Cholinesterase inhibitors slow the progression of Alzheimer's: How can they be made more potent?

What is it about?

Forty years of trying to slow or stop Alzheimer's disease by targeting amyloid have resulted in complete failure. However, the so-called cholinesterase inhibitors have now unexpectedly been shown to slow Alzheimer's-induced shrinkage of the brain. Therefore, it is essential to improve the power of the cholinesterase inhibitors. One method proposed for increasing the power of cholinesterase inhibitors is to combine them with so-called "anticholinergics". Unfortunately, this method is expected to speed up the progression of Alzheimer's disease. It would be better to simply use newly developed and fundamentally more powerful cholinesterase inhibitors, the so-called "irreversible" cholinesterase inhibitors.

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Why is it important?

For the first time in the history of Alzheimer's, a drug treatment has been shown to intervene in the biological pathology of the disease and slow its progression. These drugs are the cholinesterase inhibitors, the mainline low-cost drugs which are now used by essentially all Alzheimer's patients to treat their memory and improve their quality of life. The problem is that the currently available cholinesterase inhibitors are too weak and ineffective to achieve strong disease-slowing benefits. To maximize effectiveness, they need to be taken at higher doses that cause nausea, vomiting, and diarrhea, but the patients cannot tolerate these toxic side effects. Therefore, it has been proposed that the cholinesterase inhibitors be taken along with an "anticholinergic" to oppose the toxic effects of the cholinesterase inhibitors and allow them to be taken in higher and more effective doses. Unfortunately, the anticholinergics not only oppose the effects of the cholinesterase inhibitors, but they INCREASE the rate at which Alzheimer's disease progresses. The long-term use of the anticholinergics can be very damaging. It would be better to use the stronger cholinesterase inhibitors which are inherently more powerful and which do not cause toxic side effects, the "irreversible" cholinesterase inhibitors.

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