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July/August 2013
What Should You Tell Patients About Alzheimer’s?By R. Scott Turner, MD, PhD Although genetics predisposes some patients to Alzheimer’s disease, others can reduce their risk of developing the country’s fourth-leading cause of death. Sons, daughters, sisters, and brothers of newly diagnosed Alzheimer’s disease (AD) patients frequently pose difficult questions related to their own risk of developing it. Is it inherited? Will they develop AD? Are there ways to prevent or delay its onset? Their concerns spring from knowing this terminal disease’s frightening and inevitable progression. Although individuals whose parents or siblings have or have had AD are at increased risk for AD, it can affect older adults with no familial history of the disease. For patients whose parents or siblings have AD, their risk doubles and it increases exponentially with age. Although the evidence often is only epidemiologic, the suggestions that follow provide ammunition with which patients can arm themselves to promote good brain, heart, and general health as patients age. Facts by the Numbers Unfortunately, with increasing life expectancy come increasing years of cognitive and physical disability, now averaging up to six to seven years. Poor diet; alcohol, tobacco, or drug use; high BMI; hypertension; high fasting plasma glucose; physical inactivity; and high total cholesterol all contribute to disease in the United States. To some extent these are lifestyle choices and thus are potentially modifiable. The major risk factors for dementia due to AD are aging; family history/genetics, mostly from carrying the apolipoprotein E4 (ApoE4) allele; and diabetes or metabolic syndrome. While aging and genetics are nonmodifiable risks, diabetes may be prevented or delayed by diet, exercise, and maintaining an ideal body weight. If diabetes is diagnosed, safe and effective medications can be prescribed in addition to implementing nondrug strategies for glucose control. Other general recommendations for preserving brain health include maintaining mental activities and social networks, and avoiding traumatic brain injuries such as accidents and sports injuries in youth or falls in the elderly. While the evidence for engaging in mental exercises and games to preserve brain health is controversial, these activities are relatively harmless. However, hobbies and lifelong mental activities that are enjoyable are more likely to be sustained over the long term. There are no known supplements (eg, ginkgo biloba) proven to prevent cognitive decline with aging, thus no supplements are recommended because they carry risks and add unnecessary expense for patients. A suggested prescription for patients to prevent or delay cognitive decline with aging includes eating a Mediterranean diet, not smoking, maintaining an ideal body weight, monitoring and treating hypertension, monitoring and treating prediabetes or diabetes, engaging in regular physical exercise, consuming alcohol in moderation, monitoring and treating high cholesterol; and avoiding drug abuse or seeking treatment. Monitoring AD Symptoms Complex activities of daily living, such as driving, handling household finances, and taking daily medications as prescribed, become difficult. The ability to form new memories is increasingly impaired while older memories are relatively preserved. Mild depression and/or mild anxiety often accompany memory loss, and these may in fact be the first symptoms of AD. Antidepressants (eg, selective serotonin reuptake inhibitors) are commonly prescribed to treat depression and anxiety. Paranoid delusions, such as accusing others of hiding or stealing objects or money or believing a spouse has been unfaithful, can be treated with low-dose atypical antipsychotics but only if required. These symptoms should prompt a referral to a neurologist, psychiatrist, geriatrician, or other health care provider experienced with dementia evaluation, diagnosis, and treatment, perhaps at a memory disorders clinic. An accurate dementia diagnosis is valuable, and it’s possible that treatable causes of memory loss, such as obstructive sleep apnea, depression, hypothyroidism, vitamin B12 deficiency, subdural hematoma, or normal-pressure hydrocephalus, may be uncovered during a workup. A review of prescription and over-the-counter medications may reveal the use of drugs that impair memory, such as anticholinergic drugs or longer-acting benzodiazepines for insomnia. Pharmacological Treatment None of these drugs is disease modifying, but they do provide modest temporary and palliative benefits. Limited data are available on recommendations for discontinuing these medications. Typically hospice is consulted at the terminal stages of AD or other dementia