What Can be Done to Slow the Progression of AD or Lessen its Effects?

What Can be Done to Slow the Progression of AD or Lessen its Effects?

The research advances described in the two previous sections of this report have vastly increased our understanding of brain function, the transformation from healthy aging to AD, and the factors that influence the development of AD. These findings have opened doors to a range of potential therapeutic approaches being investigated in various ways by NIA, other NIH Institutes, other research institutions, and private industry. Studies are underway on dozens of compounds and strategies to:

• Help people with AD maintain cognitive function over the short-term;
• Treat AD-associated behavioral and neuropsychiatric symptoms;
• Slow the progression of the disease; and
• Prevent AD.

As this report has shown, AD research has progressed to a point where scientists are increasingly able to think about how they can intervene to treat AD or perhaps even to prevent it. They think about the importance of timing—when is it best to intervene and what interventions are most appropriate at what time? For example, a physician would certainly provide different treatments to a patient who is having a stroke than to a patient who is seemingly healthy but at higher risk of having a stroke at some point in the future. AD develops over the course of years or decades, and a person’s brain is affected well before any symptoms are evident. It may be that one kind of intervention with a particular compound or approach may be most effective if it is applied well before any symptoms are evident. Other interventions may be most appropriate for use after AD is established.

Investigators are working to develop an array of options from which clinicians can choose. For example, developing new and better drugs and broadening the range of nondrug therapeutic approaches are critically important for those who already have AD because of the long-term nature of the disease and its high emotional and physical toll. Slowing the progress of the disease and alleviating psychiatric and behavioral problems could do much to delay or prevent institutionalization, maintain the dignity of people with AD, reduce physical and emotional stress on caregivers, and reduce the financial costs associated with the disease. Finding ways to prevent the disease altogether is an increasingly urgent priority because of the enormous impact of AD on our society. Scientists use clinical trials to pursue all of these goals.

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Clinical Trials
Clinical trials, which compare a potential new treatment with a standard treatment or with a placebo, are the only way to determine whether a drug, other compound, or nondrug approach is effective. These complex and expensive studies involve hundreds or even thousands of people and are often conducted over a long period of time. Some clinical trials are focused on treatment strategies—helping people with AD preserve cognitive function for as long as possible, for example, or helping people with behavioral or psychiatric problems associated with AD. Other clinical trials are focused on prevention strategies—using specific compounds to help people reduce the risk of developing AD in the future. The sections that follow describe some of NIH’s AD treatment and prevention clinical trials. Recruitment is ongoing for a number of these trials. For more information about the clinical trials described here and other trials, visit NIA’s ADEAR Center website.

AD Treatment Clinical Trials
The NIH is currently supporting 22 clinical trials of treatments for people who already have AD. Many of these are conducted as part of the Alzheimer’s Disease Cooperative Study, an NIA-supported national consortium of more than 50 research sites that conduct clinical trials for both cognitive and behavioral symptoms of AD. Here are highlights of just a few of these trials.

Divalproex sodium and agitation. An ADCS clinical trial of divalproex sodium (Valproate), conducted among 150 nursing home residents, was designed to see whether this medication could ease agitation in people with severe AD. Data from this study are being analyzed and results should be available before the end of 2005. A second trial that has recently begun will examine whether divalproex sodium can delay or prevent agitation and psychosis in individuals with mild to moderate AD. Researchers are also interested in seeing whether its possible neuroprotective properties have any effect on slowing the rate of cognitive decline.

Simvastatin and AD progression. This 18-month ADCS trial, which began in 2003, is testing whether simvastatin (Zocor), a commonly prescribed cholesterol-lowering drug, can safely and effectively slow the rate of disease progression in people with mild to moderate AD. Data from epidemiologic and animal studies indicate that high cholesterol levels increase the risk of AD and that statin drugs specifically may help reduce this risk. The trial, which is being conducted in about 40 sites nationwide, will enroll 400 participants. To date, 350 people have been enrolled and recruitment of participants continues. Some participants will receive 20 mg of simvastatin for 6 weeks and then 40 mg of the statin for the rest of the study period. Others will receive a placebo during the entire study. Clinical trial staff are tracking changes in participants’ cognitive health by measuring a number of indicators, including mental status, functional ability, behavioral disturbances, and quality of life.

