AMDA: Publications - Caring for the Ages

This is the second of a two-part series on Alzheimer's disease. Part one appeared in the March 2004 issue on p. 1.

New research on the genetic sources of Alzheimer's disease, a larger commitment to limiting the high cost of the disease, and a drug combination for advanced disease may soon provide more opportunities for earlier treatment and a better understanding of this devastating disease.

An estimated 4.5 million Americans have Alzheimer's disease, and by the year 2050 it is estimated that between 11 million and 16 million will join their ranks. Currently, one in 10 people over age 65 has Alzheimer's disease, and nearly half of those over 85 have it. The cost of Alzheimer's disease in the United States is in excess of $100 billion annually.

The National Institute on Aging (NIA) is "looking at earlier stages of the disease and how the normal aging brain moves to dementia," said Marcelle Morrison-Bogorod, MD, associate director, Neuroscience and Neuropsychology of Aging Program at NIA. Some $28 million will be spent on Alzheimer's disease trials by the NIA this year, with $10 million designated for prevention trials.

New Initiative to Search for Genetic Source

Studying the genes of families with a history of Alzheimer's disease is key to understanding genetic risk factors for late-onset (after age 60) Alzheimer's disease and developing new treatment and prevention strategies, said Richard P. Mayeux, MD, MSc, professor of neurology, psychiatry, and epidemiology, Columbia University.

Dr. Mayeux is leading the Alzheimer's disease Genetics Initiative for Late Onset Alzheimer's Disease. This initiative teams the NIA and other NIA-supported Alzheimer Research Centers with the Alzheimer's Association to recruit, over the next three years, 1,000 U.S. families with a history of Alzheimer's disease in order to identify the genes responsible for late-onset disease. The late-onset type affects 90% of Alzheimer's disease patients.

"This initiative will hopefully provide the large numbers we need to make a firm determination about the genes that are involved in Alzheimer's disease," said Dr. Mayeux. "Gene discoveries may point to a pathway that we've never even considered."

The nationwide initiative will recruit families with three living members who can donate blood, including two living siblings who developed Alzheimer's disease after age 60 and another family member over age 50 who may have memory loss, or a family member over the age of 60 who doesn't have memory loss.

Participants will be asked to undergo a neurological examination or submit medical records and will provide demographic, medical, and family histories. The blood collected will be made into cell lines in order to provide a genetic database of DNA that any Alzheimer's disease researcher can access.

"We've known for decades that amyloid deposition is a factor in Alzheimer's disease," said Dr. Mayeux. "If we can tease out the genes that regulate amyloid production and processing, it will be a major advance in understanding this disease. However, genes in other pathways may also be important."

Genes play a strong role in how well memory works, according to Dr. Mayeux's research of families with more than one person with Alzheimer's disease. A recent study published in Neurology (2004;62(3):414-421) involved 1,036 people from 266 families (mainly in the Dominican Republic and Puerto Rico). Most of the families had more than one person living with Alzheimer's disease in the extended family. All study participants were tested for memory, attention, abstract reasoning, language, and visual-spatial ability.

"We found that about half of the variation in memory performance among individuals is due to genetics," explained Dr. Mayeux. "The other half is due to environmental factors, such as education. This shows that memory performance has a strong genetic influence."

The influence of genetics was not as strong in the areas of attention, abstract reasoning, language, and visual-spatial ability. He noted that the study participants differ from the general U.S. population--especially in years of education, which was limited to an average of six years among Dominican participants. Because education has been shown to protect against the development of Alzheimer's, the risk of the disease in this study group may be higher than in the United States.

"The larger the number of related people with Alzheimer's disease that can be identified, the better the chance we can identify important risk-factor genes," said Dr. Mayeux. "Finding these genes is crucial for finding targets for drug development."

This new initiative will help "heighten awareness of Alzheimer's disease across the nation," said Eric Tangalos, MD, CMD, professor of medicine and chair, Division of Community Internal Medicine, at the Mayo Clinic, Rochester, Minn. "If we can get enough families, we will be able to probe for linkages and provide clues to another piece of the Alzheimer's disease puzzle."