to arrange a death with dignity, according to a patient’s and his or her family’s prespecificied wishes. At this point, decisions about fluids, feeding, medications, antibiotics, resuscitation, and other end-of-life considerations are evaluated. The major side effects of cholinesterase inhibitors are nausea, vomiting, diarrhea, vivid dreams or nightmares, muscle cramps, bradycardia and, rarely, syncope. These side effects can be minimized by using the recommended stepped-dose increments and by suggesting patients take the medication with a meal. The majority of patients with AD can tolerate cholinesterase inhibitors. If a patient can’t tolerate a particular cholinesterase inhibitor, either a second one or another delivery form may be considered, such as a patch rather than a pill. The goal is stabilization of cognitive and functional abilities for perhaps as long as one or two years, although clinical improvements may be reported anecdotally. For those who cannot tolerate any of the cholinesterase inhibitors, memantine alone is prescribed once dementia advances beyond the mild stage (ie, Mini Mental State Examination score below 20, for example). Genetic Testing While genetic discrimination in obtaining medical insurance is banned, the potential for discrimination in securing life, disability, or long-term care insurance remains. If insurance plans are secured and an individual wishes to discover his or her ApoE genotype, the test is available at AthenaDiagnostics.com. Obtaining reimbursement from third-party payers may be difficult, and results have implications for the first-degree relatives, including parents, siblings, and children. Clinical Trials Many novel therapies are based on passive immunotherapy (IV administration of antiamyloid monoclonal antibodies) designed to promote the clearance of neurotoxic amyloid aggregates from the brain. Despite recent high-profile failures, antiamyloid therapies remain the leading approach for potential disease-modifying therapies. Targeting individuals with mild to moderate AD may in fact already be too little too late. Lack of funding and lack of adequate numbers of patient volunteers and study partners has hampered progress toward new AD treatments. Fewer than 1% of individuals with AD volunteer for clinical studies. In fact, many individuals with dementia remain undiagnosed and unaware of treatment and research options. A dementia diagnosis must be further defined as being due to AD, which is the most common cause, or to Lewy body, frontotemporal, vascular, alcoholic, or mixed dementia (more than one etiology). If a second opinion is desired or if the individual or caregiver expresses an interest in research, referral to a clinic that offers these options is appropriate. Until new treatments are discovered, aging and genetics eventually will trump any prescription for preventing dementia, but current prescriptions also may delay its onset. But what is the value of our ever-increasing quantity of life without quality of life? — R. Scott Turner, MD, PhD, is a professor of neurology and the director of the Memory Disorders Clinic at MedStar Georgetown University Hospital in Washington, DC.
Evidence Suggests Mental Exercise Inhibits Cognitive Decline Researchers at the University of Toronto reviewed 32 randomized controlled trials of potential methods for preventing cognitive decline in people over the age of 65. The studies included in the review assessed several potential prevention strategies, including hormone replacement therapy, gingko biloba, vitamins, physical exercise, and cognitive training exercises. While most people experience some decline in memory and thinking skills as they age, some will develop mild cognitive impairment (MCI), a state of memory and thinking problems not severe enough to be classified as dementia. Some people with MCI will go on to develop a form of dementia, usually Alzheimer’s disease. Understanding how to prevent cognitive decline is a key research goal. The researchers looked at data only from people who had normal cognitive skills at the start of a trial to investigate whether there was strong evidence that any method could prevent cognitive decline in these subjects. The trials ranged from two weeks to five years in length, and the number of participants included in the studies also varied, with only 244 people involved in three trials for physical exercise and 19,568 people involved in seven trials examining the effects of estrogen. Researchers concluded that the evidence for most of the prevention strategies was inconsistent. They found no evidence that gingko biloba or vitamins could prevent cognitive decline but found some evidence that cognitive training may help prevent it. While the authors concluded that evidence for physical exercise was