The Mechanisms Of The Cellular Phase Of Alzheimer's Disease

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Alzheimer's disease (AD) remains one of the areas of greatest unmet medical need. AD is a slow process evolving over decades, with a long prodromal phase before clinical symptoms appear. This, together with the complex genetic architecture of sporadic AD, made it necessary to revise the reductionist models for AD pathogenesis. We defined the concept of "the cellular phase of AD", discussing how all cell types of the brain react to amyloid pathology yet maintain the brain for a long time in homeostasis. It is only in the end phase of the disease that the brain functionally collapses giving rise to the clinical phase. In addition, the high heritability (58-79%) of sporadic AD suggests that genetic risk is an important determinant of these cellular reactions. A large part of genetic risk of AD is in genes that are expressed in cells other than neurons, reinforcing the concept that the cellular phase is crucial to understand the progression of AD towards dementia. In the current project we focus on our chimeric mouse models and how they can be used to capture polygenic risk in human cellular models of disease with the aim of understanding mechanisms. The overall aim of the work is to provide a cellular theory for AD and to identify critical steps in the pathological process. In contrast to current therapies that focus on blocking the appearance of the biochemical hallmarks of AD or attempting to treat end-stage dementia (Long and Holtzman 2019), therapies that engage the natural resilience mechanisms of AD promise a new and possibly more effective path to a cure.