Currently available medications for Alzheimer’s disease (AD) provide only modest and temporary symptom relief. Accumulating evidence suggests that disease processes may begin decades prior to symptoms. A better understanding of changes that drive disease during the prodromal period may provide an opportunity for meaningful intervention. Advanced chronological age is the greatest risk factor for developing AD risk regardless of other factors (sex, genetics, diet, etc.). By focusing on the intersection between aging and disease, we have discovered a fundamental cellular aging process, called cellular senescence, as a target for intervention in AD. 

Cellular senescence is a complex stress response that increases in frequency with advancing age. We recently found that neurons in brains from patients with AD have developed features of senescence. This is not common to all neurons, but instead to those that have accumulated tau protein aggregates in the form of neurofibrillary tangles (NFTs), one of the key pathologies of AD. The neurons are unhealthy and resistant to death. They are contributing to chronic tissue damage by releasing toxic factors that damage neighboring healthy cells. Members of our study team have identified medications that selectively target senescent cells. We have tested these drugs, called senolytics, in mouse models of AD in early and late disease stage. Our results indicate that senolytics clear these toxic senescent cells, reduce pathology and improve overall brain structure and function. Moreover, the mice perform better in learning and memory tasks. 

We have demonstrated safety and efficacy of senolytics in Phase I trials for other chronic age-associated health conditions. The treatments have been well tolerated, reduced senescent cells and improved physical function. With these strong pre-clinical findings and proof-of-concept clinical data, we are proposing to conduct the first phase II randomized, placebo-controlled study of senolytic treatment in individuals with prodromal or early AD.