Excerpt 1 – The Epiphany – 1981
My Journey to a
Next Generation Treatment
Donald E. Moss, Ph.D.
[Setting and Summary by Jim Summerton, Ph.D.]
[ Setting and Summary: By 1981 research scientists studying Alzheimer's had made real progress in identifying the biochemical basis for the severe memory decline characteristic of Alzheimer's disease. They discovered that in Alzheimer's there was a substantial drop in acetylcholine, the key neurotransmitter involved in memory. This led scientists to attempt various means to remedy this decline in acetylcholine. These attempts led to development and commercialization of Cognex, the first-generation Alzheimer's treatment, now abandoned because of liver toxicity. Subsequently, three second-generation drugs were developed and approved by the FDA (Aricept, Razadyne, and Exelon). And these three drugs became widely prescribed to improve memory in Alzheimer's patients. Regrettably, even these second-generation drugs are only poorly effective for improving memory and they are plagued by dose-limiting side effects (cramps, diarrhea, nausea, vomiting). Nonetheless, because there are no other options currently available to patients, these
second-generation drugs are still widely prescribed for Alzheimer's patients today.
Back in 1981 Moss' past years of experience and growing expertise with acetylcholine and the enzyme involved in its degradation, positioned him for the crucial epiphany described in this chapter. That epiphany was a flash of insight into how to overcome the serious side effects that plagued the second-generation drugs then being developed to increase acetylcholine and thereby revive memory. His key insight would ultimately lead to Moss' superior third-generation drug for Alzheimer's - as chronicled in this book.]
A 1981 report from Peter Whitehouse and a group at Johns Hopkins shook up the Alzheimer’s world by finding a deficiency of acetylcholine-producing neurons in the brains of patients. This confirmed the original report by Peter Davies in 1976 who had found a general deficiency of acetylcholine in the cortex. But the new report pinpointed the origin of this loss to in the medial forebrain, far below the cortex. These dying cells supplied smaller and smaller amounts of this vital neurotransmitter up to the cortex as the disease progressed. The loss of cells in the medial forebrain was the origin of the acetylcholine shortage and the related memory loss.
The confirmed discovery of the acetylcholine deficiency in Alzheimer’s opened up an avenue for treatment. All we had to do was to increase acetylcholine in the brain to restore memory. It seemed easy.
The first attempt at treating dementia involved trying to replace acetylcholine by loading the patients with a nutritional supplement, either raw choline or lecithin. The hope was that the remaining undamaged nerve cells would take these materials and make more acetylcholine.
This approach didn’t work because simply flooding neurons with the building blocks for acetylcholine didn’t actually turn on the metabolic machinery to make it. And, unfortunately, the patients loaded with choline, besides being demented, had a hard time socially because the therapy gave them a body odor that made them smell like fish.
The second strategy for treating memory loss did not involve trying to increase the amount of acetylcholine being made, but by stopping AChE from breaking it down. This would make whatever acetylcholine that still remained in the patient’s brain last longer and have a greater effect. This approach had the advantage of specifically amplifying memory signals. It would only increase acetylcholine in the connections between nerve cells where it was being released by the sputtering neurons still trying to make memories.
The use of an AChE inhibitor to treat a disorder in the brain introduced a whole new set of problems because acetylcholine also slows the heartbeat and stimulates muscles to contract. Too much acetylcholine outside the brain can cause severe toxicity. This is why potent AChE inhibitors are used as military nerve gases. Therefore, long-term use of an AChE inhibitor to treat dementia seemed almost inconceivable.
In spite of the exceedingly narrow line between improving memory and making the patient sick, some investigators tried physostigmine, a short-acting AChE inhibitor, to see if this strategy could wake up memory for an hour or two. As hoped, the patients showed detectable but fleeting improvement. The problem was that the effect could only be seen at doses that could be barely tolerated by the patients. The amount of AChE inhibition needed to improve memory in the brain was too much for the smooth muscles of the stomach and intestines. This caused the patients to suffer nausea, vomiting, and diarrhea.
Another study published by William Summers and his colleagues in 1981 really set the Alzheimer’s world abuzz with hope. They reported that tacrine, another cholinesterase inhibitor, significantly improved memory when it was given to twelve patients over a period of days in an exploratory experiment.
Although the amount of improvement in memory using physostigmine and tacrine was disappointingly small, these experiments provided a proof-of-concept for AChE inhibition as a treatment strategy and ignited a race to find a cholinesterase inhibitor that could be used to treat Alzheimer’s. These clinical results also showed real-world significance for acetylcholine in memory, what I had been working on since my first experiments at Colorado State.
* * *
I remember the night. I settled into the sofa for an evening of reading, away from the distractions of students, meeting classes, and the telephone.
Jo Anne had retreated to our bedroom which was also fitted out with a desk. She was studying to become a radiation therapist and it was a rigorous program. Leslie and Kelley were in the kitchen washing the dishes and cleaning up like they did most nights.
I had the living room to myself. So I built a fire in the fireplace and put my feet up on the coffee table and opened my copy of a 1981 book entitled Strategies for the Development of an Effective Treatment for Senile Dementia. The book had come in the mail that day and I looked forward to reading it.
The chapters, each written by an expert, laid out the growing animal and human studies that showed that acetylcholine was absolutely necessary for memory and that a deficiency of acetylcholine contributed to dementia in Alzheimer’s disease. Peter Davies, who had made the original discovery that the cortex of Alzheimer’s patients is deficient in acetylcholine, described some of the well-known problems related to the use of AChE inhibitors to facilitate memory. If they were given in doses high enough to assist memory, they also unavoidably caused the plague of nausea, vomiting, and diarrhea. What we needed, he concluded, was a relatively nontoxic AChE inhibitor that worked effectively in the brain.
I sat there for a few minutes thinking. I already knew of such an AChE inhibitor. My own studies, although they were in test tubes, had shown that PMSF strongly inhibited rat brain AChE. Also, the words published years before by Turini and her colleagues, the ones I had read while preparing to publish the PMSF paper with Dave, crashed their way into my mind, crowding out everything else. Turini and her colleagues had found that PMSF given to living rats readily entered the brain and had no discernable effect on muscles. PMSF toxicity in mice was remarkably low.
I tossed and turned the entire night, thoughts racing through my mind, forcing out sleep. By morning, the combination of what I knew about PMSF and what Turini had published in 1969 convinced me that PMSF could be an ideal treatment for Alzheimer’s dementia. It had to be. I would have to check some things to be sure it worked the way I expected.