With the growing global prevalence of dementia and continuing failures in Alzheimer’s drug trials, there has never been greater urgency to develop a platform that will help to embrace the wider complexity of systems and processes at play within a healthy brain to understand what sets it along the path of neurodegeneration.
The amyloid cascade hypothesis, which presumes the deposition of the amyloid-ß (Aß) peptide in the brain, is the main event triggering Alzheimer’s disease, was formulated in the early 1990s by one of our key project team members, Prof. John Hardy. This influential hypothesis has underpinned and influenced most research and drug trials. Nearly 30 years on, Prof. Hardy and others now believe the hypothesis is too simplistic, which has contributed to failures of drug trails aimed at reducing the amount of Aß in the brain.
It’s not that the hypothesis is wrong, it’s just that more information needs to be integrated and we need to move away from its linear concept. The direct implication of the current amyloid cascade model is that reducing levels of Aß in the brain would lead to reduced symptoms of Alzheimer’s, such as cognitive impairment. This has not happened, and so our project is considering three of the ways the model is oversimplified:
- Time: it is clear the disease process begins, probably with Aß deposition some 20-30 years before dementing symptoms become clinically evident
- Spread: the disease begins in one brain area, usually the hippocampus, and then spreads, possibly by a templating process in a non-random pattern throughout the brain
- Tissue, not just neurons: the model as drawn implies that this is a neuron-only process. Genetics led cellular biology is increasingly pointing to the importance of other cells types, especially microglia as also being crucial to pathogenesis.
Adding the critical component of time would enable the dynamic process of neurodegeneration to be studied in a model of Alzheimer’s, to understand at which point in the disease progression a potential drug therapy (or therapies) would need to be introduced.