Does Androgen Deprivation Therapy (ADT) increase the dementia risk?

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By A/Prof Miranda Xhilaga - PCFA Research Team

More than half of men diagnosed with prostate cancer may receive ADT treatment. This treatment is efficient in decreasing male hormone levels which in turn slows tumour growth. There are established side effects of ADT but the impact of ADT on the brain function has not been established. What we do know is that male hormones (androgens) play a critical role in neuron maintenance and growth. Hence, decreasing androgen levels for extended periods of time could have a major impact on the normal function of the brain.

To date, findings on this research topic have shown conflicting results. In 2016, the conflicting nature of the overall findings led two experts to analyse the literature on the association of ADT for prostate cancer treatment with dementia risk¹. Such analysis is called meta-analysis. Meta-analyses use either a fixed effect or a random effects statistical model. A fixed effect meta-analysis assumes all studies are estimating the same (fixed) treatment effect, whereas a random effects meta-analysis allows for differences in the effect of treatment from study to study.

In their systematic review these authors looked at reported outcomes of dementia among patients on ADT versus no ADT and those on continuous ADT compared to patients on intermittent ADT via various databases. Of nine studies included in the systematic review, seven studies reported an adjusted estimation of the effect for dementia risk. A random-effects meta-analysis of studies reporting any dementia outcome, included 50 541 individuals and showed an increased risk of dementia among ADT users. Authors concluded that the current evidence suggests an ADT associated risk with an increased dementia. They further suggested that such risk should be discussed with patients and be further evaluated via prospective studies.

A prospective cohort study is a longitudinal cohort study that follows over time a group of similar individuals (cohorts) who differ with respect to certain factors under study, to determine how these factors affect rates of a certain outcome.

A retrospective cohort study (also known as a historic study or longitudinal study) is a study where the participants already have a known disease or outcome. The study looks back into the past to try to determine why the participants have the disease or outcome and when they may have been exposed.

After the publication of this review, a major study, looked retrospectively at the risks of occurrences of long-term side effects such as sexual dysfunction, bone fractures, diabetes, cardiovascular disease, and dementia in 201,797 patients². These men were 66 years or older, diagnosed with prostate cancer between 1992 and 2009; 94,528 patients received ADT and 107,269 patients did not receive ADT and were on active surveillance (AS). The study reported that men receiving ADT were at higher risk of bone fractures, diabetes, dementia and coronary heart disease compared to men on AS. The results supported the conclusion of the review mentioned earlier but again, the study was conducted retrospectively.

In the contrary, a prospective study followed more than 45 000 patients who received radiotherapy with or without ADT, for non-metastatic prostate cancer and found that vascular dementia developed in 335 patients, Alzheimer disease in 404, and any other dementia in 758 over a median of 6.8 years³. But when they conducted statistical analyses using these data they did not find a significant correlation between ADT treatment and these forms of dementia. The researchers concluded that there is no link between ADT treatment for prostate cancer and an increased risk of dementia.

While more prospective studies are needed to establish an undisputed link between ADT treatment and diminished cognitive function* in general, men diagnosed with prostate cancer should be aware of the potential of such risk and should discuss the side effects of ADT including risk of dementia with their doctor.

Cognitive functions* can be defined as cerebral activities that lead to knowledge, including all means and mechanisms of acquiring information. It encompasses reasoning, memory, attention, and language and lead directly to the attainment of information and, thus, knowledge.

¹ Nead KT1, Sinha S2, Nguyen PL2. Androgen deprivation therapy for prostatecancer and dementia risk: a systematic review and meta-analysis. Prostate Cancer Prostatic Dis. 2017 Sep;20(3):259-264.

² Nguyen C, Lairson DR, Swartz MD, Du XL. Risks of Major Long-Term Side Effects Associated with Androgen-Deprivation Therapy in Men with Prostate Cancer. Pharmacotherapy. 2018 Oct;38(10):999-1009. doi: 10.1002/phar.2168.

³ Deka R, Simpson DR, Bryant AK, et al. Association of androgen deprivation therapy with dementia in men with prostate cancer who receive definitive radiation therapy. JAMA Oncol.2018; published online ahead of print. doi:10.1001/jamaoncol.2018.4423