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Short-circuiting the need for expensive clinical trials, researchers have uncovered an association between androgen blockers and cognitive decline by examining patient medical records.
The researchers scanned the records of about 5.5 million patients from two hospitals: Stanford Health Care, in Palo Alto, and, through a prior institutional research agreement, 3.7 million patients from Mount Sinai Hospital, in New York City.
Among this cohort, they identified about 9,000 prostate patients at each institution, 16,888 of whom had non-metastatic prostate cancer. A total of 2,397 had been treated with androgen deprivation therapy.
- Using two different methods of statistical analysis, the team showed that the ADT group, compared to the control group, had significantly more Alzheimer’s diagnoses in the years following the initiation of androgen-lowering therapy.
- By the most sophisticated measure, members of the ADT group were about 88 percent more likely to get Alzheimer’s during the follow-up period.
“There was some chatter in the literature,” said Shah. But no one had formally tried to find out if ADT therapy leads to cognitive defects.
“This is the kind of question that typically you would need a large clinical trial to answer,” said Shah. But a formal clinical trial would be enormously expensive.
“So instead, we’re making secondary use of existing clinical data collected as part of routine medical care” — clinical data that’s practically free.Although ADT may increase the risk of defects in cognition and hand-eye coordination for reasons other than Alzheimer’s disease, the team decided to focus specifically on Alzheimer’s because the condition is easier to identify in medical records, said Shah.
“Broader dementias and vascular dementia are kind of hard to quantify and define, so we had to narrow the scope of the analysis to make it feasible with the methods that we have available,” he said.
After making statistical adjustments to control for biases, the team performed two kinds of tests to assess the reliability of the findings.
- In “falsification tests,” they looked for false associations in the data. Specifically, they looked for five associations with medical conditions such as tuberculosis and allergies unlikely to be connected to testosterone levels. Those tests all came back negative.
- They also looked for associations likely to be positive, such as age and cardiovascular disease — both conditions known to be associated with a risk of Alzheimer’s disease. Those positive associations were confirmed by the data.
“The association found in this study should be evaluated in the context of the overall treatment choices available to any specific patient,” Shah said. “This study demonstrates the value of using existing EMR data to quantify the trade-offs that various treatments offer.”How low testosterone would lead to increased Alzheimer’s risk isn’t precisely known, but there is some evidence that testosterone has a general protective effect on brain cells, so that lowering testosterone would leave the brain less able to resist the processes leading to Alzheimer’s dementia.
Studies in mice and in humans also have suggested that lower testosterone levels may allow greater production of the Alzheimer’s protein amyloid beta. Moreover, low testosterone may increase Alzheimer’s risk indirectly, by promoting conditions such as diabetes and atherosclerosis that are known to predispose to Alzheimer’s.
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Androgen deprivation therapy (ADT), also called androgen suppression therapy, is an antihormone therapy whose main use is in treating prostate cancer. Prostate cancer cells usually require androgen hormones, such as testosterone, to grow.
The findings were published in the Journal of Clinical Oncology.
Sources Penn Medicine, Stanford University
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