Multifunctional Tasks and an Energy Crisis are Crucial Players in Determining the Vulnerability of the Entorhinal Cortex to Early Damage in Alzheimer's Disease.

Alzheimer's disease (AD) is a devastating neurological disorder that affects synaptic transmission between neurons. Several theories and concepts have been postulated to explain its etiology and pathogenesis. The disease has no cure, and the drugs available to manage AD symptoms provide only modest benefits. It originates in the brain's entorhinal cortex (EC), with tau pathology that can proceed overt symptoms by decades and then spreads to other connected areas and networks to cause severe cognitive decline. Despite decades of research, the reason why the EC is the first region to be affected during AD pathophysiology remains unknown. The EC is well connected with surrounding areas to support the brain's structural and functional integrity, participating in navigation, working memory, memory consolidation, olfaction, and olfactory-auditory coordination. These actions require massive energy expenditure; thus, the EC is extremely vulnerable to severe hypometabolism and an energy crisis. Unfortunately, the crucial events/factors that make the EC vulnerable to pathological sequelae more than other brain regions have not been thoroughly explored. An in-depth analysis of available research on the role of the EC in AD could provide meaningful insights into the susceptibility of this region and its role in propagating AD. In this review article, we highlight how the functional complexities of the EC account for its vulnerability in AD.