Questions and answers on launch of NIA memory impairment study
1. What is Mild Cognitive Impairment?
Mild cognitive impairment (MCI) is a condition characterized by memory impairment with otherwise unaffected cognitive functioning.
2. How can MCI be distinguished from normal forgetfulness?
Normal memory changes associated with aging are characterized by momentary lapses, such as misplacing an item, forgetting someone's name, or forgetting to pick up something at the store. In contrast, memory loss associated with MCI is a more persistent and troublesome problem. People with MCI have much greater difficulty, for example, remembering a fact after a relatively short time. In cognitive testing, people with MCI, after a delay, remember significantly less of a paragraph they have read or details of simple drawings they have seen compared to people with normal memory changes associated with aging. A person with MCI is likely to forget important events repeatedly, while significant information is retained in normal aging.
3. What about MCI and dementia?
Is there a relationship between MCI and Alzheimer's disease? As its name indicates, MCI is a condition of mild impairment, specifically in the area of memory, while dementia is characterized by additional and severe problems in other areas of cognition, such as orientation, language, and attention. Alzheimer's disease (AD) is the most common form of dementia among people age 65 and older. While most patients with MCI get worse, not all will. AD invariably results in a gradual decline, eventually progressing to severe, debilitating dementia.
Scientists have been interested in MCI in part because a significant number of people over the age of 65 with MCI eventually develop AD – in some studies approximately 12-15 percent of them per year (or about 40 percent after three years). This is much higher than the 1 percent or so per year in a normal population of people 65 and older. As such, MCI is a risk factor for developing AD. Researchers are examining the possible relationship between the two conditions.
4. How is MCI diagnosed?
A new report in the Archives of Neurology (March 1999), by Dr. Ronald Petersen, et al., at the Mayo Alzheimer's Disease Center, suggests that a diagnosis of MCI can be made on the basis of five criteria: 1) memory complaints, 2) abnormal memory for age, 3) ability to carry out normal activities of daily living, 4) normal general cognitive function, and 5) no dementia. In this study, scientists compared the cognitive test results of people with MCI to those of healthy people and patients with mild AD. People with MCI typically performed worse on the memory measures than healthy people, but scored roughly the same as patients with AD.
However, on other cognitive tests, measuring a person's disorientation and confusion about routine activities, MCI individuals' scores were equivalent to those of healthy people and better than those of AD patients. MCI, therefore, represented a detectable failure in memory in people with otherwise normal cognitive abilities. Before now, evaluating people with MCI has been difficult because researchers have had no agreed upon definition of the symptoms of the condition. The findings by Petersen and colleagues and related studies can now be used to help identify people with MCI. The study, primarily supported by the National Institute on Aging (NIA), is part of ongoing efforts to refine early clinical diagnosis of memory impairment and AD and assess brain changes that occur. Ultimately, identifying people with early memory changes will allow for timely intervention as therapies are developed.
5. What causes MCI, and does it run in families?
As with AD, the causes of MCI remain unclear. No genetic link has yet been found for the condition, although it is possible that, like AD, a genetic component, might be a risk factor for people with MCI to develop AD.
6. Why is NIA supporting the Memory Impairment Study, and why now?
Studies to date have looked at the effectiveness of drug treatments in the stages of Alzheimer's disease when the condition is mild to moderate, and when it has already interfered with daily function. By intervening earlier -- before signs of memory impairment have developed into clinically diagnosed AD -- scientists hope to delay the onset of AD or prevent it altogether. The Memory Impairment Study is the first major prevention trial for AD supported by NIA which is specifically designed to test drug interventions in relatively healthy and well-functioning people.
7. What is the Memory Impairment Study going to examine?
This study will investigate the effectiveness of donepezil, a drug generally prescribed for patients with mild to moderate AD, and vitamin E ("-tocopherol) in delaying or preventing the onset of AD in people with mild cognitive impairment. The Memory Impairment Study is sponsored by the Alzheimer's Disease Cooperative Study (ADCS) headed by the University of California at San Diego, with grant funding from the NIA and contributions from Pfizer, Inc., and Eisai, Inc. Additional support is from Roche Vitamins, Inc.
8. Who will participate in the Memory Impairment Study? How many people will participate? How will they be recruited?
Approximately 720 men and women ages 55 through 90 will be recruited for the 3-year, multicenter study. The major requirements for participation in the study include recent memory complaints, abnormal memory function on standardized tests, good general health, and no clinical diagnosis of AD. Some people may not be able to take part in the study. They may have certain conditions that would exclude them from participation, including: significant neurologic diseases such as Parkinson's or Huntington's diseases; major depression; history of recent alcohol or substance abuse; history of cancer or heart disease; recent use of medications such as centrally active beta-blockers, narcotics, or anti-convulsants; and any prior use of medications (Cognex, Aricept) approved by the Food and Drug Administration (FDA) for the treatment of AD.
The Memory Impairment Study will be conducted by the ADCS, an established nationwide network of research centers supported by the NIA and coordinated by the University of California at San Diego. The ADCS sites will be joined by other clinics and centers around this country and Canada. Between 65 and 80 sites are expected to conduct the research. A national participant recruitment campaign is planned, targeting older people in cities where the study sites are located. Potential study participants will be asked to call a toll free number, 1-888-455-0655, at the ADCS central pre-screening agency. The callers initially will be screened over the telephone for inclusion in the study. Those who may qualify for participation will, in turn, be referred to study sites in their area for additional screening.
