Researchers are investigating a deeper understanding of why numerous men diagnosed with prostate cancer also develop Alzheimer’s disease. They aim to discover whether the common hormone therapy used for prostate cancer treatment or an excessive immune response is a contributing factor to this issue.
Researchers at the Medical College of Georgia at Augusta University are delving into the reasons many men with prostate cancer develop Alzheimer’s disease, examining whether standard hormone therapy treatments or heightened immune responses play a role in this connection.
The hormone therapy called androgen deprivation therapy (ADT) treats cancer by lowering testosterone levels, which the cancer relies on for growth. However, androgens are crucial for managing amyloid metabolism, and their absence can lead to an increase in amyloid formation, resulting in the plaques associated with Alzheimer’s.
Dr. Qin Wang, an MD/PhD and the Georgia Research Alliance Eminent Scholar in Neurodegeneration at MCG, stated, “Prostate cancer mainly affects men older than 65, a group already at increased risk for Alzheimer’s due to age. However, the specific impact of ADT in relation to cancer and Alzheimer’s is not well understood.”
Wang’s team theorized that an overactive immune response and inflammation could be contributing factors.
To gain insights, they created an animal model simulating both Alzheimer’s disease and cancer, administering ADT for eight weeks while tracking androgen levels and tumor sizes. “Our initial goal was to validate our model and assess cognitive impairments within that group,” Wang explained.
They also developed additional models, including wild type (without Alzheimer’s or cancer), a group with only Alzheimer’s, and a group with only cancer undergoing ADT therapy, which helped clarify the complex interactions at play. Throughout the study, researchers consistently checked for immune markers in the blood.
After eight weeks, they evaluated amyloid accumulation in the brain but were surprised to find no significant difference in plaque density across any groups.
However, they observed notable reactivity in glial cells among the groups with only cancer and those treated with ADT. Glial cells, which support nerve cells in the central nervous system, exhibited heightened activity, a key sign of brain inflammation, according to Wang.
The researchers identified an increase in pro-inflammatory cytokines—proteins that promote inflammation—along with a reduction in anti-inflammatory cytokines, particularly in the animals diagnosed with Alzheimer’s and cancer receiving ADT.
They also assessed the blood-brain barrier of these animals, finding significant damage. Typically, this barrier safeguards the brain from harmful substances while allowing necessary molecules to pass. Wang and her team reported in the journal Science Advances that “the ADT treatment appears to make the blood-brain barrier more porous. This allows for greater immune cell infiltration into the brain, leading to inflammation and cognitive decline.”
To address the issue of immune cell infiltration, Wang and her team explored a drug already available for treating multiple sclerosis and Crohn’s disease. Natalizumab is a disease-modifying therapy that binds to immune cells, preventing their movement across the blood-brain barrier and into the central nervous system.
The treatment of mice with both cancer and Alzheimer’s using a combination of ADT and natalizumab not only curtailed immune cell infiltration but also enhanced the integrity of the blood-brain barrier.
Wang noted, “We then measured inflammation markers and observed a decrease in their levels. Essentially, we diminished the pro-inflammatory pathways and enhanced cognitive function. We’ve concluded that the action of the immune system is a significant factor, not just the presence of amyloid plaques.”
Given that this drug is already approved for use, future steps may involve conducting clinical trials with patients undergoing ADT for prostate cancer.
In addition to Wang, the research team included AU graduate student Mae Aida; Shalini Saggu, PhD, an assistant professor in the Department of Neuroscience and Regenerative Medicine; Chao Zhang, MD/PhD, a cancer and inflammation researcher at the University of Alabama at Birmingham; and Lizhong Wang, MD/PhD, a professor in Genetics and the Comprehensive Cancer Center at UAB.
This research received funding from the National Institute on Aging.
