How far the search for Alzheimer's treatments

has come and where it is heading.

The human and economic burden of Alzheimer's disease is growing steadily. It's recently been estimated that if the present trend continues, 10 to 15 million Americans will be suffering from the mind-devastating disorder by the year 2050, and millions more will be occupied in caring for them. But it may not have to happen. Inspired by heightened concern and increased funding, the pace of discovery is speeding up. With the use of animal models, genetic technology, new drug discoveries, brain imaging, and statistical surveys, we have learned a great deal in just the last few years about the early signs of the disease and how to slow its progress. Now there are even hopes of preventing or reversing what has seemed to be inevitable brain deterioration. Here is a report on some of the latest findings.
Genetic testing and genetic risk

If your mother, father, brother, or sister has Alzheimer's disease, you have a much greater than average chance of developing the disorder. But recent research is suggesting that heredity influences mainly the age when symptoms appear. The relatives of people who develop the disease after age 85, these findings show, are not more vulnerable than average. This means that for the very old (whose numbers are growing fast), the risks are either entirely environmental or genetically universal. At age 85, nearly half of us already have Alzheimer's disease; it's possible that almost all human beings would fall victim if they lived long enough.

The most notorious genetic risk factor for Alzheimer's disease --or for relatively early appearance of its symptoms -- is the E4 variant of the gene that supplies the recipe for the production of apolipoprotein E, a substance involved in the transport of cholesterol. This gene variant accounts for 10%-15% of the risk in American whites and has also been associated with susceptibility to memory loss in healthy adults. But according to recent research, it does not increase the risk for African Americans who inherit the gene from only one parent.

Researchers are looking for other genetic clues to the sources of Alzheimer's disease. A study supported by the National Institute of Mental Health has found that people who carry a certain variant of the gene that codes for brain-derived neurotrophic factor (BDNF) --a substance involved in the development and regeneration of nerve cells --perform worse on certain memory tests as they age and may be more vulnerable to Alzheimer's disease.

To identify other Alzheimer's-related genes, the Alzheimer's Association is working with the National Institute on Aging to create a gene bank with samples from more than 1,000 families in which at least one person has the disease.

In a recent survey, about 80% of adult children of Alzheimer's patients said they would be willing to take a genetic test for the disease, although that proportion dropped to 45% if the test had a 10% chance of being wrong. The National Human Genome Research Institute is exploring the risks and benefits of genetic tests. It is funding research that addresses ethical, legal, and social implications of the issue from the perspective of relatives at risk.
Early detection and diagnosis

A survey last year found that people who care for those with early Alzheimer's disease wait an average of three years to seek help after noticing symptoms. It matters more than ever because early detection and diagnosis are becoming increasingly accurate and meaningful. Knowing something about the probable future can help people arrange their affairs, plan for long-term care, provide advance directives for the later stages of the illness, and decide whether to take one of the drugs that may slow the progress of the disease.

We are able to trace the origins of Alzheimer's back further than ever before. In the last few years, it's become clear that the troubling memory gaps known as mild cognitive impairment -- which can now be more accurately distinguished from the usual losses that come with age --are, in 80% of cases, actually the earliest stage of Alzheimer's disease. People diagnosed with mild cognitive impairment go on to develop Alzheimer's at a rate of 10%-15% per year.

But screening for Alzheimer's disease by general practitioners and other health care providers is still unworkable. The United States Preventive Services Task Force, an independent panel convened by the federal government, says there are no sufficiently brief and accurate tests available. The complete recommendations of the task force can be found at the National Guideline Clearinghouse

Picturing dementia

Images of the working brain have become surprisingly accurate in identifying early signs of dementia. In some studies, positron emission tomography (PET) scans are nearly 90% correct in making the diagnosis. The main indication is low blood flow and energy consumption in and around the hippocampus, a region that consolidates memories. As the illness progresses, images clearly show spreading atrophy and loss of function.

