Green shoots in dementia’s desert

First, let me say I am not a neurologist or a neuroscientist, but I worked in a Pathology and Cell Biology Department where I had colleagues who were both of those things. I went to their seminars and their graduate students’ Ph.D defenses. I taught in a course on cell biology and histology where neuroscience was a major subject. The College of Physicians and Surgeons at Columbia teaches serious basic science to its medical and graduate students. I followed neuroscience for years, not knowing I would write about it.

In the previous column we established that progress with dementia and other neurological diseases had been depressingly slow. No new treatments for Alzheimer’s or Parkinson’s diseases had been introduced in years. Then, a few green shoots appeared in this desert. The first (for me) was a population study that suggested the people who had been vaccinated for shingles were 20% less likely to develop Alzheimer’s disease than unvaccinated peers. Such studies are called Natural Experiments. There is no effort to intervene, but patterns are still observed. Charles Darwin’s observations, mostly natural experiments, led to the theory of evolution, which is the organizing concept of biology.

The second study with a weight reduction and anti-diabetes drug slowed but did not stop the shrinkage of the brains of patients in the early stages of Alzheimer dementia. More news on such drugs, which are being tested in interventional studies should be forthcoming.

The third study involves two papers from Harvard Medical School and took a molecular approach which concentrated on the genes that are turned on or off in brain neurons as dementia begins and proceeds. Proteins that turn genes on or off are part of the intellectual heartland of molecular biology and thus reassuring to people like me; we know how to do this. After many experiments the Harvard scientists arrived at a compound called lithium orotate, which we will leave hanging while I tell you about mice with Alzheimer’s disease.

Humans, mice, other mammals, and even fruit flies have brains with specific regions devoted to various tasks: sight, small, hearing, short-term memory, long term memory, reasoning, and many others.

A mouse neuron is hard to distinguish from a human neuron under a microscope.We can now introduce mutations into mice that cause human diseases, whether spinal muscular atrophy, cystic fibrosis or dementia, which allows us to study the disease in an animal; this is a sort of biological bootstrapping.Mice live two years and dementia appears early in animals carrying these mutations. They lose their memories and can no longer locate where they are in a maze. We can do experiments on mice that would be ethically impossible in humans. (There are strict rules on minimizing pain for animals and a staff of animal care people and veterinarians to maintain the facility and instruct graduate students and other workers in the proper use of animals.)A research university like Columbia or Harvard may house 80,000 or more mice for the study of various disease conditions.

In our Alzheimer mice, tau and beta-amyloid (both proteins; sequences of amino acids) are overproduced, as in humans with Alzheimer’s disease. Some human patients have high amounts of tau and beta-amyloid but are cognitively normal. These proteins are part of the disease process, but do not cause it. Something else must occur for the neurons to progress to the full disease. According to scientists in the Yanker lab at Harvard Medical School, beta amyloid protein binds to lithium and takes it out of circulation.(Lithium, a small element, has been used in psychiatry for a long time.)

...Progress with dementia and other neurological diseases has been depressingly slow. No new treatments for Alzheimer’s or Parkinson’s diseases have been introduced in years. Then, a few green shoots appeared in this desert.

What is the consequence of sequestering lithium?The neurons (and the mice) progress to the final stages of Alzheimer’s disease: the brain continues to shrink, synapses and cognitive functions disappear.Would more lithium in the mouse drinking water help preserve neurons? Yes,at least in mice.Positively charged lithium bound to a negatively charged organic molecule called orotate is the most effective formulation.

Three years ago, some of the same authors discovered a protein complex called REST that acts to suppress the expression of genes involved in late Alzheimer’s disease. If a cell makes a lot of REST, it does not progress to full dementia, much as if one gives it lithium orotate. Lithium orotate and REST are called checkpoint regulators, well known in other biological processes. The authors of this paper put the case this way: ‘Here we show that endogenous lithium (Li) is dynamically regulated in the brain and contributes to cognitive preservation during ageing.’

None of these potential treatments: Herpes zoster vaccination, anti-diabetes/weight loss compounds, or lithium orotate, in variations or combinations, is guaranteed to be therapeutic; mice are not humans after all, but after years of frustration, it is a relief to try new approaches.

Richard Kessin, PhD, is Emeritus Professor of Pathology and Cell Biology at the Columbia University Irving Medical Center.

Editor’s Note: The Yanker laboratory at Harvard Medical School, which did these studies, lost much of its funding in the recent NIH cuts.