From the Guidelines
Age affects the dentate gyrus while Alzheimer's disease primarily impacts the entorhinal cortex due to their different vulnerability to specific biological processes. The dentate gyrus, a region critical for forming new memories, experiences reduced neurogenesis (production of new neurons) as we age, leading to normal age-related memory decline [ 1 ]. This occurs because stem cells in this region gradually lose their ability to divide and produce new neurons, and blood flow to this area diminishes with age. In contrast, Alzheimer's disease initially targets the entorhinal cortex because this region is particularly susceptible to tau protein tangles and amyloid-beta plaque accumulation, as suggested by the preclinical stages of Alzheimer's disease [ 1 ]. The entorhinal cortex serves as a critical gateway connecting the hippocampus to the neocortex, and its early deterioration in Alzheimer's disrupts this vital pathway for memory formation.
Some key points to consider include:
- The pathophysiological process of Alzheimer's disease begins years, if not decades, before the diagnosis of clinical dementia [ 1 ]
- Biomarker evidence of amyloid beta (Aβ) accumulation is associated with functional and structural brain alterations, consistent with the patterns of abnormality seen in patients with mild cognitive impairment (MCI) and AD dementia [ 1 ]
- The long preclinical phase of AD provides a critical opportunity for potential intervention with disease-modifying therapy, if we are able to elucidate the link between the pathophysiological process of AD and the emergence of the clinical syndrome [ 1 ]
- A hypothetical intervention that delayed the onset of AD dementia by 5 years would result in a 57% reduction in the number of patients with AD dementia, and reduce the projected Medicare costs of AD from $627 to $344 billion dollars [ 1 ]
These different patterns of deterioration explain why normal aging typically causes gradual memory decline while Alzheimer's disease produces more severe and progressive memory impairment along with other cognitive deficits.
From the Research
Age-Related Effects on the Dentate Gyrus
- The dentate gyrus is affected by age, with decreased volume observed in older individuals 2.
- This decrease in volume is associated with impaired pattern separation, a critical process for effective memory 2.
- The dentate gyrus is also involved in neurogenesis, which persists in the aged human brain but is poorly understood in pathological conditions such as Alzheimer's disease 3.
Alzheimer's Disease-Related Effects on the Entorhinal Cortex
- Alzheimer's disease is characterized by lesions in the entorhinal cortex, which is the origin of the perforant pathway, a major input to the dentate gyrus 4, 5.
- The density of senile plaques in the dentate gyrus is positively correlated with the density of neurofibrillary tangles in the entorhinal cortex 4.
- Astrocytosis, an increase in fibrillary astrocytes, is observed in the molecular layer of the dentate gyrus in Alzheimer's disease patients, consistent with the progressive course of the illness 5.
Interaction between the Entorhinal Cortex and Dentate Gyrus
- The entorhinal cortex-dentate gyrus circuit is centrally involved in memory processing, conveying spatial and nonspatial context information to the hippocampus 6.
- Astrocytes play a critical role in controlling the entorhinal cortex-dentate gyrus circuit, modulating neurotransmitter release probability and setting basal synaptic strength 6.
- The astrocytic control is circuit-specific and dependent on the cytokine TNFα, which can lead to impaired contextual memory performance during inflammation or infection processes 6.