Huperzine A and cognitive function. This ADCS trial is evaluating whether huperzine A, a natural cholinesterase inhibitor derived from the Chinese herb, Huperzia serrata, can slow the progression of cognitive decline in people with mild to moderate AD. A number of small, randomized controlled trials in China have indicated that people with AD who were treated with huperzine performed better on memory tests than those on placebo. Investigators also are interested in huperzine because it has antioxidant and neuroprotective properties that suggest it may be useful in treating AD. The study, which will enroll 150 participants, is taking place at about 20 sites nationwide, and recruitment is ongoing. Participants will be randomly assigned to three equal groups—two groups will receive varying amounts of huperzine A every day and the third group will receive a placebo. All participants will receive huperzine A during the last 8 weeks of the 24-week trial.

Supplements to reduce homocysteine and slow the rate of cognitive decline. High homocysteine levels are associated with increased AD risk. Levels of this amino acid can be reduced by high-dose supplements of folate and vitamins B6 and B12. This ADCS clinical trial, which began in 2003, is designed to determine whether reduction of homocysteine levels with high-dose supplements of folate, vitamin B6, and vitamin B12 will slow the rate of cognitive decline in older adults with AD. Participants in this clinical trial were divided into two groups: 60 percent of participants will receive daily high-dose supplements (5 mg of folate, 25 mg of vitamin B6, 1 mg of vitamin B12) and 40 percent will receive a placebo. Enrollment of the 400 participants has been completed.

Sertraline to treat depression in AD. Major depression affects approximately 25 percent of people who have AD, so finding effective ways to treat this condition is an important priority for AD research. NIMH-funded researchers at Johns Hopkins University are conducting a clinical trial to assess the efficacy and safety of the antidepressant medication sertraline (Zoloft) for the treatment of major depression in AD (Lyketsos et al., 2003). The trial is still ongoing, but preliminary results from 44 participants indicate that sertraline reduced depressive symptoms in 84 percent of those treated. In contrast, depressive symptoms were reduced in 35 percent of those treated with a placebo. Participants taking sertraline also experienced a lessening of behavioral disturbances, such as apathy, anxiety, or irritability, and improvements in activities of daily living, such as bathing, dressing, and feeding. Their cognitive functions did not improve, however. The research team is continuing this trial with other groups of people with AD in hopes that similar treatment with antidepressant medication can benefit those with milder depression or with differing profiles of depressive symptoms.

Atypical antipsychotics to treat psychosis in AD. NIMH-funded investigators at the University of Southern California Keck School of Medicine have recently completed a clinical trial called the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) (Schneider et al., 2003). This trial was designed to assess the effectiveness of atypical antipsychotic drugs for use in people with AD who experience hallucinations, delusions, or agitation. These symptoms are very common in people with AD, and they can be very distressing to caregivers. The trial ended in October 2004, and publication of results is underway.

AD Pilot Treatment Trials
Before beginning a full-scale clinical trial, NIH Institutes often conduct pilot clinical trials to collect initial data on the safety, effectiveness, and best dosage of a potential treatment. These data help the Institutes determine which interventions should go to the next step. Here are highlights of a few current pilot clinical trials in AD:

Combination vitamin supplement in the treatment of AD in Down syndrome. This high-potency supplement consists of two cellular antioxidants (vitamins E and C) and a mitochondrial antioxidant (alpha-lipoic acid). The aims of this 24-month intervention trial are to determine whether cognitive function improves with antioxidant supplementation and to determine its safety and tolerability.

Nicotine skin patch and amnestic MCI. Some of the 60 participants in this study will be given the nicotine patch and others a placebo patch. Research has suggested that one of the causes of memory disorders may be a reduction in the neurotransmitter acetylcholine. Acetylcholine is critically important in the process of forming memories, and nicotine imitates many of the actions of acetylcholine. Preliminary studies have suggested that short-term administration of nicotine appears to improve memory in patients with mild memory loss and early AD. Furthermore, nicotine administration appears to have significant neuroprotective effects, and it may have positive influences on APP processing. The primary goal of this pilot trial is to demonstrate whether the nicotine patch is safe to administer to the nonsmoking amnestic MCI participants over a 1-year period. Study investigators also hope to determine whether nicotine can improve memory loss symptoms over the longer term and whether it can help delay the progression of memory loss symptoms.

