By Tim Armour

From the new findings about oligomers, many supported by Cure Alzheimer’s Fund, we know a lot more about the toxicity of the Abeta42 oligomers and how that affects the neural synapses. None of these first or second generation drugs were aimed at stopping Abeta 42 aggregation or oligomerization; nor were any of them directed toward protecting the neural synapses. They were more directed toward stopping Abeta production altogether through modifying or eliminating steps in the production process.

Furthermore, from new and potentially paradigm-breaking research also sponsored by Cure Alzheimer’s Fund, we now know that Abeta42 may be an integral part of the innate immune system. In other words, it is actually good for fighting off bugs in our system, particularly in the brain, and to develop drugs to stop its production completely or dramatically reduce it would be a big mistake.

Third, Cure Alzheimer’s Fund is supporting new research on more promising approaches to the regulation of Abeta. One of these tracks is the exploration of a whole new class of “gamma secretase modulators” which are safe and more potent that those used in Flurizan or other failed drug tests. A second is experimentation with drugs that specifically target one step of the cholesterol pathway, acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitors, reducing generation of toxic Aβ peptide in cells and in an animal model of AD. And finally, other research being funded by Cure Alzheimer’s Fund is screening all approved (and therefore safe) drugs in the entire human pharmacopeia to see which ones lower Abeta levels.

Were those first and second generation drugs “failures?” If measured by their ability to stop the disease or provide immediate relief to patients — then yes — and that is clearly what is most important. However, in their failure, they have helped to correct the direction along the “Abeta trail” and help us focus on more effective therapeutic approaches.

Where do we go from here? One conclusion is to keep following the Abeta trail. It is increasingly clear that it is the seminal actor in Alzheimer’s pathology.

Second, primary therapeutic targets based on this information should be focused on at least three approaches:

• Continue to find ways to “modulate” the production of Abeta to prevent over-production, but allow that amount that is actually helpful or protective to continue to be made and safely deployed;
• Find ways to prevent the “oligomerization” of the Abeta42 peptide in its most toxic forms.
• Continue to explore the Abeta/neural synapse relationship to maximize Abeta’s potential protective capability and reduce its toxicity.

This will require heeding the lessons from what we are learning from genetics, now having identified over 100 candidate Alzheimer’s genes for more study about how they affect risk for the disease, what the first and second generation drugs have taught us, and aggressive exploration of newer perspectives on the role of Abeta42 and how it can be modulated safely for effective reduction or elimination of risk for Alzheimer’s.

It is a challenging task that will require significantly increased resources. But the way forward is clear; follow the Abeta trail.