Abstract
Background/Aim: In a meta-analysis of 14 studies, men who received androgen deprivation therapy (ADT) for prostate cancer had a higher risk of dementia and/or Alzheimer disease (AD) than men who did not receive ADT. The effect was more pronounced when ADT was given for more than 12 months. However, in all these analyses, two of the strongest AD risk factors after age, family history of AD and the apolipoprotein e4 allele, were not included. In the current study, we have used data from the UK Biobank (UKB) that incorporates these two factors. Patients and Methods: Our analysis included all subjects with prostate cancer and AD. Prostate cancer diagnosis was ascertained using the 10th Revision of the International Classification of Diseases (ICD10), C61. AD diagnosis was ascertained using the 10th Revision of the International Classification of Diseases (ICD10) G30. Single nucleotide polymorphism (SNP) data for rs429358 and rs7412 were used to determine ApoE genotypes. ADT was in UKB field 20003, Treatment/medication code, Medications. Family history of AD was in UKB data fields 20107, Illnesses of father; 20110, Illnesses of mother; 20111, Illnesses of siblings. Results: We studied 13,203 men with prostate cancer. The age of 132 subjects that received ADT was 64±5.6 (mean±standard deviation), and the age of 13,071 subjects that did not receive ADT was 62±5.6 (p<0.001). ADT was not associated with AD, but Apoe3e3 was significantly associated with diminished risk of AD when compared to e4e4. Moreover, every year of age was associated with increased risk of AD. ADT was unrelated to AD (p=0.997). Conclusion: Our UK Biobank data analysis does not confirm that ADT causes AD in men with prostate cancer. Large studies that include family history of AD and ApoeE genotype are needed. Mendelian randomization would also be desirable for a more definitive result.
Androgen deprivation therapy (ADT) is used to treat prostate cancer in half a million men in the United States every year. Although prior research suggested that ADT use in prostate cancer treatment is linked to cognitive deficits, no study had found that ADT increased the risk of Alzheimer’s disease (AD) (1) until a 2016 study of 16,888 men, which indicated that the use of ADT in the treatment of prostate cancer was related to an elevated risk of AD (2). With both a propensity score–matched analysis and a multivariable-adjusted Cox regression analysis, a substantial association between ADT use and the risk of AD was found.
In 2018, a second study found no association between ADT and dementia in males who received definitive radiation for non-metastatic prostate cancer. At the US Department of Veterans Affairs, the researchers conducted an observational cohort study that included 45,218 males diagnosed with non-metastatic prostate cancer. Between January 1, 2001, and October 31, 2015, all participants received definitive radiation with or without ADT. There was no statistically significant link between ADT use and any type of dementia, including vascular dementia and AD (3). A population-based cohort in 2019 revealed no evidence of an elevated risk of AD in men taking ADT; however, there was a modest rise in the risk of non-AD. For a median of four years, 25,967 men with prostate cancer and 121,018 men without prostate cancer were followed. Six percent of the men in both groups were diagnosed with dementia (4).
Jayadevappa et al. used data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results–Medicare database in a fourth a retrospective cohort study. Between 1996 and 2003, 154,089 men were newly diagnosed with prostate cancer. Older males who received ADT had a greater risk of developing AD or other dementia later in life (5).
In a meta-analysis of 14 studies, men who received ADT for prostate cancer had a higher risk of dementia and/or AD than men who did not receive ADT. The effect was more pronounced when ADT was given for more than 12 months (6).
In all these analyses, two of the strongest AD risk factors, family history of AD and the apolipoprotein E4 allele, were not included. In the current study, we have used data from the UK Biobank (UKB) that incorporates these factors.
Patients and Methods
Our UK Biobank application was approved as UKB project 57245 (S.L., P.H.R.). Our analysis included all subjects with prostate cancer and AD. Prostate cancer diagnosis was ascertained using the 10th Revision of the International Classification of Diseases (ICD10), C61. AD diagnosis was ascertained using the 10th Revision of the International Classification of Diseases (ICD10) G30.
Single nucleotide polymorphism (SNP) data for rs429358 and rs7412 were used to determine ApoE genotypes (7). ADT was in UKB field 20003, Treatment/medication code, Medications. Family history of AD was in UKB data fields 20107, Illnesses of father; 20110, Illnesses of mother; 20111, Illnesses of siblings.
Ethics approval. UK Biobank has approval from the Northwest Multi-center Research Ethics Committee (MREC), which covers the UK. It also sought the approval in England and Wales from the Patient Information Advisory Group (PIAG) for gaining access to information that would allow it to invite people to participate. PIAG has since been replaced by the National Information Governance Board for Health & Social Care (NIGB). In Scotland, UK Biobank has approval from the Community Health Index Advisory Group (CHIAG).
Results
We studied 13,203 men with prostate cancer. The age of 132 subjects that received ADT was 64±5.6 (mean±standard deviation), and the age of 13,071 subjects that did not receive ADT was 62±5.6 (p<0.001, two tailed t-test). 96% of subjects were white British.
Incidence of AD family history in 178 men with prostate cancer is presented in Figure 1A. The mother was most often affected, corresponding to the known maternal transmission of AD (8). Figure 1B shows the use of ADT drugs in 178 men with prostate cancer. Bicalutamide was the most common.