Rosiglitazone and amnestic MCI. This 18-month clinical trial will test whether rosiglitazone (Avandia), a drug that has anti-inflammatory properties and that improves sensitivity to insulin, can improve memory in people who have amnestic MCI. Epidemiologic studies indicate that people with insulin resistance are at increased risk for both MCI and AD. Insulin resistance also is associated with inflammation, which may increase AD risk through several mechanisms. These findings provide the rationale for this novel treatment strategy. Study participants will be divided into two groups—one group will receive the rosiglitazone, the other a placebo. Participants also will have MRIs before and at the end of treatment to determine whether rosiglitazone slows the rate of atrophy in brain structures that support memory. This trial will provide valuable data about the effects of improved insulin sensitivity, reduced insulin levels in the body, and reduced inflammation on cognitive function and biomarkers in MCI with memory loss.

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AD Prevention Trials
NIH is currently conducting seven AD prevention clinical trials. Although two of these trials have been suspended, investigators are still periodically assessing the participants’ health.

The Multiple Outcomes of Raloxifene Evaluation. This clinical trial, conducted with nearly 5,400 postmenopausal women with osteoporosis, was designed to determine whether treatment with raloxifene (Evista), a selective estrogen receptor modulator (SERM) that is used to treat osteoporosis, affects the risk of developing AD and cognitive impairment (Yaffe et al., 2005). The women were divided into three groups: one group received a placebo, one group received 60 mg of the drug every day, and the third group received 120 mg daily. After 3 years of treatment, the 60 mg group and the placebo group did not differ. However, women who took 120 mg had a statistically significantly lower risk of developing MCI and a somewhat lower risk of developing AD and any cognitive impairment than did the women who took the placebo. Additional clinical trials are needed to confirm these results.

The Memory Impairment Study. Over the course of 3 years, this study compared the effectiveness of vitamin E, donepezil (Aricept), and a placebo in delaying the onset of a diagnosis of AD in 769 people with amnestic MCI. Results indicated that participants taking donepezil were at reduced risk of progressing to AD during the first 12 months of the study, but this benefit disappeared by 18 months (Petersen et al., 2005b). However, in the subset of patients who carried the APOE-e4 allele, donepezil appeared to decrease the risk of progression to a diagnosis of AD for the full 36 months of the study. Vitamin E did not appear to slow the progression to AD. The investigators are conducting additional analyses to determine why donepezil’s effect dropped off over time and to assess the practical and clinical implications of this complex study.

This landmark MCI trial, which took place in 69 sites in the U.S. and Canada, represents a major advance in clinical trial methodology, as it demonstrated that investigators could use standardized criteria in a multi-center trial to define and differentiate individuals with amnestic MCI, healthy people, and those with AD. Future clinical trials in people with this type of MCI should be instrumental in research to detect, treat, and delay AD (Grundman et al., 2004).

NSAIDs and inflammation. Some epidemiologic studies have suggested that NSAIDs might help slow the progression of AD, but clinical trials thus far have not demonstrated a benefit from these drugs. A clinical trial studying two of these drugs, rofecoxib (Vioxx) and naproxen (Aleve) showed that they did not delay the progression of AD in people who already have the disease. Treatment in another trial, testing whether the NSAIDs celecoxib (Celebrex) and naproxen could prevent AD in healthy older people at risk of the disease, was suspended after some participants showed indications of increased cardiovascular risk with long-term use of these drugs. Investigators are examining data about possible cardiovascular risk and continue to assess the participants’ health periodically. However, researchers are continuing to look for ways to test how other anti-inflammatory drugs might affect the development or progression of AD.

The Prevention of Alzheimer’s Disease with Vitamin E and Selenium (PREADVISE) trial. This trial is NIA’s add-on to NCI’s Selenium and Vitamin E Cancer Prevention Trial (SELECT), which is evaluating whether taking selenium and/or vitamin E supplements can prevent prostate cancer in healthy men older than 60. PREADVISE is evaluating whether these agents can help prevent memory loss and dementia, such as that found in AD. Studies show that increased oxidative stress may damage brain cells and is linked with AD. Animal and tissue culture studies of vitamin E and selenium suggest that they can protect brain cells from oxidative damage.

