Abstract:

Alzheimer’s disease (AD) is the most common form of dementia among the elderly. It currently affects approximately 5.1 million Americans, a number predicted to triple by 2050. AD is clinically manifested as progressive loss of memory and cognitive function, and is characterized pathologically by the formation of amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFT). Since its discovery in 1906, extensive research has been undertaken to define AD pathogenesis and to develop treatments; however, the cause of AD remains largely unknown and no therapeutic success has been achieved in over 200 AD drug trials conducted in the past decade. These challenges underscore the need for increased research focus to better understand AD risk mechanisms that would allow for the development of strategies aimed at AD prevention and early intervention. In the past 20 years, ApoE2 has been increasingly recognized as a neuroprotective variant; however, the underlying mechanisms have been largely unexplored. Our recent findings offer new perspectives for further in-depth studies that will increase our understanding of the roles of ApoE2 and of how ApoE genotypes interact with sex to modulate the adaptation and defense mechanisms in the aging brain. The insights gained from these mechanistic investigations could potentially be translated into therapeutic strategies aimed to transform an aging —in particular, an ApoE4 brain—into an ApoE2-like brain, thereby preventing and reducing the risk for AD.