental Table S11). The main results and directions remained similar to those without stratifications.

 

Discussion

This study examined a large nationwide and population-based cohort of older men who were diagnosed with prostate cancer to determine the long-term risk of AD and other types of ADRD in association with CVD, stroke, hypertension, diabetes, and other factors. The study found that CVD, stroke, hypertension, and diabetes were associated with a significantly higher risk of developing AD, vascular dementia, and total ADRD combined, even after considering death as a competing risk and also after controlling for potential inverse causation bias by excluding those incident dementia cases that occurred within first 1 or 5 years. The risk of AD and all other types of ADRD increased significantly with increasing numbers of 4 vascular diseases (CVD, stroke, hypertension, and diabetes) combined as compared to those without any of these diseases. Furthermore, the study found that chemotherapy was associated with a significantly elevated risk of AD and ADRD, but radiation therapy and androgen deprivation therapy were associated with a significantly decreased risk of AD and ADRD in men with prostate cancer.
Strong associations between the risk of ADRD and vascular diseases have been extensively addressed in general population, including cardiovascular disease (6-10), cerebrovascular disease (11-15), hypertension (16, 17), and diabetes (18-20). These associations were observed in a cohort of women who were diagnosed with breast cancer (21). This study also demonstrated that patients with vascular diseases had significantly higher risks of ADRD in men with prostate cancer, indicating that association between vascular diseases and the risk of ADRD was robust regardless of cancer history. However, it should be noted that a number of studies have documented a potential complex inverse association between cancer and the risk of AD. Several observational studies and systematic reviews reported that patients with cancer could have had their risk of AD reduced by 35% (22-31). This inverse association between cancer and AD were unlikely due to a higher mortality in patients with cancer or due to bias or confounding (26, 30). A few biological mechanisms that have been suggested include striking differences between post-mitotic neurons and regular mitotic cells, differential regulation of common genes in AD and cancer, and proteins that suppress tau and amyloid-β deposition and regulate the cell cycle (26).
Another unique issue related to cancer is the receipt of cancer therapies such as chemotherapy and androgen deprivation therapy which were shown to be associated with the risk of AD or ADRD. A few small-scale clinical trials have reported that cancer chemotherapy agents were associated with an increased risk of difficulties in memory, attention, and concentration (31-38). Several observational studies demonstrated that the receipt of chemotherapy was associated with an increased risk of dementias (36-38), but other observational studies showed no significant association between chemotherapy and ADRD in women with breast cancer and in men and women with colorectal cancer (54, 55). Similarly, the findings were also mixed on the association between androgen deprivation therapy and the risk of AD in men with prostate cancer. Several studies showed that androgen deprivation therapy was associated with an increased risk of AD, but not associated with the risk of vascular dementia (39-46), whereas other studies showed no significant association between androgen deprivation therapy and ADRD (47-51). Our study found that among men with prostate cancer, the receipt of chemotherapy was associated with an increased risk of AD, vascular dementia, DLB, MCI, and overall ADRD. The use of androgen deprivation therapy was not significantly associated with the risk of AD, vascular dementia, or ADRD after adjusting for patient socio-demographic and tumor characteristics. However, after considering death as a competing risk, the study showed that androgen deprivation therapy was significantly associated with a decreased risk of AD, vascular dementia, all other types of dementias, and overall ADRD. Because of some mixed findings, further studies may be needed to clarify the association between androgen deprivation therapy and ADRD and potential mechanisms, if confirmed.
This study has several limitations that need to be kept in mind. First, vascular diseases (CVD, stroke, hypertension and diabetes) were identified by diagnosis codes available in Medicare data that were present within 12 months prior to and 30 days after the date of prostate cancer diagnosis. However, duration of these vascular diseases and their treatment status were unknown, which could have affected the risk of dementia. Second, cancer treatment variables for chemotherapy, radiotherapy and androgen deprivation therapy were dichotomized without details on treatment duration and doses. Hence, residual confounding could have distorted the estimated risk of ADRD in association with cancer treatments. Third, the study outcomes on the incidence of ADRD were ascertained from diagnosis codes in Medicare claims. It is possible that total ADRD or specific types of ADRD could be either overestimated or underestimated because the sensitivity and specificity of Medicare claims data for identifying overall ADRD were 85% and 89% (58, 59). Fourth, the study only included men with prostate cancer at age 65 years or older with Medicare Parts A and B without Medicare Advantage. The findings may not necessarily be generalizable to younger men or other patients with Medicare advantage plan. Fifth, the study did not have all relevant variables available in analyses, including education, exercises, and smoking, which may have affected the study results. In addition, immortal time bias is common in an observational study (60), in which the entry time to the exposed population was delayed, so that the study outcome cannot occur during this delayed immortal time period in the exposed group but may still occur in the unexposed group. However, this immortal time bias is minimal, if any, in this study for a number of reasons. First, the study cohort entry time was the date of prostate cancer diagnosis rather than the date of vascular diseases (CVD, stroke, hypertension and diabetes). The date of prostate cancer diagnosis as an entry time was the same for the exposed group (vascular diseases) and the unexposed group (no vascular diseases). The main exposures are vascular diseases (CVD, stroke, hypertension and diabetes) which were defined if they occurred within 12 months (1 year) prior to the date of prostate cancer diagnosis or 30 days after the date of prostate cancer diagnosis to allow additional time to ascertain the exposures to vascular diseases for completeness. Second, because dementia (ADRD) is the main outcome of this study, all dementia cases that occurred at the baseline (i.e., within 12 months prior to and 30 days after the date of prostate cancer diagnosis) were excluded, so that all subjects who remained in this cohort for both the exposed (vascular diseases) and the unexposed groups were free of outcomes at the baseline and were considered as population-at-risk for ADRD. Third, we presented the risk of main outcome (dementia) by excluding dementia cases that occurred within first 1 and 5 years after the cohort study entry (at the date of prostate cancer diagnosis) for both the exposed and unexposed groups, as shown in Table 5.

