Alzheimer’s Research on Treatment

August 27, 2014

What kinds of new drugs are being tested in clinical trials?

Today, an estimated 50 to 60 compounds are presently or will soon be tested in human Alzheimer's disease (AD) clinical trials. These studies are sponsored by a number of sources, including the National Institute on Aging (NIA), other institutes of the National Institutes of Health (NIH) and the private sector, primarily pharmaceutical companies. Compounds now under scrutiny focus on three major areas of treatment: short-term maintenance of cognitive function; slowing the progress of the disease, delaying its onset or preventing the disease altogether; and managing behavioral problems associated with the disease.

Currently available drugs approved by the Food & Drug Administration (FDA) for Alzheimer's maintain cognitive function in a subset of AD patients, but only for a limited time. NIH-funded clinical trials are, for the first time, targeting prevention of disease. Current clinical trials are examining a number of compounds to determine what works – and what may not – to slow the onset of AD or retard its development. Interest is now focusing on compounds that directly target disease-related changes in the brain. These include estrogen, anti-inflammatory agents, and anti-oxidants, such as vitamin E. Recently completed studies have moved our knowledge forward, and it is hoped that a great deal more will be learned from newly initiated efforts. Interestingly, some important new findings, in patients who already have AD, have been negative, showing no relationship between treatment with certain drugs and an effect on progression of the disease.

What is the status of the Alzheimer's vaccine?

Several scientific teams at medical universities and pharmaceutical companies are working to develop a vaccine that can induce the body's own immune system to attack the amyloid plaques that build up in the brains of those with Alzheimer's disease. While the first clinical trial for an Alzheimer's vaccine was halted in early 2002 due to serious safety problems, many experts remain convinced that there is still hope for developing an immune-based approach to treating Alzheimer's.

A number of different approaches to vaccine development are in the works. In one novel approach, scientists administered the vaccine to mice through the nose, rather than by injection. In that study, when young mice bred to have symptoms of Alzheimer's were repeatedly given the human amyloid via the nasal route, the mice had a much lower amyloid burden at middle age than animals not receiving the vaccine. Interest in the vaccine approach heightened upon recent preliminary reports that amyloid vaccination prevents cognitive decline in another mouse model of the disease, suggesting that a vaccine might indeed make a difference in the clinical symptoms of Alzheimer's. Preliminary studies in animals are now underway to test the safety and potential efficacy of these vaccines, which may one day be a valuable part of the armamentarium doctors employ to battle Alzheimer's.

What potential therapies are in early (pre-clinical) development?

None of the treatments presently approved for Alzheimer's disease alter the progressive underlying disease processes. Early changes in the brain, including amyloid deposits and formation of neurofibrillary tangles, may play a causative role in AD. Interfering with these processes may be one way to treat or prevent the disease. One promising approach reported recently involves blocking the activity of enzymes (specialized proteins) involved in the formation of amyloid, offering a new target for drug development.

Amyloid is a small molecular fragment (peptide) produced as a result of snipping (cleavage) of the much larger amyloid precursor protein (APP) by two enzymes known as beta (ß) and gamma (γ) secretases. For years, scientists knew that something was snipping the APP into fragments and they even went so far as to name the suspect secretases. But no one had been able to physically and precisely identify the enzymes that did the actual clipping of APP until recently, when the identities of the beta and gamma secretases at last were revealed.

The identity of beta secretase was discovered simultaneously by several drug companies. However, gamma secretasehas proven more elusive. Its activity was known to be affected by mutations in one of the genes (presenilin 1, or PS1) that cause early-onset AD in families. PS1 was identified several years ago, and recent research strongly suggests that PS1 is itself the gamma secretase. It is believed this line of research could lead to the discovery of drugs that inhibit the production of amyloid without inhibiting other essential functions these secretase enzymes might have. Ultimately, clinical trials on such secretase-inhibiting drugs will show whether this approach will work.

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