Approximate 200 papers in the medical literature over the last six years have commented on a possible association of long-term ADT with dementia for prostate cancer (PCa) patients. We have reviewed some of those papers in previous blog entries. Yet the papers keep coming out and some have seemingly contradictory conclusions. Here are two examples:
“Cumulative ADT exposure was associated with dementia.” [Lonergan et al. 2022]
“Androgen deprivation therapy was associated with a significantly decreased risk of AD for men with prostate cancer.” [Du & Song, 2023; note “AD” stands for Alzheimer’s disease]
The first paper sounds bad, but the second one sounds surprisingly good. So, what is going on here?
The Du & Song study was a retrospective look at data from the SEER database linked to a Medicare database in the USA. It included information on 350,000 men diagnosed with PCa, who were all over the age of 65. Some had been on ADT and some also had an AD diagnosed. A separate epidemiological study by Lehrer & Rheinstein (2023) using data form the UK’s Biobank reached a similar conclusion. Both studies suggested that ADT does not cause Alzheimer’s disease and may even be associated with lower risk of that disease. Both studies depended on large registry files with formal neurological diagnoses, plus drug prescription data to define the study populations.
The conclusion that ADT doesn’t cause AD may seem somewhat problematic considering that many studies suggest that long term ADT may lead to some cognitive impairment. To make sense of these papers one needs to realize that Alzheimer’s disease is a specific form of cognitive impairment. Both the Du & Song and Lehrer & Rheinstein papers distinguish Alzheimer’s disease from a variety of other forms of dementia. AD is one form of dementia, but there are others.
A patient who says, after starting on ADT that he is more likely to misplace his car keys or glasses may never be diagnosed with any form of dementia, as that sort of daily cognitive challenge is common with aging. Occasional “senior moments” are not classified as clinically significant dementia. They are just common with aging and are not likely to be recorded in databases like the SEER, which relies on rigorous criteria for neurological diagnoses.
Age turns out to be a key factor here. As we get older, we are all likely to show some signs of cognitive impairment. That is a sad reality of aging, but in and of itself is not a definitive sign of AD. Notably the PCa patients on ADT were on average older than the patients not on ADT. However, if ADT helps men live longer, then they are more likely to experience some decline in cognitive function over time.
Conversely, if AD shortens one’s life expectancy, then it will be less likely to be linked to long term use of ADT. The complicating variable here is that ADT use and the emergence of AD are both more common with old age, but not necessarily causally linked to each other.
So, does ADT cause cognitive impairment? A variety of studies, but not all of them, would say “yes”, as there is some statistical association at the population level between cognitive performance and the long-term use of ADT. But that does not mean that all men on ADT will experience cognitive impairment and it may not show up at all, if they are relatively young and otherwise healthy.
Does ADT specifically increase the chances of getting AD? The data on that suggests the answer is “no”. That is particularly true if they are relatively young and otherwise healthy.
References:
Du, X.L., Song, L. A (2023) 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. J Prev Alzheimers Dis. https://doi.org/10.14283/jpad.2023.8
Lehrer S, Rheinstein PH. (2023) Androgen Deprivation Therapy Unrelated to Alzheimer's Disease in the UK Biobank Cohort. Anticancer Res. 2023 43(1):437-440. doi: 10.21873/anticanres.16179. PMID: 36585167.
Lonergan PE, Washington SL 3rd, Cowan JE, Zhao S, Broering JM, Cooperberg MR, Carroll PR. (2022) Androgen Deprivation Therapy and the Risk of Dementia after Treatment for Prostate Cancer. J Urol. 207(4):832-840. doi: 10.1097/JU.0000000000002335