Ginkgo biloba. Extracts of leaves from the ginkgo tree are thought to have beneficial effects on brain function, especially those related to dementia and AD. NIA is co-funding a National Center for Complementary and Alternative Medicine prevention trial comparing ginkgo to placebo in more than 3,000 people older than 70 who are cognitively healthy at the beginning of the trial. The study’s results should indicate whether ginkgo is helpful in preventing or delaying the onset of dementia. As part of this trial, University of Pittsburgh investigators have used brain imaging techniques to determine whether cognitively healthy individuals and those with amnestic MCI show any differences in activation in specific parts of the brain that are normally related to an aspect of cognitive function called attentional control (Rosano et al., 2005). They have been able to detect differences in activation in these brain regions between the two groups, and these changes are likely to be related to early changes in cognitive impairment.

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Improving Support for Caregivers
Although much of NIH’s AD research effort is focused on the causes, characteristics, diagnosis, and treatment of AD, researchers never lose sight of the enormous personal and emotional toll exacted by AD on those with the disease as well as their families, friends, and caregivers. Investigators supported by several Institutes, including NIA, NIMH, and the National Institute of Nursing Research (NINR) are exploring the emotional, psychological, and physical costs of caregiving, and they are investigating ways to ease the burden.

For example, it is well established that AD caregivers often experience stress, anxiety, depression, and other mental health problems as a result of the continuing and demanding nature of AD care. This chronic stress is known to have detrimental affects on caregivers’ physical health. A research team at the University of California at San Diego explored this issue by assessing whether different emotional symptoms had different physical effects (von Kanel et al., 2004).

Working with a group of 48 older participants, the researchers found that although stress-associated depression and anxiety both raised the level of certain molecules in the blood that are associated with increased coronary risk, anxiety appeared to have a stronger effect than depressive symptoms. Having a more nuanced understanding of the effects of caregiving stress may inform the development of interventions to help caregivers cope with the daily stresses of caring for a loved one with AD.

A recent study, conducted by NINR-funded researchers at the University of Texas Health Science Center in San Antonio explored another aspect of caregiving stress by examining how male and female caregivers respond differently to the emotional and biological stresses of caregiving (Thompson et al., 2004). The researchers found that although the two groups of caregivers did not differ in the number of distressing caregiving experiences, men reported a lower sense of burden and a lower level of perceived stress than women. In addition, men had lower scores for depression, anxiety, anger, and physical symptoms, and higher scores for relaxation, social functioning, mental health, role performance, and sense of coherence. These findings point out the need for tailored caregiving support interventions that take caregivers’ individual characteristics into account.

The emotional and psychological costs of caregiving are amenable to interventions, according to a recent study conducted by New York University School of Medicine scientists funded by NIA and NIMH (Mittelman et al., 2004). This study was conducted as part of the NYU-Spouse Caregiver Intervention Study, the longest study devoted to interventions that improve the mental health and well-being of AD caregivers. The Caregiver Core of the New York University ADC provided the infrastructure for this study. A total of 406 caregivers were enrolled in the study over its 17-year duration, and were divided into two groups. Half the caregivers, the control group, received counseling upon request. The other half, the enhanced treatment group, were given three additional types of counseling: two sessions of individual counseling, four sessions of family counseling, and weekly meetings with a support group of fellow caregivers. A key feature of the enhanced group was that each member was served by a single counselor for the duration of the study. After one year, nearly 30 percent of caregivers in the enhanced treatment group had symptoms of clinical depression, compared with more than 45 percent of those in the control group. Three years later, caregivers who received the enhanced care still had fewer symptoms of depression, on average, than those in the control group. This was true even for caregivers whose spouses moved to a nursing home or died, both of which are known to be highly stressful events for caregivers. Interestingly, many of the effects of the enhanced treatment were not felt immediately. The two groups of caregivers did not begin to show significant differences in their depression symptoms until a year after they enrolled in the study. The effects appeared to last for about 5 years; after that time, the level of depression in the control and intervention groups became the same. The researchers note that the use of multiple types of coordinated therapy was one of the most important factors in decreasing depression among caregivers. Another important aspect of the study was that the counseling was tailored to the particular coping challenges that each caregiver and family were dealing with. These findings have important clinical implications because they offer evidence that the distress and depression experienced by family caregivers can be effectively eased and that the benefits can be sustained over a long period of time.

