Alzheimer’s disease – the journey of a healthy brain into organ failure

As the most common dementia, Alzheimer’s disease (AD) exacts an immense personal, societal, and economic toll. AD was first described at the neuropathological level in the early 1900s. Today, we have mechanistic insight into select aspects of AD pathogenesis and have the ability to clinically detect and diagnose AD and underlying AD pathologies in living patients. These insights demonstrate that AD is a complex, insidious, degenerative proteinopathy triggered by Aβ aggregate formation. Over time Aβ pathology drives neurofibrillary tangle (NFT) pathology, dysfunction of virtually all cell types in the brain, and ultimately, overt neurodegeneration. Yet, large gaps in our knowledge of AD pathophysiology and huge unmet medical need remain. Though we largely conceptualize AD as a disease of aging, heritable and non-heritable factors impact brain physiology, either continuously or at specific time points during the lifespan, and thereby alter risk for devolvement of AD. Herein, I describe the lifelong journey of a healthy brain from birth to death with AD, while acknowledging the many knowledge gaps that remain regarding our understanding of AD pathogenesis. To ensure the current lexicon surrounding AD changes from inevitable, incurable, and poorly manageable to a lexicon of preventable, curable, and manageable we must address these knowledge gaps, develop therapies that have a bigger impact on clinical symptoms or progression of disease and use these interventions at the appropriate stage of disease.