Measuring levels of amyloid plaque and tau protein in the spinal fluid is another possible way to detect Alzheimer's disease at an early stage. Most experts believe the disease begins with the deposit of plaques-clumps of tissue made of a substance called beta-amyloid that accumulate in the spaces between nerve cells due to the abnormal breakdown of amyloid precursor protein (APP). Tau protein, which serves as a structural support in functioning nerve cells, is the main ingredient of the dead neurons called tangles that are another feature of Alzheimer's (see Harvard Mental Health Letter, October and December 2001). It's now known that plaques and tangles begin to appear in the brain long before (sometimes decades before) any symptoms of dementia.

Despite the advances in brain imaging, there are no physical tests for Alzheimer's that can substitute for clinical interviews and neuropsychological examination. PET scans and other images of brain activity are still mainly research tools. The pictures of brain structure provided by magnetic resonance imaging (MRI) are used chiefly to uncover signs of a stroke or tumor or to identify rare forms of dementia. But scientists are developing new techniques for observing changes in the living brain over shorter periods of time and in more microscopic detail.

Beginning next year, an Alzheimer's Disease Neuroimaging Initiative -- with funding from the federal government, pharmaceutical companies, academic centers, and the Alzheimer's Association -- will collect images from brain scans and correlate them with symptoms over a period of years in 400 people diagnosed with mild cognitive impairment and 100 people the same age with better preserved memory.
Cholinesterase inhibitors

The only drugs currently approved by the FDA for the treatment of mild to moderate Alzheimer's disease are the cholinesterase inhibitors tacrine (no longer in use), donepezil (Aricept), rivastigmine (Exelon), and galantamine (Reminyl). They help to maintain the activity of the neurons critical for memory formation by obstructing an enzyme that breaks down the neurotransmitter acetylcholine. The last of these drugs has been available only since 2001, and we are still learning more about them. New research shows that their effects, although modest, persist longer than expected -- possibly at least three to four years. In one study, rivastigmine has been found to improve the behavior problems of nursing home patients even in later stages of the disease. The cholinesterase inhibitors may also benefit patients with vascular dementia, and some preliminary laboratory evidence suggests that they could slow the development of plaques. Nicotine is another drug that enhances the activity of acetylcholine, by a different mechanism. A recent study found that nicotine patches helped slow deterioration of memory in some older people. Several pharmaceutical companies are looking into chemically related drugs that, unlike nicotine, are not addictive and can be patented.
Anti-inflammatory drugs

Many scientists suspect that brain inflammation contributes to the degenerative process that begins with amyloid plaques. They have been encouraged by surveys indicating that people who regularly take aspirin, ibuprofen (Motrin), naproxen (Naprosyn), and other nonsteroidal anti-inflammatory drugs (NSAIDs) have a relatively low rate of Alzheimer's disease. But, as we have learned repeatedly, most recently from research on hormone replacement therapy, that kind of evidence is unreliable. So researchers are now conducting a seven-year study called the Alzheimer's Disease Anti-inflammatory Prevention Trial, in which hundreds of elderly people who have a close relative with Alzheimer's are taking naproxen, rofecoxib (Vioxx), a new type of NSAID, or a placebo. In the first year, neither of these drugs has prevented cognitive decline, while both seem to be raising the rate of cardiovascular problems and bleeding ulcers. There are no controlled studies involving any other NSAIDs.

