Does ADT increase risk for all types of dementia?

Back in December last year, a group of researchers suggested that androgen deprivation therapy (ADT) might be associated with increased risk for Alzheimer’s disease (see “Is ADT giving you Alheimer’s disease?“)

Now the same research group has published data from a second study (see Nead et al. and this media release from Stanford University), suggesting that the association is broader than just an increased risk for Alzheimer’s disease and is actually an association between ADT and dementias in general — i.e., all forms of significant cognitive decline (including Alzheimer’s). However, the authors are also extremely clear that

prostate cancer patients who are receiving ADT shouldn’t make changes to their medications without talking to their physicians

and Dr. Nead has stated explicitly that

I would definitely not alter clinical care based on our results.

We would repeat our oft-used statement that this type of “association” is not any proof of a cause and an effect. The authors cautions are entirely appropriate.

Nead and his colleagues conducted an analysis of electronic medical records from a 9,272-patient Stanford prostate cancer database. That database included 1,827 men who had received ADT. It excluded any men who had dementia at the time of diagnosis of their prostate cancer.

What they have shown is that:

  • The average (mean) age of their 9,272 patients was 66.9 ± 10.9 years.
  • 5,450 of those patients (58.8 percent) were Caucasian.
  • 1,827 men (19.7 percent) had received ADT.
  • The average (mean) follow-up was 3.4 years.
  • There was a statistically significant association between use of ADT and
    • Risk for all forms of dementia including Alzheimer’s disease  (hazard ratio [HR] =2.17; P < 0.001).
    • Risk for all forms of dementia except Alzheimer’s disease (HR = 2.32; P < 0.001)
  • The absolute risk for onset of dementia of any type among these 9,272 patients at 5 years was
    • 3.5 percent among men who had no ADT
    • 7.9 percent among men who received ADT
  • Compared to the men who had no ADT,
    • Patients treated with ADT for a minumum of 12 months had the highest absolute increase in risk for dementia (HR = 2.36; P < 0.001).
    • Patients who were ≥ 70 years of age and who received ADT had the lowest cumulative probability of remaining dementia free.

Thus, what the authors have actually shown is that less than 8 percent of men with prostate cancer go on to have dementia over a 3.4-year follow-up period, but that that risk doubles in men who have ADT compared to those who don’t have ADT (at least in this cohort of patients being treated at Stanford).

What the authors conclude from this is only that

Androgen deprivation therapy in the treatment of prostate cancer may be associated with an increased risk of dementia. This finding should be further evaluated in prospective studies.

We would emphasize their use of the term “may be associated” and the need for further study.

In the Stanford media release, Prof. Kenneth Mahaffey (another Stanford physician who was not involved in this study) is credited with pointing out that a prospective, randomized clinical trial to study whether this association is “real” would probably require thousands of patients as well as many years and millions of dollars to complete. Mahaffey is quoted as stating that

This work is important, but there are a number of examples of such retrospective studies where the results have been completely wrong.

The chances of a prospective, randomized clinical trial ever happening to study this effect is near to non-existent in the current financial climate.

What we would expect the authors to do now is to conduct similar database studies using the electronic record systems from other, large health care systems to see if they can replicate the findings from the Stanford database. Nead also suggests that monitoring patients for onset of dementia in clinical trials that are designed to randomize patients to ADT as compared to no ADT would be another opportunity.

11 Responses

  1. This is interesting timing. Dr. Tanya Dorff asked me to write a paper to add to her proposal of a new prospective trial testing specifically the effects of ADT on dementia and Alzheimer’s. I supported her in the effort and perhaps sometime in the near future a more formal trial will be coming down the road. But I personally can attest that something changed in me after 3 years on ADT that I attribute to the ADT. It’s already known that certain AR drugs, specifically enzalutatmide and bicalutamide, already include language on the label about the possibility of changes in coherency while taking the drugs. The question is whether this is a permanent change.

  2. I know they controlled for diabetes, smoking, and cardiovascular disease, but I wonder if the correlation would different if they controlled for use of anesthesia as well. Of course, one can’t rule out a genetic or epigenetic factor that increases the likelihood of both more virulent prostate cancer (which requires ADT) and dementia.

