USC Health Now

While the barriers to Alzheimer’s treatment remain complex, progress has pushed research closer to a breakthrough.

USC Health Magazine
Spring 2006
by Monika Guttman

His work on Alzheimer’s disease has appeared in most of the prestigious medical journals—_The Journal of the American Medical Association, The New England Journal of Medicine_ and dozens more. Name a drug, a vitamin, an herb that has been linked with hopeful headlines about Alzheimer’s in the past three decades and, most likely, he has run it through a clinical trial. He has tested compounds few others have tried, and with some success.

He is Lon Schneider, M.D., professor of psychiatry, neurology and gerontology at the Keck School of Medicine of USC.

And he remains extraordinarily optimistic about the potential for a treatment breakthrough, even with what he calls “a frustrating lack of progress” in treating Alzheimer’s disease. Despite the advocacy of former United States President Ronald Reagan and his wife Nancy, despite the fact that the National Institute on Aging estimates the number of Americans with Alzheimer’s has more than doubled since 1980 to 4.5 million, despite $647 million in federal funds spent for Alzheimer’s research in 2005 alone. Despite all of this, only two classes of medication have been approved by the U.S. Food and Drug Administration specifically for the treatment of Alzheimer’s disease: memantine, which is an N-methyl-D-asparate (NMDA) receptor antagonist and acetylcholinesterase inhibitors (tacrine, donepezil, rivastigmine and galantamine). Acetylcholinesterase is the enzyme that deactivates the neurotransmitter acetylcholine. Acetylcholine is involved in memory and learning. By inhibiting the enzyme that breaks it down, more acetylcholine continues to be available to stimulate neurons. This may improve Alzheimer’s symptoms early on in some patients, but it does not stop the progression of the disease.

Other medications such as anti-depressants and anti-psychotics help control behavioral symptoms of Alzheimer’s such as sleeplessness, aggression, delusions, wandering, anxiety and depression. While treating these symptoms often makes patients more comfortable and makes their care easier for caregivers, the drugs available today are far from a cure.

As Schneider points out, “From a clinical perspective we have not really made substantial progress since 1993, when the first cholinesterase inhibitor was introduced.”

Study support

But Schneider believes there has been progression in research. “We’ve made huge amounts of progress understanding dementia and understanding that not all forms of memory loss are Alzheimer’s,” he says. “There have been large degrees of progress in understanding the molecular biology of Alzheimer’s, which has led us to understand it is heterogeneous both in its molecular genetics and pathology. We’ve made huge progress in understanding the role of beta-amyloid and phosphorylated tau proteins, which are a major contributor to development of Alzheimer pathology.”

These developments, he states, are leading to progress in the search for treatments. For example, greater understanding that beta (ß)-amyloid, a protein fragment that accumulates by stages into the amyloid plaques considered one hallmark of the disease, led to the development of a new drug that began clinical trials last year. The drug, he says, blocks the accumulation of ß-amyloid. There also are active and passive immunization approaches that create antibodies to ß-amyloid.

Schneider is conducting clinical trials to see if statin drugs, which lower cholesterol levels, can help prevent dementia. He is also optimistic about his current trial involving R-flurbiprofen, a drug also being tested for prostate cancer that may stop the formation of the potentially toxic ß-amyloid particles.

As well as potential new pharmaceuticals, Schneider likes to test substances that major drug companies may not fund. He is designing a trial to test the preventive possibilities of omega 3-fatty acids. “We need to do good quality trials as opposed to accepting anecdotes from health gurus,” he says. “The truth is, until we do the studies, we don’t really know.”

The federal government is encouraging research into use of non-pharmaceuticals in treating Alzheimer’s. One example is huperzine A, a naturally occurring compound extracted from club moss that grows in tropical woodlands, which has long been used by traditional Chinese healers as a fever and inflammation remedy. Huperzine A appears to improve memory and retard the emergence of other symptoms of Alzheimer’s, especially in the early stages.

Schneider is spearheading USC participation in a multi-center Phase II trial of huperzine A sponsored by the National Institute on Aging. Earlier trials suggested huperzine A works much like current medications prescribed to treat Alzheimer’s symptoms. “The current drugs are expensive and have side effects,” Schneider says. “What’s potentially attractive about huperzine A is that it’s available and easy to extract from the plant, may have fewer side effects and would cost much less than the current drugs for Alzheimer’s.”

The huperzine A study, Schneider says, is intended to show whether it does improve cognitive function in those already diagnosed with Alzheimer’s. It also will show what dosage may be most effective, and whether there are significant adverse effects. “Most of the information we have so far is anecdotal since there hasn’t been well-designed clinical trials of this herb,” he says.

Clinical concerns

Finding a treatment that could delay onset of some symptoms by even five years could reduce the number of individuals with Alzheimer’s disease by nearly 50 percent after 50 years, according to the Alzheimer’s Association. But Schneider finds it difficult to recruit people for trials such as the huperzine A or R-flurbiprofen studies because “it’s hard to convince them to take something different when there’s an availability of drugs that help with the symptoms.” Then, too, patients and their families may think simply going to a health food store and buying a supplement is enough. “That becomes a concern because if they add huperzine A to an acetylcholinesterase inhibitor such as Aricept, they may have nausea, vomiting, slowing of their heart rate, confusion and even seizures,” he says.