The usefulness of NSAIDs could be a matter of time, or timing. A recent report to the American Academy of Neurology indicates that people who took NSAIDs regularly for more than two years had less than a third the average rate of Alzheimer's. In a case study published this year, researchers reported on a pair of 90-year-old identical twins, only one of whom was free of Alzheimer's disease. She had been taking anti-inflammatory drugs for decades; her sister had not. Maybe, if these drugs are effective at all, it's necessary to start taking them long before the accumulation of plaques and tangles begins to affect memory and learning.
Estrogen

Laboratory experiments, animal studies, and surveys of women taking hormone replacement therapy encouraged the hope that female hormones could help to prevent or delay the development of Alzheimer's disease or slow its progress. Unfortunately, the evidence against that proposition is mounting. Results from the Women's Health Initiative Memory Study reported this year indicate that combined hormone therapy (estrogen plus progesterone) in women over 65 may actually increase the risk for dementia. The effect of estrogen alone is still being examined in this study, but other research suggests that it does not help women with early Alzheimer's disease. Some still untested combination or dose of female hormones might yet turn out to be a weapon against Alzheimer's, but it's looking less and less likely.
Ginkgo biloba

This plant extract -- a bestseller in some European countries -- is used for assorted purposes including the treatment of depression and memory loss. It is marketed in the United States as an unregulated dietary supplement. The likely active ingredients are the phytochemicals known as flavonoids. How they work (if they do) is unknown. A six-week controlled study published in the Journal of the American Medical Association in 2002 found that ginkgo biloba had no effect on learning and memory in healthy older people. But a combined analysis of controlled studies indicates some improvement in patients with Alzheimer's disease. With funding from the National Institutes of Health, a five-year study with 3,000 participants comparing ginkgo biloba to a placebo for the prevention of Alzheimer's disease is in progress.
Breaking up and disentangling

Scientists are expanding the search for ways to prevent plaques and tangles from forming or doing damage. Theory and experiment suggest many points where the process might be halted or reversed. All this research is at an early stage, and results are tentative.

Protease inhibitors, related to those used in the treatment of AIDS, might hinder the activity of beta-secretase, the enzyme that cuts up amyloid precursor protein into the abnormal fragments that accumulate into plaques.

Neprilysin, an enzyme that declines with age, cuts up beta-amyloid before it can form even small plaques.

Human neprilysin reduces levels of beta-amyloid in the brains of genetically engineered mice. Some scientists now believe that the damage in Alzheimer's disease is done before plaques develop, by smaller, soluble packets of beta-amyloid that move around in the brain and attack neurons. According to this theory, plaques are not an active destructive force but merely a waste deposit.

Serum amyloid P (SAP) is a protein that facilitates the clumping of beta-amyloid into plaques. Researchers are seeking a way to prevent it from attaching itself to beta-amyloid.

Caspases are enzymes found in plaques that may contribute to the destruction of tau protein and the formation of tangles. Some scientists are looking for a substance that blocks the action of caspases.

Another enzyme, Pin1, may prevent the deterioration that leads to tangles by altering the shape of tau protein. Mice lacking the gene that codes for this enzyme develop tangles as they age.

Nerve growth factors promote the development and regeneration of nerve cells. Some of these substances have been shown to prevent the death of neurons in brain-damaged animals. A controlled study of a nerve growth factor in patients with early Alzheimer's found no short-term effects, but experiments are continuing --including the injection of genetically modified skin cells designed to make the brain produce nerve growth factors.
Antioxidants

Age weakens defenses against the oxygen free radicals produced by the chemical reactions that generate the body's energy. These hyperactive molecules are eager to combine with almost any substance they encounter, so it's plausible that they contribute to the formation of amyloid plaques and the degeneration of neurons.

The diet contains many antioxidants, including vitamin C, beta carotene, and the metal selenium, but most of them have not been found to be helpful for Alzheimer's disease at any stage. Only vitamin E may have some promise. A study published in 2003 found that people who take it in food or supplements are less likely to suffer cognitive decline with age. But it proved ineffective in other research in which 1,000 elderly people were followed for four years. The Alzheimer's Disease Cooperative Study, conducted by a group of research centers sponsored by the National Institute on Aging, has enrolled thousands of participants with mild cognitive impairment for an ongoing, three-year controlled study comparing a high dose of vitamin E with a placebo.

Last updated Jan 4/07