Up to now, research on family caregiving has generally focused on assessing the demands of providing care at home and developing interventions to reduce those burdens. Recently, an NIA/NINR-funded team of nurse researchers at the Rush University College of Nursing interviewed more than 170 caregivers to explore their concerns and identify best caregiving practices (Farran et al., 2003; Farran et al., 2004). Most caregivers said that they felt stressed as they responded to changes, reevaluated their life goals and lifestyle, adapted to new roles, and faced competing demands from other family members, work, and outside responsibilities. Many caregivers admitted frustration about the limitations that caregiving placed on their own lives. The most sensitive and skillful caregivers learned to read the emotional and physical cues of the person with AD and understand the sequences that often led to inappropriate behaviors, and they responded to the needs of the person in a variety of creative ways. They also maintained their flexibility in the face of many demands, educated themselves about the disease and practical strategies, used their available resources, involved other family members and friends, and balanced the needs of the patient with their own needs. These findings could lead to the development of interventions to help caregivers cope with their stress and develop new caregiving skills.

In an effort to reduce the overall stress levels of caring for a person with AD at home, University of Minnesota researchers funded by NINR developed an innovative intervention that focused on changes in the home environment (Gerdner et al., 2002). Nurses taught care plans that emphasized changes in the home environment that would enhance safety, compensate for the cognitive decline of the person with AD, and reduce confusing stimuli. The impact of the intervention on the frequency of problem behaviors in care recipients and the home caregivers’ reactions to these behaviors were then assessed. This psychoeducational intervention improved responses to the care recipient’s memory and behavioral problems by both spouse and nonspouse caregivers.

More recently, some researchers have begun to focus on learning about transitions into and out of the caregiving role. A study conducted by University of Pittsburgh scientists explored this issue by examining the experiences of caregivers when they place a relative into a nursing home or other care institution (Schulz et al., 2004). In particular, this study looked at the forces leading to the institutionalization, the frequency and types of contact among caregivers and their relatives, and the psychiatric and physical health status of caregivers after placement. Caregivers included in this study were enrolled in the NIA/NINR jointly-funded Resources for Enhancing Alzheimer’s Caregiver Health (REACH) study, a multi-site clinical trial that is testing the feasibility of various psychosocial interventions and their impact on the health and well-being of family caregivers. The study found that many caregivers who placed their relative in care reported depressive symptoms and anxiety to be as high as when they were in-home caregivers. In addition, caregivers who said that providing help to their relative made them feel useful, needed, appreciated, and important were less likely to institutionalize their relative than were caregivers who did not report these feelings. The authors note that bereavement studies have shown that caregivers do recover after the death of their loved one, but the benefits to the caregiver of placing a relative into a care setting appear to be less positive, possibly because the caregiving role is not wholly relinquished after placement. Clearly, it is important to remember that caregivers are at risk for adverse health outcomes not only while providing care at home, but also after their loved one has been placed into a care setting.

REACH has recently published findings from a number of other caregiver studies as well:

• An assessment of the burdens of end-of-life AD care and the caregivers’ response to the death showed how time-consuming and difficult this phase of caregiving can be (Schulz et al., 2003). University of Pittsburgh investigators found that many participating caregivers were assessed as being at risk of clinical depression before the person’s death, but that these numbers dropped significantly within a year after the death.
• An exploration of caregiving practices among African-American and white caregivers by scientists at the University of Alabama revealed that a majority of African-American caregivers were caring for a parent or other nonspouse family member, whereas most white participants were caring for their spouses (Roff et al., 2004). African-American caregivers also were younger and had a lower family income than the whites. Interestingly, the African-American caregivers reported finding more positive aspects to caregiving, had lower anxiety, a higher degree of religious faith, and were less bothered by the behavior of the person with AD than were whites. Examining the positive aspects of caregiving may provide useful lessons and new strategies for all caregivers.
• A 6-month follow-up evaluation of nine different REACH interventions involving more than 1,000 caregivers showed that the interventions were successful in helping lessen the perceived burden felt by caregivers, though only one intervention significantly reduced caregiver depression (Gitlin et al., 2003). One clear lesson from this evaluation, conducted by investigators at Thomas Jefferson University in Philadelphia, is that caregiver interventions need to target multiple aspects of caregiving and be tailored to the characteristics and circumstances of the caregiver.

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