Beta Amyloid Hypothesis
Research over the last one and a half decades, focused on the pathobiology of AD support the hypothesis which includes the following:
- A progressive cerebral accumulation of AB which initiates a complex multi-cellular cascade.
- Neuritic dystrophy
- Neuronal dysfunction and loss
- Synaptic alterations
- Neurotransmitter deficits
- This cerebral accumulation is due to a gradual and chronic imbalance in the production vs clearance of AB.
Updating the Amyloid Hypothesis
- The hallmark of progressive deposition of insoluble fibrillar AB in senile plaques was proposed initially.
- The magnitude of fibrillar AB load correlates poorly with severity of clinical dementia challenges the original hypothesis.
- Many studies demonstrate that the best statistical correlation occurs with measures of synapse density and degree of dementia and not fibrillar AB load.
- A new understanding suggests that soluble assembly states of AB peptides are better candidates for inducing neuronal and/or synaptic dysfunction.
- These small soluble oligomers can cause cognitive decline by disrupting synaptic function in the absence of significant neuro-degeneration.