  3. Tony C:

    So NOW I finally understand why you keep harrassing me about the Yorkshire Pudding … It’s a mild form of dementia! :O)

  4. I still haven’t figured out why you Brits like to make pudding out of terriers. But then again I don’t even understand bubble and squeak. But I can see why Spam is so popular across the pond. :-)

  5. What a coincidence mentioning Spam on the same week you mention Monty Python here?

  6. I must really be a fortunate guy! Twenty years playing the ADT game following failed surgical removal followed by salvage radiation and still playing the game — and have not experienced any of the ADT medications causing me the side effects now being listed. If I do end up experiencing something, it will more likely be age-related since I’m already up to 84 on my way to 100!

  7. Sitemaster and Tony — I didn’t know that Yorkshire pudding was made from terriers. Yuk! Thought that was just a Korean thing. And to think that Yorkshire Pudding was one of my few cooking successes one holiday when my wife was unable to cook! (I followed the recipe book precisely, achieving really good results and a family laugh that has lasted decades.) At least no one has ever snuck any Marmite into our dishes. (It’s probably been at least 17 years since I’ve had a serving of beef — or terrier.)

  8. Proposal for Dementia Research Related to ADT for Dr. Dorff

    Tony, I’m glad she is undertaking this, but I hope she will take great care to sort out the separate effect of aging on dementia. I scanned or read the subject paper, and I’m not confident they eliminated the effect of aging, though they made an attempt and some of the data suggested that there was no significant effect (using a cut-point of age 70), which is contrary to a lot of other general data on dementia and aging.

    I also found no distinction in the paper between continuous versus intermittent ADT. This could be very important, as, in recent years, intermittent ADT is probably a lot more popular than continuous unless a patient has metastatic disease. If the patient does have metastatic disease, then a lot of other treatment factors likely come into play and would complicate the analysis. Also, as IADT allows intermittent recovery of testosterone for the vast majority of us, that could make a critical difference if there is some causal effect due to long-term continuous ADT.

    Also, such a simple problem as getting enough quality sleep while on ADT — which involves overcoming the challenge of hot flashes and sweats for most of us — can be done, but needs attention, and needs to be controlled for in the study. It could be that a deficiency in quality sleep falsely appears as dementia, especially for older men who face other problems due to aging.

    Like Chuck, despite 31 + 19 + 19 + 18 = 87 months of ADT in four rounds spread over 14.3 years, I am aware of no signs of dementia despite being 73 years old. (I have a good friend, a few years older, with a roughly similar history who clearly has dementia, but “age” might very easily be the cause instead of ADT.)

    Thanks for the work you do!

  9. I can think of one possible confounding factor: patients who for one reason or another were not happy with the care they were getting at Stanford and decided to go elsewhere when ADT was proposed. This might select in favor of an excess of mentally less agile patients in those remaining. I don’t know how large the group of departers is, but I do know that I am one.

    By the way, it would be worth mentioning the seemingly well-done Canadian case-control study that found no link between ADT and cognitive decline in a 3-year follow-up, which was reported on this web site on September 7 this year.

  10. Dear Tom:

    I feel the need to point out that that Canadian case-control study by Alibhai et al. was very small indeed, and certainly no more definitive that this study by Nead et al.

    At present, we really have a serious lack of good information about how many men on ADT go on to have serious mental issues as a direct consequence of being on continuous ADT for a meaningful period of time (e.g., a year or more). However, if we were to assume that you might be correct, and that the Stanford cohort was biased towards men who were less mentally agile to begin with (which could be the case, even though I doubt it), then that increases the probability that the overall percentage of men in whom ADT induces serious, long-term mental impairment is relatively small.

  11. Jim,

    They are trying to come up with the best metrics to determine the cognitive effects. To be clear, dementia is but one of the possible cognitive side effects being researched. Other cognitive side effects such as the impacts on short-term and long-term memory, for example, are also being researched, as is the ability to respond to tough or tricky reasoning opportunities. This is an area that the bicalutamide label refers to. Enzalutamide as well. But if and when such a trial comes out, there will be a control arm that will hopefully provide a baseline that can tell us the normal rate of cognitive decline versus the changes on ADT.

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