Family history of Alzheimer’s disease and androgen deprivation therapy (ADT) drugs in this study. A) Family members affected with Alzheimer’s Disease in 178 men with prostate cancer. The mother was most often affected. B) ADT drugs used in 178 men with prostate cancer. Bicalutamide was the most common.
ApoE genotype versus AD in 9,396 prostate cancer patients is presented in Table I. The effect of genotype was significant (p<0.001, two tailed Fisher exact test). The e4e4 genotype was most associated with AD.
ApoE genotype versus Alzheimer’s Disease (AD) in 9396 prostate cancer patients. The effect of genotype was significant (p<0.001). The e4e4 genotype was most associated with AD.
The number of subjects with a family history of AD versus the number of subjects with AD in 13,203 prostate cancer patients, is shown in Table II. The relationship between AD family history and AD was significant (p=0.032 two tailed Fisher exact test). ADT versus AD in 13,203 prostate cancer patients is shown in Table III. The relationship between ADT and AD was insignificant (p=1.0, two tailed Fisher exact test).
Family history of Alzheimer’s disease (AD) in subjects studied versus those with AD in 13,203 prostate cancer patients. The effect of family history was significant (p=0.032 two tailed Fisher exact test).
Androgen deprivation therapy (ADT) versus Alzheimer’s Disease (AD) in 13,203 prostate cancer patients. The effect of ADT was insignificant (p=1.0, two tailed Fisher exact test).
Multivariate analysis by logistic regression of the effect of ADT on the occurrence of AD in prostate cancer patients is shown in Table IV. Apoe3e3 vs e4e4 was associated with an odds ratio (O.R.) 0.068 (p<0.001), that is, an AD O.R of 14.7. Thus, Apoe4e4 increased the risk of AD when compared to e3e3. Every year of age was associated with an AD O.R. of 1.29. Therefore, every year of age increased the risk of AD. ADT was unrelated to AD (p=0.997).
Multivariate analysis by logistic regression of the effect of androgen deprivation therapy (ADT) on the occurrence of Alzheimer’s Disease (AD) in prostate cancer patients.
Discussion
In the largest study of ADT to date, Jayadevappa et al. (5) reported that men with prostate cancer who received ADT had a 14 percent or 20 percent higher likelihood of acquiring AD or dementia, respectively. Those who received four or fewer doses of ADT had a 19 percent chance of developing either illness, while those who received five to eight doses had a 28 percent chance of developing AD and a 24 percent chance of developing dementia. With eight or more doses, chances were 24 and 21%, respectively. The study found a link between ADT and dementia but did not investigate probable biological reasons. The authors suggest that clinicians should carefully consider the long-term hazards and benefits of ADT exposure in patients with a long life expectancy and stratify patients based on dementia risk before starting ADT (5).
Jayadevappa et al. looked at 154,089 men with average age 75 or older and excluded those with prior history of AD. Our analysis above examined whether ADT and AD occurred together. Jayadevappa et al. removed pre-existing AD and dementia.
Because our population was 65 and over, the older population in the Jayadevappa et al. study had a higher AD background rate. With our multivariate analysis we were able to separate any effect of ADT on AD from the effects of ApoE isoform and age.
Age is the most powerful risk factor for AD. Family history of AD and ApoE genotype are the next most powerful risk factors for AD (9). With these two risk factors included in our multivariate analysis, ADT had absolutely no relationship to AD in men with prostate cancer. In addition, univariate analysis did not reveal an association between ADT and AD.
In elderly men, ADT and testosterone deficiency can impair memory (10), whereas testosterone supplementation can improve memory and spatial awareness. ADT has been shown to have a negative impact on cognition in patients with prostate cancer (11), which returned to normal after the treatments were stopped (12).
Symptoms of AD are frequently preceded by a preclinical period of up to 16 years (13). We hypothesize that ADT dosage reflects the malignancy of the tumor, which is determined by its genetics and is totally unrelated to AD. AD is not caused by ADT. The oncologist uses more ADT to treat higher-grade prostate cancer, which acts as a surrogate metric for disease severity. Patients with a higher Gleason score were more likely to get pharmacologic therapy, according to the Cancer Genome Atlas (TCGA) data (14). The stress of prostate cancer treatment, particularly ADT and its formidable side effects, could easily bring on the symptoms of AD.
A weakness in our study is that UKB records only the diagnosis of prostate cancer. Currently UK Biobank does not have information on Gleason score, stage, or prostate specific antigen (PSA).
Nevertheless, our analysis of UKB data does not confirm that androgen deprivation therapy causes AD in men with prostate cancer. Large studies that include family history and ApoE genotype are needed. Mendelian randomization would also be desirable for a more definitive result (15).
Acknowledgements
This work was supported in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai. Research reported in this paper was also supported by the Office of Research Infrastructure of the National Institutes of Health under award numbers S10OD018522 and S10OD026880. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Footnotes
Authors’ Contributions
Dr. Lehrer and Dr. Rheinstein contributed equally to all aspects of this work.
Conflicts of Interest
The Authors have no conflicts of interest to declare in relation to this study.
- Received July 4, 2022.
- Revision received August 6, 2022.
- Accepted August 8, 2022.
- Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