inconsistent, they argued that exercise still should be encouraged because of its other known benefits. “Reviews can be a very useful way of pulling together existing scientific evidence to help understand any trends resulting from research,” says Eric Karran, PhD, director of research at Alzheimer’s Research UK. “The studies included in this review had limitations, and as the authors point out, we currently lack a large body of evidence from clinical trials on which to draw firm conclusions for preventing cognitive decline. “Research has been able to shed light on measures that can protect against diseases such as cancer and heart disease, and this review highlights the need for stronger evidence on possible preventions for cognitive decline and dementia,” he continues. “With 820,000 people affected by dementia, research to understand how to prevent the condition is vital.” — Source: Alzheimer’s Research UK
Could Cinnamon Compounds Prevent Alzheimer’s Disease? Two compounds found in cinnamon—cinnamaldehyde and epicatechin—are showing promise in the effort to fight the disease. The compounds have been shown to prevent the development of the filamentous tangles found in brain cells that characterize Alzheimer’s disease. Responsible for the assembly of microtubules in a cell, a protein known as tau plays a large role in the structure of the neurons as well as their function. “The problem with tau in Alzheimer’s is that it starts aggregating,” explains Roshni George, a graduate student researcher. When the protein does not bind properly to the microtubules that form the cell’s structure, it has a tendency to clump together, forming insoluble fibers in the neuron, according to George. As people age, they become more susceptible to these twists and tangles, and Alzheimer’s patients develop them more often and in larger amounts. The use of cinnamaldehyde, the compound responsible for cinnamon’s bright, sweet smell, has proven effective in preventing the tau knots. By protecting tau from oxidative stress, the compound, an oil, could inhibit the protein’s aggregation. To do this, cinnamaldehyde binds to two residues of an amino acid called cysteine on the tau protein. The cysteine residues are vulnerable to modifications, a factor that contributes to the development of Alzheimer’s disease. “Take, for example, sunburn, a form of oxidative damage,” says Donald Graves, PhD, an adjunct professor in the department of molecular, cellular, and developmental biology. “If you wore a hat, you could protect your face and head from the oxidation. In a sense, this cinnamaldehyde is like a cap.” While it can protect the tau protein by binding to its vulnerable cysteine residues, it can also come off, which can ensure the protein’s proper functioning, he explains. Oxidative stress is a major factor in cell health. Through normal cellular processes, free radical-generating substances like peroxides are formed, but antioxidants in the cell work to neutralize them and prevent oxidation. Under some conditions, however, the scales are tipped with increased peroxide and free radical production and decreased amounts of antioxidants, leading to oxidative stress. Epicatechin, which also is present in foods such as blueberries, chocolate, and red wine, has proven to be a powerful antioxidant. Not only does it quench the burn of oxidation, but it also is activated by oxidation so the compound can interact with the cysteines on the tau protein in a way similar to the protective action of cinnamaldehyde. “Cell membranes that are oxidized also produce reactive derivatives, such as acrolein, that can damage the cysteines,” George says. “Epicatechin also sequesters those by-products.” Studies indicate that there is a high correlation between type 2 diabetes and the incidence of Alzheimer’s disease. The elevated glucose levels typical of diabetes lead to the overproduction of reactive oxygen species, resulting in oxidative stress, a common factor in both diabetes and Alzheimer’s disease. Other research has shown cinnamon’s beneficial effects in managing blood glucose and other problems associated with diabetes. “Since tau is vulnerable to oxidative stress, this study then asks whether Alzheimer’s disease could benefit from cinnamon, especially looking at the potential of small compounds,” George says. Although their research shows promise, Graves says the researchers are “still a long way from knowing whether this will work in human beings.” The researchers caution against ingesting more than the typical amount of cinnamon used in cooking. If cinnamon and its compounds live up to their promise, it could be a significant step in the ongoing battle against Alzheimer’s disease. — Source: University of California, Santa Barbara
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