Androgen deprivation therapy exacerbates Alzheimer’s-associated cognitive decline via increased brain immune cell infiltration

Abstract

Androgen deprivation therapy (ADT) for prostate cancer is associated with an increased risk of dementia, including Alzheimer’s disease (AD). The mechanistic connection between ADT and AD-related cognitive impairment in patients with prostate cancer remains elusive. We established a clinically relevant prostate cancer–bearing AD mouse model to explore this. Both tumor-bearing and ADT induce complex changes in immune and inflammatory responses in peripheral blood and in the brain. ADT disrupts the integrity of the blood-brain barrier (BBB) and promotes immune cell infiltration into the brain, enhancing neuroinflammation and gliosis without affecting the amyloid plaque load. Moreover, treatment with natalizumab, an FDA-approved drug targeting peripheral immune cell infiltration, reduces neuroinflammation and improves cognitive function in this model. Our study uncovers an inflammatory mechanism, extending beyond amyloid pathology, that underlies ADT-exacerbated cognitive deficits, and suggests natalizumab as a potentially effective treatment in alleviating the detrimental effects of ADT on cognition.