Biomarkers to Evaluate Androgen Deprivation Therapy for Prostate Cancer and Risk of Alzheimer’s Disease and Neurodegeneration: Old Drugs, New Concerns

Abstract

Androgen deprivation therapy (ADT) is a standard treatment for prostate cancer patients, routinely used in the palliative or in the curative setting in association with radiotherapy. Among the systemic long-term side effects of ADT, growing data suggest a potentially increased risk of dementia/Alzheimer’s disease in prostate cancer patients treated with hormonal manipulation. While pre-clinical data suggest that androgen ablation may have neurotoxic effects due to Aβ accumulation and increased tau phosphorylation in small animal brains, clinical studies have measured the impact of ADT on long-term cognitive function, with conflicting results, and studies on biological changes after ADT are still lacking. The aim of this review is to report on the current evidence on the association between the ADT use and the risk of cognitive impairment in prostate cancer patients. We will focus on the contribution of Alzheimer’s disease biomarkers, namely through imaging, to investigate potential ADT-induced brain modifications. The evidence from these preliminary studies shows brain changes in gray matter volume, cortical activation and metabolism associated with ADT, however with a large variability in biomarker selection, ADT duration and cognitive outcome. Importantly, no study investigated yet biomarkers of Alzheimer’s disease pathology, namely amyloid and tau. These preliminary data emphasize the need for larger targeted investigations.

Low-Dose Radiation Therapy Impacts Microglial Inflammatory Response without Modulating Amyloid Load in Female TgF344-AD Rats

“…Moreover, testosterone could be directly involved in neuroprotective mechanism against AD, participating to A␤ processing reduction and indirect degradation as examples [42][43][44][45]. Androgen deprivation therapy, classically used for the treatment of high-risk and locally advanced prostate cancer, is suspected to increase the risk of AD [46]. In the brain, sex hormones could act on the astrocytic and microglial response in inflammatory conditions.…”

A Comprehensive Review and Androgen Deprivation Therapy and Its Impact on Alzheimer’s Disease Risk in Older Men with Prostate Cancer

“…The probable association between ADT and dementia is particularly concerning, given all of these issues are associated with low testosterone levels in the blood. 55 …”

“…The probable association between ADT and dementia is particularly concerning, given all of these issues are associated with low testosterone levels in the blood. 55 The Link Between Androgen Deprivation Therapy (ADT) and Cognitive Dysfunction in PCa…”

Androgen Deprivation Therapy for Prostate Cancer: Focus on Cognitive Function and Mood

“…Gender-based differences in AD risk combined with the likelihood that pathways are shared amongst dementias lead us to surmise that revealing the mechanisms and genetic factors underlying ADT-related changes in cognition could move dementia research forward and lead to insights into AD pathophysiology [209,210]. Further, the use of ADT in persons vulnerable to develop AD could accelerate neurodegenerative processes and bring forth the appearance of symptoms of cognitive decline [211].…”