Alzheimer’s disease (AD) is a devastating neurodegenerative disease that can begin decades before cognitive deficits are obvious, making it difficult to identify and treat individuals effectively. It is therefore critical to identify early alterations that manifest in preclinical stages of disease, and understand how they contribute to disease progression. Our studies in transgenic mouse models of AD neuropathology have focused on spontaneous subclinical epileptiform activity and on sleep deficits, both of which begin in preclinical stages in both AD patients and mouse models. I will discuss how they contribute to cognitive deficits and disease progression, and our recent efforts to develop effective measures to mitigate them to slow or prevent disease progression. Notably, a small proportion of individuals and mice with AD neuropathology remain cognitively intact and are “resilient” to AD. I will also discuss how we can take advantage of this phenomenon to develop novel strategies to enhance resilience or reduce susceptibility to AD, which may pave the way for personalized medicine approaches.