Medications - On The Horizon: Improving Memory Understanding Age Related Memory Loss

Content provided by the Faculty of the Harvard Medical School

Medications

Research in structural and functional imaging technology (see "Watching the brain at work") has enabled scientists to identify parts of the brain that change with age. Now these imaging methods are being used to evaluate the effects of potential memory-enhancing medications on these brain regions in the hope of finding drugs that might stop or minimize age-related brain changes and, in so doing, reduce or even eliminate age-related memory loss.

Many new drugs are under investigation for the treatment of dementia and mild cognitive impairment. Some work on the same principle as the medications on the market today, aiming at controlling symptoms by boosting levels of acetylcholine, a brain chemical involved in memory (see "Cholinesterase inhibitors"). One candidate is Huperzine A, which is derived from a Chinese herb and widely used to treat Alzheimer's disease in China. Huperzine A is currently being evaluated as a treatment for Alzheimer's disease in a multicenter clinical trial sponsored by the National Institute on Aging and the Alzheimer's Disease Cooperative Study, a research consortium. But several experimental drugs that work in completely different ways hold the potential for actually preventing or reversing the disease.

Ampakines. An international clinical trial of Ampalex (CX516) for the treatment of Alzheimer's disease is near completion. Ampalex is one of a class of drugs called AMPA-receptor potentiators, or ampakines, which accelerate communication between nerve cells. Ampalex is also being studied as a treatment of mild cognitive impairment. Small preliminary trials found that ampakines were safe and that they improved learning and memory in healthy adults. A 2005 British study found that an ampakine drug called CX717 enhanced wakefulness and cognitive function in healthy men ages 18–45.

Secretase inhibitors. Scientists believe that two particular enzymes, called beta- and gamma-secretases, are key players in the sequence of events that results in the buildup of beta-amyloid, the protein that is thought to be the primary cause of brain damage in people with Alzheimer's disease. Drugs are being developed that might treat Alzheimer's by inhibiting the action of these enzymes.

Lithium-like drugs. Long used to treat bipolar disorder (manic-depressive illness), lithium is now being studied for its potential to treat Alzheimer's disease. The drug blocks an enzyme that is essential to the formation of beta-amyloid plaques. A study reported in the journal Nature in 2003 found this to be the case when lithium was given to mice that carried genetic mutations that cause Alzheimer's disease in humans. It is doubtful that lithium itself would constitute a practical treatment for Alzheimer's disease because it causes many side effects, and elderly people with dementia would be especially prone to them. However, similar drugs might be developed that inhibit the Alzheimer's process in the same way as lithium, but without the side effects.

Alzhemed. This compound is being studied for its potential to modify the course of Alzheimer's disease, not just give symptomatic relief. A multicenter clinical trial begun in 2004 found that Alzhemed stopped the progression of symptoms in people with mild to moderate Alzheimer's disease. It is believed that Alzhemed works by preventing beta-amyloid from becoming sticky and forming destructive plaques in the brain. It may also reduce inflammation, another possible mechanism for interrupting the Alzheimer's disease process.

Alzheimer's disease vaccine. A nasal spray vaccine against Alzheimer's disease was developed several years ago by Elan Pharmaceuticals in the hope of removing the accumulation of destructive beta-amyloid protein in the brain. The purpose was to induce the body to produce antibodies against the protein and destroy it before the pathological changes of Alzheimer's occurred. However, the clinical trial of this vaccine had to be stopped midway because of a serious inflammatory reaction in a number of participants.

Follow-up studies on the remaining participants at centers around the world have been mixed. A 2003 study published in the journal Neuron found that 19 of the 28 people in Switzerland who received the vaccine developed antibodies, and that 12 of these people had scores on memory tests that either stabilized or improved over the course of a year. In untreated patients, scores on memory tests typically declined. But other researchers participating in the multicenter trial have not found that people who received the vaccine did better on tests of cognitive function than those who didn't get the vaccine.

More recent follow-up of the participants from the discontinued trial suggests that those who mounted an immune response from the vaccine performed better on some of the cognitive test measures and had a striking reduction of beta-amyloid levels in their brains and spinal fluid.

Another formulation of the vaccine (AAB-001) entered clinical trials at a number of sites around the United States. Rather than using an active vaccination approach (in which the vaccine instigates the recipient's immune system to produce specific antibodies to beta-amyloid), this formulation relies on a passive immunization strategy, in which monoclonal antibodies attach to the beta-amyloid and get rid of it. Because AAB-001 does not stimulate the immune system, it is unlikely to cause the adverse inflammatory response in the nervous system that led to the termination of the earlier vaccine trial.

Nonsteroidal anti-inflammatory drugs. Common pain relievers known as nonsteroidal anti-inflammatory drugs, or NSAIDs, have been studied for their potential to prevent Alzheimer's disease. These include traditional pain relievers such as ibuprofen (Advil, Motrin, and others) and naproxen (Aleve, Anaprox, and others) as well as the COX-2 inhibitors, such as celecoxib (Celebrex). These agents may reduce the nerve cell inflammation that is associated with the disease. But the drugs may also have a more direct effect on the Alzheimer's disease process by breaking apart amyloid plaques, the brain abnormalities that are the hallmark of Alzheimer's.

However, studies have raised the possibility that long-term use of some of these drugs might cause unwanted cardiovascular effects, including stroke or heart attack, and other effects. It is important to discuss your personal health risks with your doctor when considering the long-term use of NSAID or COX-2 medications. The ability of these drugs to prevent Alzheimer's disease remains unknown.

Last updated:	January 23, 2007