This writer began his research career in 1980 in academia (Wayne State University and Lafayette Clinic in Detroit) trying to understand and elucidate the biological processes within the brain that underlie learning and memory. My initial research was in animals where I found that I could easily and reliably impair or enhance learning and memory performance following the administration a variety of drugs that modified how nerve cells communicated within the brain. However, the general population is not interested in making a dumber or smarter mouse or rat. What they want to know is how the results of such research could be extrapolated to help improve a person’s ability to learn and remember on the one hand, or, more importantly, slow or ameliorate the cognitive impairments caused by such devastating neurodegenerative disorders as Alzheimer’s disease or Lewy Body dementia. As a natural extension to my research in animals, I set up an Outpatient Dementia Research Program at my clinic and began overseeing the conduct of pharmaceutical industry sponsored Alzheimer’s Clinical Trials. It was these and other trials being conducted by research institutions and pharmaceutical companies around this time that ultimately resulted in the approval of the drugs that are currently available to treat cognitive impairments in people with Alzheimer’s disease.
Unfortunately, one of the major problems that remains to this day is that the animal models do not predict reliably a clinical response in humans. As I said earlier, I and others were able to easily and reliably turn learning and memory on and off using a variety of pharmacological approaches. However, when these same strategies were tried in normal individuals or Alzheimer’s patients, there was either no response or the response was a fraction of the magnitude of what it was in animals. We still do not have an insightful explanation for why this is so. Clearly, the mouse/rat brain is far less complicated than that of a human’s. However, the basic structures that underlie the processing of information by the brain are similar. Animal models have served us well in the past. One of the most compelling examples is in the area of Parkinson’s disease. Scientists could simulate the movement disorder seen in Parkinsonian patients in animals by destroying or damaging a specific area within the brain. They could then reverse the movement disorder by administering drugs that acted like the chemical messenger that the damaged cells would have produced. When such drugs were subsequently tried in Parkinsonian patients, replacement of the deficient chemical messenger worked and significantly reversed the movement impairments experienced by these patients.
So why doesn’t the same approach work for people suffering from Alzheimer’s disease? Well, the area within the brain affected by Parkinson’s disease is small and very localized. Alzheimer’s, on the other hand, affects multiple areas of the brain at the same time. Within these areas are nerve cells and fibers that utilize many different types of chemical messengers to make communication between nerve cells possible. Therefore, stimulating or replacing one specific neurotransmitter has a low probability of making a significant impact. Moreover, the brain is highly redundant. If one pathway is not working as well as it should, the brain has the ability to reroute the pathway around the problem similar to the way police reroute traffic when there is an accident or obstruction in the roadway.
This is not to say that significant advances in our understanding of what goes on in the brain as Alzheimer’s disease progresses have not been made. They have. We certainly know a great deal more about the types of changes that occur, where they occur and the order in which they occur. While a small percentage (approximately 5%) of people who contract Alzheimer’s disease have a clear predisposing familial/genetic risk of contracting the disease, for the vast majority of people there are clearly other factors involved and these continue to elude detection.
It is for this reason that the conduct of Alzheimer’s Clinical Trials is so important. As I stated earlier, the drugs that have thus far been approved do not always work, and, in those people who do derive a benefit, the improvement is small and short-lived. This is why it is important for people at risk or who have measurable cognitive impairments to volunteer to participate in Alzheimer’s Clinical Trials. Even if you or your loved one does not personally derive a benefit from participating in one of these trials, the data you provide can help medical science and the pharmaceutical industry to refocus their strategy toward alternative approaches to treatment that may have an even better probability of producing a significant effect.