Cellular Vulnerability to Pathological Tau Protein Accumulation in Alzheimer’s Disease

The vast majority of people who develop Alzheimer’s disease (AD) are age 65 or older. The aging of the baby-boom generation will significantly increase the number of people in the world with AD, which has been described as an advancing ‘silver tsunami.’ However, AD is not a normal part of aging, and older age alone is not sufficient to cause this disease. Aging is, however, the major risk factor, and we believe that understanding how the brain ages will allow us to devise ways to better protect it against AD. We propose that certain brain cells are especially vulnerable to aging, making them more likely to go awry in older age, leading to the cascade of events that results in AD. The aging process is poorly understood, and its impact is very often not considered in molecular and cellular studies of AD, making the effect of therapeutics administered to the elderly unpredictable. Recently, using a cutting-edge method to jointly determine brain cell identity and aging-related functional impairments, we identified brain cells that are uniquely vulnerable to aging as they fail to enhance a protective response. Here, we propose to explore these brain cells in the context of AD pathology to understand how aging predisposes the brain to develop AD and how to better protect it.