Dementia risk associated with androgen deprivation therapy (ADT) for prostate cancer (PCa) depends on the class of medication used, according to investigators.

In a study of 23,651 men with newly diagnosed PCa, investigators in Taiwan found that use of oral antiandrogen monotherapy was significantly associated with a 34% and 52% increased risk for all-cause dementia and Alzheimer disease (AD), respectively, compared with not receiving ADT in adjusted analyses, a team led by Lai-Chu See, PhD, of the Chang Gung University College of Medicine in Taoyuan, Taiwan, reported in JAMA Network Open. The investigators found no significant difference in all-cause dementia or AD risk associated with use of gonadotropin-releasing hormone (GnRH) agonists or orchiectomy compared with no ADT use.

The investigators used linked data from the Taiwan National Cancer Registry, National Health Insurance Research Database (NHIRD), and the Taiwan National Death Registry. Their analysis included the following ADTs: the oral antiandrogens bicalutamide, flutamide, and cyproterone; the GnRH agonists leuprolide, goserelin, triptorelin, and buserelin; and bilateral orchiectomy.

Of the 23,651 men, 11,817 (50%) received GnRH agonists, 4054 (17.1%) received antiandrogen monotherapy, 876 (3.7%) underwent orchiectomy, and 6904 (29.2%) did not received ADT. A total of 1525 men were diagnosed with incident dementia during a median follow-up period of 3.46 years.

In a discussion of study limitations, the authors noted that dementia or AD events recorded using diagnostic codes in the claims data may be inaccurate. “However, we examined patient records from more than 2 clinic visits by specialists rather than general practitioners to increase diagnostic validity,” they wrote. In addition, as the study was observational and the NHIRD has inherent limitations, they could not account for residual confounding from unmeasured variables, such as smoking status, family history, physical inactivity, and education level.

Dr See and colleagues noted that the underlying mechanism by which ADT causes dementia is unclear and could be multifactorial. They cited epidemiologic and in vivo studies suggesting that luteinizing hormone (LH) contributes to cognitive decline and beta-amyloid accumulation, a pathologic hallmark of AD. GnRH agonists reduce testosterone and LH levels, they explained, and their study found no clinically meaningful effect of these medications on dementia or AD risk compared with no ADT use.

“We speculated that increased LH level on treatment using antiandrogen monotherapy could partly explain the association of antiandrogen monotherapy with dementia and AD,” they wrote.

The new findings differ from those of a previous study of 30,903 men with newly diagnosed nonmetastatic PCa in the United Kingdom. The study, which was published in the Journal of Clinical Oncology in 2017, found no significant increase in dementia or AD risk associated with GnRH agonists alone, oral antiandrogens alone, GnRH agonists plus oral antiandrogens, and other types or combinations of ADT in adjusted analyses.