In a recent study with follow-up spanning an average of 8 years, exposure to androgen deprivation therapy (ADT) was found to be associated with a higher risk for Alzheimer’s disease or dementia in older patients with prostate cancer (JAMA Netw Open. 2019;2[7]:e196562).

Ravishankar Jayadevappa, PhD, Research Associate Professor, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, spoke with Oncology Learning Network about these findings and what they mean for recipients of ADT.

What existing data led you and your co-investigators to conduct this research?

There has been growing concern in the possible association between ADT exposure and cognitive dysfunction. There are several purported mechanisms behind this. Decreasing androgen levels may increase risk factors for Alzheimer’s and dementia, including loss of lean body mass, diabetes, cardiovascular disease, and depression. There may be a causative relationship between lower testosterone levels and impaired cognitive function, perhaps via impaired neuron growth and axonal regeneration or accumulation of abnormally folded β-amyloid protein.

Studies using national samples have reported conflicting results regarding the diagnosis of Alzheimer’s or dementia among older prostate cancer patients exposed to ADT. Limitations of these studies include inadequate adjustment for cancer stage, ADT dose and duration; reliance on single-institution data; lack of generalizability to the United States population; and measured and unmeasured bias associated with cohort studies.

Clarifying the association between ADT and dementia could improve shared decision-making around the risks and benefits of ADT in prostate cancer.

Please briefly describe your study and its findings. Were any of the outcomes particularly surprising?

Using SEER-Medicare linked data we demonstrate that exposure to ADT is associated with an increased hazard of subsequent Alzheimer’s or dementia among prostate cancer patients over an average 8.3 years of follow-up post prostate cancer diagnosis.

Exposure to ADT was associated with a 14% higher hazard of diagnosis of Alzheimer’s and 20% higher hazard of dementia. The association was stronger for higher doses of ADT. This association continued within different treatment groups.

To our knowledge, this is the largest study to date examining the association between ADT exposure and subsequent dementia in elderly fee-for-service Medicare enrollees with prostate cancer.

What are the possible real-world applications of these findings in clinical practice?

Physicians must carefully weigh the long-term risks and benefits of exposure to ADT in patients with prolonged life expectancy, and stratify patients based on dementia risk.

Do you and your co-investigators intend to expand upon this research?

Our future research will attempt to elucidate a possible biological mechanism between exposure to ADT and development of dementia, and study this prospectively. It is crucial to establish whether this association is mediated by long-term androgen suppression, especially as dual androgen blockade with second-generation antiandrogens moves earlier in the treatment course of prostate cancer.

In addition, we will conduct further work to characterize individuals undergoing ADT who are at high risk of developing earlier dementia.