Men undergoing androgen deprivation therapy (ADT) for prostate cancer could be almost twice as likely to be diagnosed with Alzheimer’s disease (AD) than those not treated with ADT. The findings, in a study published in the Journal of Clinical Oncology, also show that the risks of developing Alzheimer’s might continue to rise as the duration of ADT treatment lengthens. Analysis, conducted by Penn Medicine and Stanford University researchers, was based on the medical records from two large hospital systems.
The results do not prove definitely that ADT increases the risk of Alzheimer’s development, the researchers noted. But, they said, they clearly point in that direction, and are in line with evidence that low testosterone levels may weaken an aging brain’s resistance to AD.
“We wanted to contribute to the discussion regarding the relative risks and benefits of ADT, and no one had yet looked at the association between ADT and Alzheimer’s disease,” lead author Kevin T. Nead, MD, MPhil, a resident in the department of Radiation Oncology at the Perelman School of Medicine at the University of Pennsylvania, and a fellow at Penn’s Leonard Davis Institute of Health Economics, said in a recent news release. “Based on the results of our study, an increased risk of Alzheimer’s disease is a potential adverse effect of ADT, but further research is needed before considering changes to clinical practice.”
Androgen deprivation therapy (ADT) is used to lower male androgens, specifically testosterone, and although most individuals return to normal testosterone levels post treatment, 20% to 30% have prolonged androgen suppression. In the United States, about half a million men are taking ADT at any given time. Low testosterone levels have been linked to a number of adverse effects, including cardiometabolic disease. Additionally, evidence supports an association between ADT and such illnesses as diabetes and cardiovascular disease, as well as a number of cognitive deficits. Specifically, ADT has been linked to impairments in visual-motor and executive functioning, which are cardinal features of Alzheimer’s disease. Men diagnosed with AD have demonstrated lower levels of circulating and brain testosterone preceding disease onset.
To test the association of androgen deprivation therapy (ADT) in the risk of Alzheimer’s disease, in the study titled “Androgen Deprivation Therapy and Future Alzheimer’s Disease Risk,” the team evaluated two large sets of medical records, the International Classification of Diseases-9th revision diagnosis and Current Procedural Terminology codes, roughly covering 5 million patients, of whom 16,888 had a prostate cancer diagnosis and met the study’s criteria. Of this group, records from some 2,400 patients who had been treated with ADT were then compared with a control group of non-ADT prostate cancer patients, matched according to age and other factors. Researchers used two different methods of statistical analysis.
Results demonstrated a statistically significant association between ADT use and Alzheimer’s risk, as well as a statistically significant increased risk of Alzheimer’s disease with increasing duration of ADT treatment. “It’s hard to determine the precise amount of increased risk in just one study and important to note that this study does not prove causation,” Dr. Nead said. “But considering the already-high prevalence of Alzheimer’s disease in older men, any increased risk would have significant public health implications.”
Evidence from studies conducted in humans and in mice have also demonstrated that lower levels of testosterone may result in a greater production of amyloid beta, a protein that plays a key role in AD. Furthermore, low levels of testosterone may indirectly increase the risk of AD by promoting diabetes, atherosclerosis, and other disorders known to predispose to AD.
Dr. Nead and colleagues are now hoping to test this link in large cancer registry datasets to see which subgroups of patients might be at greatest risk.