UC San Diego

Alzheimer’s disease (AD) is a degenerative brain disease, and the most common form of dementia in the elderly, which affects about 5.5 million individuals in the US in 2017. This number will only continue to grow as the proportion of population aged 65 years or older increases due to extending life span resulting from better medical care; currently, 10% of people in this group have AD. AD is the sixth leading cause of death in the US; deaths from this disease increased 89% from 2000 to 2014. The national cost of the disease was estimated to be $230 billion in 2017, which included significant unpaid time away from work for assisted care from friends and family of the patient, costs for providing long-term health care and for currently available palliative treatments which are limited to temporary and mild alleviation of cognitive and behavioral symptoms in a subset of patients. There is no cure, effective prevention or therapeutic regimens for altering the course of the underlying disease process.

Chapter 1 of this dissertation summarizes the current understanding of Alzheimer’s disease, the molecular pathways behind its incidence, available symptomatic treatments, and therapeutic options that are in clinical trials.

Chapter 2 addresses the aim of this dissertation, which was to test whether a γ-secretase modulator, BPN15606, is an effective disease-modifying or preventative treatment in the PSAPP mouse model of AD. We have found that BPN-15606 prevented cognitive impairment, reduced amyloid plaque load, microgliosis and astrogliosis associated with the AD phenotype of PSAPP mice when administered to pre-plaque, but was ineffective when administered to post-plaque PSAPP mice No treatment-related toxicity was observed. We have thus concluded that BPN-15606 is a viable preventative therapeutic for AD, and is a candidate for early-phase human safety trials.

Chapter 3 provides recommendations for future studies to further define the mechanism of γ-secretase modulation by BPN-15606. Additionally, it addresses the need for development and validation of combination therapies to address the multifaceted pathology of AD, and of reliable biomarker techniques to diagnose preclinical AD.