Molecules and Memory

The Coming Alzheimer's Epidemic and What Can Be Done About It

From, THE MARYLAND PSYCHIATRIST, SUMMER 2002

Copyrighted, The Maryland Psychiatric Society

Gerald D. Klee, MD

The Alzheimer's Association projects that, at current rates, the number of Americans with Alzheimer's disease will grow by 350% by mid-century—reaching 14.3 million cases, compared with 4 million in 2000. The curve will rise sharply as the first baby boomers reach 65 in 2011. There is a high risk that Medicare will be bankrupted unless ways are found to delay, prevent or ameliorate the disease.

Other epidemics are also expected to add to the rising rate of dementia. For example, the twin epidemics of obesity and diabetes will cause higher rates of cognitive dysfunction due to cerebrovascular disease. 

There are no easy solutions. This massive set of problems will require the best that medical science has to offer in addition to healthier life styles for Americans.

Neurobiologists are creating new classes of memory enhancing drugs that may provide some relief. The “decade of the brain” did not end with the 1990’s. Brain sciences continue to advance exponentially. Enormous breakthroughs have been made in understanding the molecular and physiological basis for memory. I discussed some of this in the Winter, 2002 issue of TMP (1). This article is a sequel to it.

 Some of the best minds in neurobiology are now engaged in a race to develop new classes of drugs to enhance memory in patients with brain disorders. Alzheimer’s disease (AD), schizophrenia, stroke, traumatic brain injury, Parkinson’s and AIDS are among those disorders that may be helped. Although the giant pharmaceutical companies are competing seriously, it is the small biotech firms with the best scientists that are in the lead, often with some of their financing coming from the giants.

In developing memory-enhancing drugs, biotech companies use strategies based on evidence from molecular research. Numerous genes and many types of molecules participate in memory formation. Scientists have found that they can enhance memory encoding in experimental animals by targeting some of these molecules with experimental drugs. These animals can then learn and remember better than “normal” controls. Drugs that work in animals are expected to work in humans as well because we have the same molecular mechanisms and many of the same genes.

 Kandel, Grand Master

Nobel Prize winning psychiatrist-neurobiologist Eric Kandel was featured in the Winter 2002 TMP article mentioned above. Kandel, of Columbia University, is widely considered to be the leader in the race to devise the first high-tech, memory-enhancing drugs.  Hard on Kandel’s heels are younger neurobiologists Tim Tully and Gary Lynch, who have outstanding records of their own. All three are basing their efforts on knowledge gained from their studies of molecular mechanisms involved in encoding long term memories. All are founders of biotech companies that test thousands of candidate drugs. With both fame and fortune involved, the stakes are high. A huge and growing global market awaits those who come up with successful drugs.

In the mid-nineties, Kandel founded Memory Pharmaceuticals, a biotech firm, with his friend Walter Gilbert, a Harvard University professor and Nobel laureate.  Memory is testing candidate drugs on cultured cells and slices of mouse brain in nutrient broth to see which drugs facilitate genes and molecules that help encode long-term memories. Kandel aims to produce drugs that target molecular steps in the intracellular cAMP- PKA-MAPK- CREB cascade that leads to long term memory encoding.  This cascade results in the activation of certain genes that encode proteins necessary for the growth of new synaptic connections and the conversion of short-term to long-term memory.  By enhancing one or another of the steps on the pathway Kandel can improve long term memory in mice. Kandel and Memory hold many U.S. and foreign patents and patent applications covering “core technologies and new chemical entities”.

Tim Tully, Neurogeneticist 

While Kandel is best known for his studies with sea slugs, Tully and associates of Cold Spring Harbor Laboratory in New York have identified numerous genes involved in memory and learning in the fruit fly. Sixty percent of fruit fly genes can be found in humans; the genetic and the molecular basis for memory is essentially the same in both species, with CREB activation a necessary step in forming long-term memories.

 Tully and Yin created “superflies”, flies with “photographic memory”, by engineering them with the CREB protein switched into the "on" position. Exposed to conditions that could lead to an electric shock, normal fruit flies needed ten trials, but “superflies” learned to avoid the shock in a single trial. While Kandel’s biotech lab uses mouse brain slices, Tully’s firm, Helicon Therapeutics, uses DNA chips to screen drugs. (DNA chips used in genetic studies are segments of DNA, usually attached to a tiny glass surface.) Tully also targets the CREB sequence by various routes. Helicon has already screened hundreds of thousands of compounds. Those that passed screening tests on DNA chips have enabled mice to learn events associated with mild electric shocks twice as fast as normal. Helicon holds patents on several uses of CREB.