In conclusion, this study found that CVD, stroke, hypertension, and diabetes were associated with a significantly higher risk of developing AD, vascular dementia, and total ADRD in a large population-based cohort of men with prostate cancer at age ≥65 years. The risk of AD and all other types of ADRD increased significantly with increasing numbers of 4 vascular diseases (CVD, stroke, hypertension, and diabetes) as compared to those without any of these diseases. Chemotherapy was associated with a significantly elevated risk of AD and ADRD, but radiation therapy and androgen deprivation therapy were associated with a significantly decreased risk of AD and ADRD in men with prostate cancer. Because of potential complex relationships between AD and cancer, future studies may be needed to further examine the effects of prostate cancer or other cancers on the risk of AD and other dementias.

 

Ethical statement: This study used the existing and de-identified SEER-Medicare linked datasets. There is no patient contact and no health risk to the subjects under study. This study was approved by the Committee for Protection of Human Subjects at the University of Texas Health Science Center in Houston.

Author contributions: Xianglin L. Du: Conceptualization; Funding acquisition; Investigation; Methodology; Project administration; Resources; Supervision; Roles/Writing – original draft; Writing – review & editing. Lulu Song: Data curation; Formal analysis; Methodology; Software; Roles/Writing – original draft; Writing – review & editing.

Declaration of interests: All other authors declare that there are no competing interests.

Role of the funding sources: This study was supported by the grants (numbers R01AG067498 and R01AG058971) and an Alzheimer’s-focused Administrative Supplement (3R01AG058971-03S1) from the National Institute on Aging (NIA) of the National Institutes of Health (NIH), USA. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH/NIA.

Data sharing: The National Cancer Institute’s SEER (Surveillance, Epidemiology, and End Results)-Medicare Data User Agreement (DUA) specifically requests that “You (the Investigators) will not permit others to use the data except for collaborators within your institution involved with the research as described in your proposal”. However, the SEER-Medicare linked data are available to researchers from the National Cancer Institute upon signing the DUA, having the study proposal approved, and paying the related costs, which is available in their website: https://healthcaredelivery.cancer.gov/seermedicare/. We plan to share the statistical models and statistical programs that we used to analyze these data upon request and to share study findings and related study resources. We also plan to make results and algorithms available for verification or replication by other researchers.

Acknowledgements: We acknowledge the efforts of the National Cancer Institute (NCI), Centers for Medicare and Medicaid Services (CMS), Information Management Services (IMS), and the Surveillance, Epidemiology, and End Results (SEER) registries in the creation of this SEER-Medicare linked database.

 

SUPPLEMENTARY MATERIAL1

 

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