Prostate Cancer Therapy Makes Dementia More Likely

In the largest U.S. study to date on androgen-deprivation therapy and dementia, researchers led by Ravishankar Jayadevappa, University of Pennsylvania, Philadelphia, found that among older men with prostate cancer, those who received this treatment were about 20 percent more likely to develop Alzheimer’s disease or dementia within eight years of their cancer diagnosis than the untreated men. In a July 3 JAMA Network Open paper, the authors report a dose response whereby those who received more ADT had a higher chance of developing these long-term cognitive outcomes. “Our results suggest that clinicians need to carefully weigh the long-term risks and benefits of exposure to ADT in patients with a prolonged life expectancy and stratify patients based on dementia risk prior to ADT initiation,” wrote the authors.

  • U.S. men on androgen-suppressing therapy get dementia at higher rate.
  • More treatment doses makes AD or dementia even likelier.
  • Mechanism is still unclear.

Androgen-deprivation therapy (ADT) is intended to reduce levels of male sex hormones in the body, which fuel the growth of prostate cancer cells. ADT can take the form of surgical castration, drugs that block androgen receptors, or medicine that reduces the amount of androgens made. Some previous studies have linked ADT with dementia or AD, though other studies found no such evidence (Gonzalez et al., 2015; Khosrow-Khavar et al., 2017; and, for a review, Nead et al., 2017). Many had varying inclusion criteria, didn’t account for duration of treatment, had a short follow-up, or included a heterogeneous study population.

To account for these limitations, Jayadevappa and colleagues pored through retrospective data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results–Medicare linked database. They included Medicare claims records from 154,089 men in the U.S., average age 75, who were diagnosed with prostate cancer between 1996 and 2003 and who had no evidence of dementia before diagnosis or treatment. Of those, 91,759 went untreated, while 62,330 underwent some form of ADT within two years of being diagnosed. Patients were followed for an average of 8.3 years. The authors stratified patients by how many doses of ADT therapy they received in the two years after diagnosis—fewer than five, five to eight, and eight or more.

Overall, those who underwent therapy had 14 or 20 percent greater odds of developing AD or dementia, respectively. Those who received four or fewer doses had a 19 percent chance of being diagnosed with either condition, while the five to eight group reached 28 percent likelihood of AD and 24 percent chance of dementia. Eight or more doses, and the chances were 24 and 21 percent, respectively.

The mechanism linking ADT with cognitive decline is unclear, wrote the authors. Given that Alzheimer’s symptoms are usually preceded by a presymptomatic phase longer than this study period, it’s possible that ADT is accelerating a process that is already underway, rather than causing new cases.

“This is a very interesting study because of its size. It confirms earlier work, in which testosterone deficiency has been associated with Alzheimer’s disease,” wrote Eef Hogervorst, Loughborough University, Leicestershire, U.K. “Whether the length of time ADT is given should be reviewed based on these and other data may be considered by an expert panel to adjust ADT guidelines.”—Gwyneth Dickey Zakaib

Comments

  1. This is a very interesting study because of its size. It confirms earlier work, in which testosterone deficiency has been associated with Alzheimer’s disease.

    The men who received androgen-deprivation therapy were older, less likely to be married, and poorer, all risk factors for Alzheimer’s. However, also in analyses that adjusted for this, the  risk with ADT was about 14-24 percent higher.

    At Oxford, we found that men with Alzheimer’s had lower levels of testosterone than controls. Testosterone can have multiple protective effects on the brain. A group lead by Christian Pike also found lower levels of brain testosterone in Alzheimer’s. Other studies have shown that ADT is associated with decreases in cognitive function.

    However, ADT can help slow the speed of growth of cancer cells in prostate cancer and help control it. Whether the length of time ADT is given should be reviewed based on these and other data may be considered by an expert panel to adjust ADT guidelines.

    View all comments by Eef Hogervorst

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References

Paper Citations

  1. Gonzalez BD, Jim HS, Booth-Jones M, Small BJ, Sutton SK, Lin HY, Park JY, Spiess PE, Fishman MN, Jacobsen PB. Course and Predictors of Cognitive Function in Patients With Prostate Cancer Receiving Androgen-Deprivation Therapy: A Controlled Comparison. J Clin Oncol. 2015 Jun 20;33(18):2021-7. Epub 2015 May 11 PubMed.
  2. Khosrow-Khavar F, Rej S, Yin H, Aprikian A, Azoulay L. Androgen Deprivation Therapy and the Risk of Dementia in Patients With Prostate Cancer. J Clin Oncol. 2017 Jan 10;35(2):201-207. Epub 2016 Nov 21 PubMed.
  3. Nead KT, Sinha S, Nguyen PL. Androgen deprivation therapy for prostate cancer and dementia risk: a systematic review and meta-analysis. Prostate Cancer Prostatic Dis. 2017 Sep;20(3):259-264. Epub 2017 Mar 28 PubMed.

Further Reading

Papers

  1. Cherrier MM, Higano CS. Impact of androgen deprivation therapy on mood, cognition, and risk for AD. Urol Oncol. 2019 Mar 9; PubMed.
  2. Nead KT, Gaskin G, Chester C, Swisher-McClure S, Dudley JT, Leeper NJ, Shah NH. Influence of age on androgen deprivation therapy-associated Alzheimer's disease. Sci Rep. 2016 Oct 18;6:35695. PubMed.
  3. Jhan JH, Yang YH, Chang YH, Guu SJ, Tsai CC. Hormone therapy for prostate cancer increases the risk of Alzheimer's disease: a nationwide 4-year longitudinal cohort study. Aging Male. 2017 Mar;20(1):33-38. Epub 2017 Jan 9 PubMed.

Primary Papers

  1. Jayadevappa R, Chhatre S, Malkowicz SB, Parikh RB, Guzzo T, Wein AJ. Association Between Androgen Deprivation Therapy Use and Diagnosis of Dementia in Men With Prostate Cancer. JAMA Netw Open. 2019 Jul 3;2(7):e196562. PubMed.

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