  Lynch leads in human studies

Kandel and Tully are both testing drugs in animals, but are far from ready to start human trials. However, Gary Lynch’s drugs are being tested in humans. Lynch, a neurobiology professor at the University of California, Irvine is a founder of Cortex Pharmaceuticals. Cortex has been using a new class of drugs called ampakines in human trials for several years. The ampakines, on which Lynch holds many patents, enhance the functioning of AMPA receptors. AMPA is one of a number of receptor types that respond to glutamate and is among those brain structures thought to be essential in memory formation. Glutamate is the dominant excitatory transmitter in mammalian brain and has multiple types of receptor.

Lynch's initial work showed that ampakines reduce memory impairment in middle-aged rats. In humans, he found that a type of ampakine greatly improves the memory scores of normal elderly people and also in those with mild to moderate AD. Schizophrenic patients can also be helped. Goff and Coyle at Harvard have found improvements in cognitive functions in schizophrenics given ampakines or other drugs that enhance the glutamate pathway.

Ampakines may act in more than one way to improve cognitive functions. They can increase the production of neural growth factors (neurotrophins) in critical areas of the brain. Growth factors play a role in learning, memory, mood states and cell growth.

Rx for sexual dysfunction Lynch says, “The nice thing about ampakines is that there are no receptors for the drug in the periphery, which reduces the chance of adverse side-effects" However, there may be one side effect that will give an extra boost to sales. Cortex holds patents for their use as treatment for loss of libido.

Dr. Arvid Carlsson, who was recently named  Scientific Advisor to the Cortex Board of Directors, shared the 2000 Nobel Prize with Eric Kandel and Paul Greengard.(1)

Tsien’s smart mice

Kandel, Tully and Lynch don’t have the field to themselves. Many scientists, as well as drug companies, are involved in similar pursuits. Joe Tsien, PhD, a comparatively young Chinese immigrant, is one to watch. Tsien, a former Fellow in Kandel’s lab, who is now on the faculty at Princeton, created a sensation in the neurobiology community when his genetic engineering in mice revealed that the NMDA glutamate receptor is a keystone for learning and memory. By manipulating the gene for NMDA, he was able to increase the number of NMDA receptors in mice and to get the receptor channels to stay open longer than “normal”, when they are stimulated. Experiments showed that the transgenic mice had exceptional memories for many types of experience in the lab.

Tsien was soon courted by drug makers. Don’t be surprised if he hops onto the biotech bandwagon, where greater resources will be at his disposal.

No Cure in Sight As yet, there is no cure for AD. Memory problems in AD patients are currently treated with cholinesterase inhibitors, which raise brain levels of the neurotransmitter acetylcholine. They produce many side effects and provide only modest symptomatic benefits. New drugs in the pipeline are a good bet for treating memory impairment, but don’t expect miracles in preventing or curing degenerative brain diseases in the foreseeable future. The drugs won’t reduce costs either, because most patients will still need rehabilitative treatment and other forms of care. If patients live longer, lifetime costs could increase. Drugs can help patients, but they won’t save Medicare.

 Tully puts the limitations of drug treatment into perspective. “We hope, at least, that CREB-enhancing drugs will reduce the amount of practice required to reach the therapeutic maximum”-- (in AD, stroke or other brain impairment).  By this, he means that drugs can supplement rehabilitative measures, but not replace them.

Advice for Patients

What should you say to patients who ask what they can do to reduce “normal” memory loss as they age? Taking memory-boosting drugs is not a good answer and probably never will be for most people. But you can say that regular exercise for the brain and body is a great way to accomplish the goal. A good diet also helps. Physical exercise improves cardiovascular status and boosts nerve growth factor. According to Tully, “the positive effects of physical exercise are 40 times more important for cognitive health than any other known factor.”  

Healthy lifestyles have been found to reduce the incidence of many forms of dementia, including Alzheimer’s. If all do their part, medical science, together with a responsible American public, can reduce the impact of the dreaded epidemic of dementia.

References: 1. Of Slugs and Flies and the Nobel Prize, TMP, Winter 2002

Volume 28, No. 2

Dr. Klee is a founder and Life Fellow Emeritus of the American College of Neuropsychopharmacology (ACNP).