by William K. Summers, M.D.
I am one of several research medical doctors formerly involved in the development of the drug Tacrine, (Cognex®), for the treatment of Alzheimer's disease. In 1982, I left the faculty of the University of Southern California, and joined a team formed by the late Art Kling, M.D. at UCLA.
While I remained in private medical practice in Arcadia, California, I had access to an innovative bench scientist, Ken Tachiki, PhD, who developed sensitive assays for Tacrine. I helped Dr Kling design the pre-clinical experiments on Tacrine, which he used in two different species of monkey.
The rest of the team that put together the classic New England Journal of Medicine article were Larry Majovski, PhD and Gary M. Marsh, PhD. Larry was our classical psychologist, and Gary from the University of Pittsburgh was our statistician.
On November 13, 1986, the World Without Hope, who believed that Alzheimer's was untreatable, were introduced to Tacrine (Summers WK, Majovski LJ, Marsh GM, Tachiki KH, Kling A. Oral tetrahydroaminoacridine in the treatment of senile dementia Alzheimer's type: NEJM 1986; 315:1241-1245.)
In order to preserve the commercial viability of this drug, I personally patented this discovery, embroiling me in years of lengthy litigation, from which I have emerged considerably wiser.
Pushing tacrine through the FDA became my personal issue. At one point demonstrations in front of the FDA were organized to give Alzheimer victims access to treatment. Finally, on September 10, 1993, tacrine became the first FDA approved treatment for Alzheimer's.
I was pleased but strangely unsatisfied. We were now treating this terrible disease, but I wanted to prevent it. I began to study the causes of Alzheimers disease, which today affects some 5 million people in the United States alone.
In the 1990's, other brain researchers believed that Alzheimer's was caused by the markers of the disease seen under the microscope. They believed that tau protein (neurofibrillary tangles) and beta amyloid deposits (brain plaques) caused the disease. Further, they believed the disease was genetically caused.
It made no sense to me to blame a disease of your senescence on your beloved mother who had passed away decades ago, but gave you your genes. The beta amyloid protein (plaques) or the tau protein (neurofibrillary tangles) theories of causation also made no sense to me.
The prevailing common wisdom was flawed and illogical. Plaques and tangles are accumulations of dead nerve cell debris. The corpses of former nerve cells were contained in the plaques and tangles. It was like looking at graves and declaring that tombstones cause people to die.
By my logic, Alzheimer's was a disease of aging. It did not happen to children. What happens with aging is oxidative injury over time to our cells and even our mitochondria. The brain, a highly metabolic lipid-filled organ, is very subject to oxidative injury. It weighs less than 1% of body weight and receives 20% of cardiac output. It burns oxygen and glucose. Both lead to free radicals.
The brain produces neurotransmitters - dopa, dopamine, serotonin, noradrenaline, glutamate, aspartate, and nitric oxide. All of these generate free radicals. Nerve cells become excited by sudden shifts in calcium and other electrolytes. This generates free radicals with consequent oxidative injury. Finally, about 70% of the brain by weight is lipid (fat). Thus, the brain must constantly guard against going rancid (lipid peroxidation) from the oxidative injury of free radicals.
I learned that not only is the brain lipid vulnerable to damage of this kind but mitochondrial DNA is particularly vulnerable to free radical assault. I learned that whereas nuclear DNA is relatively protected by histone sheaths the mitochondrial variety are not so protected and therefore extremely vulnerable. Thus, I felt the genetic component, if any, was due to oxidative injury to DNA that came from living our lives.
All of these thoughts of mine occurred in the 1990's. Since that time the research literature has become replete with the concept of oxidative damage and free radical injury.
Possible Prevention of Alzheimer's Disease? Part 2
by William K. Summers, M.D.