Neuropathologic Changes Provide Insights into Key Mechanisms of Alzheimer Disease and Related Dementia

Alzheimer disease (AD) is a chronic disease characterized by a progressive decline in memory and cognition. AD progression is closely correlated with neuropathologic changes and accumulation of the two main hallmark lesions, senile plaques and neurofibrillary tangles. Nevertheless, deciphering the complex biological aspects of AD requires looking for the neuropathologic changes not only as the cause but also as the collective response to a disease process that is essential to maintaining life during aging but ultimately generates a nonfunctional brain. Chronic conditions, such as AD, represent a new homeostatic balance or disease state, where the organism responds or adapts to maintain life. The pathologic diagnosis of AD still remains the gold standard for precise diagnosis of dementia, commonly in conjunction with cognitive-memory tests and brain image scans. Herein, we present a general overview of the main neuropathologic hallmarks and features of AD and related dementia, revealing the key biological and functional changes as potential drivers of age-dependent brain failure related to AD. The present work reflects some of the main ideas presented during the American Society for Investigative Pathology Rous-Whipple Award Lecture 2021.