While genetics is an interesting factor, it's only a primary factor in a small number of Alzheimer's cases, said David Brechtelsbauer, MD, CMD, associate professor of Family Medicine at the University of South Dakota School of Medicine.

"Alzheimer's is such a complicated disease, and the brain is such a complicated organ system, that it's unlikely we will find a single breakthrough answer, such as genetics," said Dr. Brechtelsbauer. "What won't change, until we find a cure, is the need for hands-on care in nursing homes to provide respect and dignity, and to support as much independence as possible."

Human & Societal Costs

The long-term disability associated with the progression of Alzheimer's disease exacts terrible private and public costs, said William Thies, PhD, vice president of medical and scientific affairs at the Alzheimer's Association.

"When people first learn that a loved one has Alzheimer's disease, they often do not understand much about the disease or the time commitment necessary to be a caregiver," he explained. "A 1999 study showed that the actual length of time spent as a caregiver averaged eight years, with a third of caregivers spending more than 10 years providing care."

Caregiving affects the mental and physical health and welfare of the caregiver, who is likely to already be elderly and, perhaps, frail, said Dr. Thies. "In addition, there is a potential for 'role engulfment'--people become so overwhelmed by the demands placed on them in their role as caregiver that they can't even look for help," he said.

Alzheimer's disease burdens the healthcare system with high costs. A nursing home patient with Alzheimer's disease may cost 20 times as much as a patient without Alzheimer's living at home.

"The personal, financial, and societal cost of Alzheimer's will continue to increase," said Dr. Thies. "There simply isn't enough money or people in the health-care system to care effectively for the many people with Alzheimer's disease."

Dr. Tangalos noted that most of the $100 billion cost of Alzheimer's disease is non-direct, which places the burden on families.

"Clearly, the nursing home patient with Alzheimer's disease is very costly to take care of. The trick is to keep Alzheimer's disease patients out of nursing homes or assisted living facilities," advised Dr. Tangalos. "Every time Alzheimer's disease patients make a transition, for example, from home to a nursing home, they lose ground. Take an Alzheimer's disease patient out of her environment--whatever it is--and she will have a more difficult time learning the new environment."

It may be possible "to integrate our enormous progress in technology into organized caregiving, perhaps providing monitoring or prompting people to take medications," said Dr. Thies. "Technology may be able to act as a multiplier of caregiver skills."

New Treatment, Imaging Technology

Combining a cholinesterase inhibitor, such as donepezil, with memantine, which appears to block the toxic effects of glutamate stimulation on the brain, seems to be a promising therapy in community-dwelling older adults.

The first randomized, double-blind, placebo-controlled trial combining these two types of drugs found that they were better than placebo in a community-dwelling population.

The study, published in the Journal of the American Medical Association (2004;291:317-324), included 404 patients with moderate to severe Alzheimer's disease who were receiving stable doses of donepezil. They were randomized to receive memantine at a starting dose of 5 mg daily, increased to 20 mg daily, or placebo for six months. Some 322 patients (80%) completed the clinical trial.

The amount of time a caregiver spent grooming, feeding, or tending to a patient lessened in the combined treatment group. There were also fewer behavioral symptoms reported by caregivers.

Memantine plus donepezil resulted in "significantly better outcomes than placebo on measures of cognition, activities of daily living, global outcome, and behavior, and was well-tolerated," stated lead author Pierre Tariot, MD, professor of psychiatry at the University of Rochester Medical Center. "It is plausible that combining donepezil and memantine, which affect separate neurotransmitter systems, may confer independent clinical benefits."

This two-drug combination "is another advance," said Dr. Tangalos. "It points out that researchers are not just looking at Alzheimer's disease from a cognitive perspective, but for function and behavior" because the drug combination was shown to be effective in reducing caregiver burden and reducing behavioral symptoms.

Another recent study uncovered a new tool to detect and measure plaque deposits in the brains of living Alzheimer's patients, which previously could only be measured through visual inspection at autopsy.

"This gives us another way of looking at brain metabolism in real time," said Dr. Tangalos. "Brain imaging helps in the design of drug studies, which allows for quicker tests of drugs that we can bring to bear on Alzheimer's disease sooner."