9. How much of a participant's time will be required for the study, and what types of medical testing will the participants undergo?
Study participants will visit their local clinical center about nine times over a 3-year period, including the initial screening visit. Evaluations of participants will begin at the second visit and continue every 3 months for the first 6 months, and then every 6 months for the remainder of the 3 years, or until a clinical diagnosis of AD is made. Testing will include neurological examinations (cognitive measures and clinical/functional testing), blood and urine collection, medication compliance measures (pill count and serum vitamin E levels), and a physical examination. Participants will be closely monitored for side effects.
10. Where is the study being conducted? How can people find out about locations?
The study will be conducted in at least 65 clinical centers throughout the United States and Canada. Each center will enroll 12 to 36 participants. It is important to note that for every participant accepted into the study, many more volunteers will need to be screened. People can find out more about their eligibility and about locations by calling toll free 1-888-455-0655.
11.Why were donepezil and vitamin E selected for this study? What dosages will be used in the study? Are they the same amounts that people take now?
Donepezil is one of two drugs approved by the FDA (tacrine is the other) to treat patients with mild to moderate AD. Donepezil helps prevent the degradation of acetylcholine --a neurotransmitter (i.e., a brain cell communication chemical) that is important for attention and memory. Vitamin E is thought to have antioxidant properties, that is, to counteract destructive damage from molecules called free radicals. The progressive loss of brain cells that occurs in dementia and AD may be related to this damage. In a previous ADCS study in 1997, also supported by the NIA, vitamin E was shown to slow down functional decline of patients with moderate AD by about seven months.
Study participants will be assigned randomly to one of three groups, and participants will receive donepezil, vitamin E, or a placebo (inactive pill). The dosage of donepezil will be 5 mg per day for the first 6 weeks and then 10 mg until the end of the study, dosages similar to those prescribed for patients with mild to moderate AD. The study's dosage of vitamin E will be 1,000 IU (International Units) per day for the first 6 weeks and then 2,000 IU per day until the end of the study. This dosage is higher than the amount typically found in vitamin supplements but was shown to be well tolerated with few side effects in the 1997 study. Participants in the placebo group will receive inactive pills similar in size to the other drugs being tested. All study participants will receive a daily multivitamin.
The Memory Impairment Study is designed to demonstrate the potential effectiveness of each treatment in preventing or delaying the onset of AD. If any participant receives a clinical diagnosis of AD before the end of the study, the participant will be offered active donepezil until three years have elapsed from the time of entry into the study.
12. A lot of people are already taking vitamin E. Isn't it already proven that vitamin E can improve health, and shouldn't people be taking it anyway now?
As an antioxidant, vitamin E is important in the body for stabilizing membranes and protecting them against free radicals. Vitamin E was demonstrated to slow some aspects of functional deterioration in patients with AD in the 1997 study. However, this study has not yet been replicated. The dose that will be used in the Memory Impairment Study is reasonably high. Only a controlled clinical trial to determine safety and effectiveness will answer whether this high dose, which the researchers believe is needed to reduce oxidative damage in the brain, is helpful in possibly preventing or delaying the onset of AD.
13. Are there any side effects associated with donepezil or vitamin E?
Donepezil has shown no serious side effects during clinical trial testing for FDA approval. No laboratory monitoring is currently mandated for the drug by FDA. Donepezil has shown minimal effects on the liver; its most common side effect is nausea. In the 1997 study, a dosage of 2,000 IU per day of vitamin E was well tolerated with few side effects. However, the long-term effects and potential hazards of such high doses are unknown. In excessively large doses (above 2,000 IU per day), vitamin E may be associated with increased risk of bleeding in certain people. Some studies also have suggested that high doses of vitamin E should not be used with anti-coagulant medications. People are encouraged to consult their family doctors before taking high doses of vitamin E as a supplement.
14. How long will the Memory Impairment Trial take? When will the findings be known?
The study will last 3 years from the date of the second visit. Data analysis will begin after two-thirds of the participants have completed the study. The faster the recruitment phase, the more rapidly the study will be completed, the results analyzed, and the findings made known.
15. Where can I find out more about clinical trials for Alzheimer's disease?
The NIA supports a new clinical trials database of promising compounds to treat AD. The database, which is being developed cooperatively with the FDA, provides information about AD clinical trials and sites and is designed to help encourage participation in research. It describes study designs and explains the possible modes of action of selected drugs. The database also outlines eligibility criteria for participants and lists locations and contact information for study sites. The database is available at the NIA's Alzheimer's Disease Education and Referral Center (ADEAR) website at or by telephone at 1-800-438-4380.
16. Where can people get more general information about memory problems, MCI, and Alzheimer's disease?
Additional information is available from the NIA-funded Alzheimer's Disease Education and Referral (ADEAR) Center at:
PO Box 8250
Silver Spring, MD 20907-8250
Information is also available from the Alzheimer's Association at: Alzheimer's Association
919 N. Michigan Avenue, Suite 1000
Chicago, IL 60611-1676