Indeed, a major barrier to clinical progress for Alzheimer’s, Schneider says, stems from the fact that recruiting for Alzheimer’s clinical trials is more difficult than for almost any other condition.

“These studies require a commitment,” he says. “The barriers in Alzheimer’s are complex and multileveled, because it’s rarely the patient who initiates volunteering in such a study. It’s one thing for the patient with heart disease or diabetes to say ‘this may help me.’ With Alzheimer’s, it’s often a spouse or an adult child who is the primary caretaker; they volunteer even less often because they’re older and may have mobility issues of their own and may not be interested in a trial, which requires more transportation and time.“

This attitude may change, he adds, as the baby boom generation advances through middle age and experiences what is known as age-associated cognitive decline. “As you grow older, there’s a general recognition that the brain doesn’t function quite the same,” Schneider says. “People in their forties realize they’re slower, and it bothers them. So this large group of boomers now in their fifties are concerned about maintaining and improving brain function and preventing these dreaded diseases of the brain.”

Also, Schneider says, there is a greater acceptance of natural substances for conserving cognitive performance. “When we’re walking the path of prevention, our society is OK with ‘maintaining your brain’ with vitamins and fish oil,” he says. “On the other hand, if we talk about cognitive enhancement, fears emerge about amphetamines, stimulants, addictions. So as a culture we’re a little split, and it affects the research into slowing cognitive decline or protecting the brain.”

For example, he says, “We don’t attempt to enhance cognition in healthy 38-year-olds. If you’re maintaining performance in people who are not ill, then that’s not the practice of medicine and the culture says we shouldn’t do that. So no drug company is looking into that.”

Schneider remains optimistic. “Medical research has come a long way in understanding this disease. As a society, we should be focused on treating both Alzheimer’s and the daily impairment of cognitive decline. We will get there; the scope of our knowledge increases each year. It will just take commitment from everyone: government, pharmaceutical companies and those who stand to benefit most, the people living with Alzheimer’s.”

For information about participation in clinical trials for memory loss visit the USC Web site www.usc.edu/memory or call the USC Memory and Aging Center at (323) 442-7600.

NOT A SENIOR MOMENT

Some change in memory is normal as we grow older, but the symptoms of Alzheimer’s disease are more than simple lapses in memory.

People with Alzheimer’s experience difficulties communicating, learning, thinking and reasoning that are severe enough to have an impact on work, social activities and family life.

The Alzheimer’s Association has developed a checklist of common symptoms to help distinguish the difference between possible warning signs of Alzheimer’s disease and normal age-related memory changes.

There is no clear-cut line between normal changes and warning signs. It is always a good idea to check with a doctor if a person’s level of function seems to be changing. The Alzheimer’s Association believes that it is critical for people diagnosed with dementia and their families to receive information, care and support as early as possible.

Ten warning signs of Alzheimer’s disease:

1. Memory loss. Forgetting recently learned information is one of the most common early signs of dementia. A person begins to forget more often and is unable to recall the information later.

What’s normal? Forgetting names or appointments occasionally.

2. Difficulty performing familiar tasks. People with dementia often find it hard to plan or complete everyday tasks, such as losing track of the steps involved in preparing a meal, placing a telephone call or playing a game.

What’s normal? Occasionally forgetting why you came into a room or what you planned to say.

3.Problems with language. People with Alzheimer’s disease often forget simple words or substitute unusual words, making their speech or writing hard to understand. For example, instead of toothbrush, asking for “that thing for my mouth.”

What’s normal? Sometimes having trouble finding the right word.

4. Disorientation to time and place. People with Alzheimer’s disease can become lost in their own neighborhood, forget where they are and how they got there, and not know how to get back home.

What’s normal? Forgetting the day of the week or where you were going.

5. Poor or decreased judgment. Those with Alzheimer’s may dress inappropriately, wearing several layers on a warm day or little clothing in the cold. They may show poor judgment, such as giving away large sums of money to telemarketers.

What’s normal? Making a questionable or debatable decision from time to time.

6. Problems with abstract thinking. People with Alzheimer’s may have unusual difficulty performing complex mental tasks, such as forgetting what numbers are for and how they should be used.

What’s normal? Finding it challenging to balance a checkbook.

7. Misplacing things. People with Alzheimer’s disease may put things in unusual places: an iron in the freezer or a wristwatch in the sugar bowl.

What’s normal? Misplacing items such as keys or a wallet temporarily.

8. Changes in mood. People with Alzheimer’s may show rapid mood swings, from calm to tears to anger, for no apparent reason.

What’s normal? Occasionally feeling sad or moody.

9. Changes in personality. The personalities of people with dementia can change dramatically. They may become extremely confused, suspicious, fearful or dependent on a family member.

What’s normal? People’s personalities do change somewhat with age.

10. Loss of initiative. People with Alzheimer’s disease may become passive, sitting for hours in front of the television, sleeping more than usual or not wanting to do usual activities.

What’s normal? Sometimes feeling weary of work or social obligations.