From the Guidelines
Age and Alzheimer's disease both affect the entorhinal cortex through different but related mechanisms, with age-related changes and Alzheimer's pathology contributing to its vulnerability. The entorhinal cortex naturally experiences age-related changes including volume loss, reduced blood flow, and accumulation of oxidative damage that impair its function as we grow older 1. This region is particularly vulnerable to aging due to its high metabolic demands and limited regenerative capacity. In Alzheimer's disease, the entorhinal cortex is among the first brain regions affected, with characteristic pathological changes including beta-amyloid plaques, neurofibrillary tangles containing tau protein, and significant neuronal loss. Some key points to consider include:
- The entorhinal cortex's critical role in memory formation and its position as a gateway between the hippocampus and neocortex make it a key region for understanding both age-related and Alzheimer's-related memory impairments 1.
- Age is the best-studied and strongest risk factor for dementia, which explains the increasing burden of cognitive disorders in the years to come 1.
- The changes in cognition will have an impact on the functional status of the individual, rendering them slowly more vulnerable and frail, and ultimately leading to dependence and death 1. The vulnerability of this region in both conditions relates to its critical role in memory formation and its position as a gateway between the hippocampus and neocortex. Key factors contributing to the entorhinal cortex's vulnerability in Alzheimer's disease include:
- Genetic risk factors such as having a first-degree relative with a history of Alzheimer's disease, having the apolipoprotein ε4 genotype or suffering from the Down syndrome 1.
- Cardiovascular risk factors such as hypertension are associated with an increased risk for both Alzheimer's disease and vascular dementia 1.
- Lifestyle factors such as low educational level or head trauma may play an important role 1.
From the Research
Age and Entorhinal Cortex
- The entorhinal cortex (EC) is a vital component of the medial temporal lobe, and its contributions to cognitive processes and memory formation are supported through its extensive interconnections with the hippocampal formation 2.
- Average aging is associated with a gradual decline of memory capacity, and the EC is susceptible to the early formation of Alzheimer's disease neuropathology, even during average trajectories of aging 3.
- SuperAgers, individuals ≥80 years old who show exceptional memory, harbor larger, healthier neurons in the EC compared with their cognitively average same-aged peers, those with amnestic mild cognitive impairment, and even compared with individuals 20-30 years younger 3.
Alzheimer's Disease and Entorhinal Cortex
- During the pathogenesis of Alzheimer's disease (AD), many of the earliest degenerative changes are seen within the EC 2.
- Atrophy in EC reflects the early pathological changes of AD and can be a strong predictor of prodromal AD 4.
- The EC seems to have an obvious advantage over the hippocampus as a biomarker when predicting future conversion to AD in individuals with mild cognitive impairment 4.
- Neurodegeneration in the EC and hippocampus during AD has been clearly linked to impairments in memory and cognitive function 2.
Mechanisms Underlying Neurodegeneration
- Molecular and functional neurodegeneration within the EC may play a primary role in cognitive decline in the early phases of AD 2.
- Early dysregulation of cellular and molecular signaling pathways in the EC involve neurodegenerative cascades including oxidative stress, neuroinflammation, glia activation, stress kinases activation, and neuronal loss 2.
- Dysfunction within the EC can impact the function of the hippocampus, which relies on entorhinal inputs, and further degeneration within the hippocampus can compound this effect, leading to severe cognitive disruption 2.