Alzheimer's Research Briefs

Acetylcholine Insight Revealed

New research published in the February 2004 issue of Behavioral Neuroscience clarified how cholinesterase inhibitors may work to improve Alzheimer's symptoms.

Scientists chemically blocked receptors for the neurotransmitter acetylcholine, and even healthy younger people found it harder to learn and remember. This finding may shed light on how cholinesterase inhibitors, which slow the breakdown of acetylcholine in Alzheimer's patients, help alleviate dementia symptoms.

The study demonstrated that acetylcholine helps keep old information from interfering with learning ability and memory. The findings may help explain why conditions associated with lower levels of acetylcholine in the brain cause problems with memory function, as well as the hallucinations and delusions that can occur in some of these conditions.

A total of 28 young healthy adults participated in the study at Massachusetts General Hospital.

Low Testosterone Levels & Alzheimer's Disease Linked in Older Men

According to research funded by the National Institute on Aging (January 27, 2004, issue of The Journal of Neurology) older men with lower levels of free testosterone circulating in their bloodstreams could be at higher risk of developing Alzheimer's disease.

Investigators examined free and total testosterone levels over an average of 19 years in relation to subsequent Alzheimer's diagnosis. Based on physical, neurological, and neuropsychological exams, 54 of the 574 men who participated were diagnosed with Alzheimer's disease.

The research team found that for every 50% increase in the free testosterone index in the bloodstream, there was about a 26% decrease in the risk of developing Alzheimer's disease. Although overall free testosterone levels fell over time, these levels dropped more precipitously in those men who later developed Alzheimer's disease.

Genetics Determine Late-Onset Alzheimer's

According to a study published in the online edition of Annals of Neurology (December 15, 2003) genetic factors contribute to Alzheimer's disease that appears after age 80, but half or more of the susceptibility can be attributed to factors other than genes. The report comes from a Swedish twin study--the first to look specifically at the relative contributions of genes and the environment in the very old. Alzheimer's disease.

"The findings indicate that environmental influences are substantial late in life, but that genetic effects are also important," said lead author Nancy Pedersen, PhD, of the Karolinska Institute, Stockholm, Sweden. "These findings are important because health-care professionals, older adults, and family members should all remember that there may be ways in which we can delay the onset of this disease, and that healthful lifestyles, throughout the lifespan, may help us avoid it altogether."

PBS Series Web Site Helps Providers Educate Alzheimer's Patients

A new Web site (www.pbs.org/theforgotten) has been created as a companion to the PBS series "The Forgetting: A Portrait of Alzheimer's." It presents a portal-type area for people dealing with Alzheimer's--whether patients, family, or health-care providers.

"There are three major parts which may be of interest to people in the long-term care industry," said Lisa Gwyther, an expert on Alzheimer's therapy and the Web site's key advisor. "The most interesting part I think is the living center. It's an activity center where long-term care staff could set a patient up and do it with them. There's one part for people who are concerned with their own memory, and there's another part for families on how to cope.

"It's a good place for long-term care professionals to take an active role with their Alzheimer's patients," she continued. "They can also make it available to families of people in the facility because the family coping section has a lot to offer."

Smarter Patients May Be Incorrectly Diagnosed with Alzheimer's

According to a study published in Neurophysiology (January 2004), high-functioning people need to be tested for Alzheimer's disease at a different level than normal functioning people. Higher test cutoffs (rather than the standard group average) more accurately predicted how many highly intelligent test subjects would deteriorate over time.

"The whole point of the article was that people who are bright will tend to score much higher on tests of ability," said lead author Dorene Rentz, PsyD. "Even a slight decline in people who are bright may indicate the very early signs of a neuro-degenerative process. So I was afraid that these people are at the most risk for not getting early treatment when it becomes available because they will tend to score in the normal range for many years despite a disease process.

For instance, if 100 was normal and you live at 120 or 130, even a 10-point decline for you is still a decline, yet it would look like you were still normal or even above average," she concluded.

--Blaine Dionne

Alzheimer's Clinical Update - Part 2

The search begins for a genetic source, a new combination drug therapy & a tool to measure plaque deposits in patients

New Initiative to Search for Genetic Source

Human & Societal Costs

New Treatment, Imaging Technology