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Alzheimer disease: What new evidence shows

Uriri-Glover, Johannah PhD, MSCR, RN; McCarthy, Marianne PhD, ANP-BC, GNP-BC, FAANP; Cesarotti, Evelyn PhD, FNP-BC, FAANP

doi: 10.1097/
Feature: CE Connection

The number of people diagnosed with Alzheimer disease is increasing. Learn about currentpharmacologic and nonpharmacologic disease management strategies.

Johannah Uriri-Glover is a clinical associate professor and core director of the ASU College of Nursing and Health Innovation, John Hartford Center for Geriatric Nursing Excellence, Arizona State University College of Nursing and Health Innovation, Phoenix. Marianne McCarthy is an associate professor and coordinator of the Adult-Geriatric Nurse Practitioner Program, Arizona State University College of Nursing and Health Innovation, Phoenix. Evelyn Cesarotti is associate dean of Operations at Arizona State University College of Nursing and Health Innovation, Phoenix.

The authors and planners have disclosed that they have no financial relationships related to this article.



Approximately 5.4 million individuals of all ages in the United States have Alzheimer disease (AD).1 This figure includes 5.2 million people age 65 and older and 200,000 individuals under age 65 who have early-onset AD.1 The number of people with AD is estimated to reach 16 million by 2050.1

AD is a progressive degenerative disease of the cerebral cortex resulting in diffuse atrophy of the cerebral cortex. The disease is characterized by neurofibrillary tangles, beta-amyloid plaques, and neuronal degeneration.

Pharmacologic and nonpharmacologic therapies are used with varying results to address memory loss, behavioral symptoms, and sleep problems in persons with AD. Clinicians who have the most current information can provide maximum help to patients with AD and their families when discussing treatment options with them.

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Review of evidence

In the last 5 years, preliminary research suggested a beneficial effect on cognition in patients with AD using: vitamins E, B12, and B6; folic acid; omega 3 in fish oil; and ibuprofen. Improvements in behavior have been noted with light therapy and physical therapy. However, other studies haven't supported these results.

Cochrane Reviews recently reported no evidence for treatment of AD with the commonly used substances cited above, which families may have heard or read about in research reports or the media.2 There's insufficient evidence reported regarding lecithin, light therapy, melatonin, thiamine, and physical activity to improve cognitive function and/or sleep disturbances in persons with AD. However, there's evidence that pharmacologic treatment using cholinesterase inhibitors (CEIs) and memantine has a beneficial effect on cognition, functioning, and behavior, especially in mild-to-moderate AD.2

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Pharmacologic treatment of AD

The diagnostic criterion for AD was originally developed in 1984. At that time, like many other brain diseases, AD was thought to exhibit a high correlation between clinical symptoms and underlying pathology. Since then, scientific knowledge about the neuropathology of AD has expanded. The diagnostic criteria were recently revised and published to incorporate scientific advances in the field and to address the needs of clinicians and researchers.

The stages of AD have been redefined (preclinical phase, mild cognitive impairment, and AD dementia) in the revised diagnostic criteria. A description of the role of biomarkers is included in the sections on each stage of the disease.3 Biomarkers play an important role in detecting AD early, during the preclinical phase of the disease. The clinical diagnosis, based on the patient's medical history and physical exam, is indicated for diagnosing more advanced stages, that is, mild cognitive impairment and AD dementia. The biomarkers may be used to complement the diagnosis in the later stages of the disease, so a definitive diagnosis can be made without the use of biomarkers for clinicians who may not have access to ways to measure biomarkers in the later stages of the disease.3

Consensus clinical guidelines for the management of AD present the available evidence on the effectiveness of the U.S. FDA–approved pharmacologic therapies for dementia that address cognition, global functioning, behavior/mood, and quality of life that affects activities of daily living (such as bathing and mobility).39 The American Association for Geriatric Psychiatry is currently working on a more comprehensive background document to support its position on the use of antipsychotic medications in persons with dementia. The authors of the document state that “there are circumstances in which it is appropriate.”410

Overall, the benefits of symptomatic treatments for AD are modest, and some authors argue that the magnitude of this benefit, although statistically significant, is marginal at best and may even be difficult to detect, measure, and quantify clinically.10 Consequently, most propose that clinicians base the decision to initiate a trial of drug therapy on individualized assessment that takes into consideration the “clinically marginal” benefits, the heterogeneous and unpredictable response in an individual patient, the potential for adverse reactions, and the stage of the disease.10

CEIs: One of the earliest pathologic findings associated with AD was the loss of neurons in the nucleus basalis, the main origin of cholinergic neurotransmission to the cortex.3 Although the cholinergic hypothesis of AD has lost favor in light of the amyloid hypothesis, overcoming this cholinergic deficit of AD continues to be a mainstay of treatment for associated cognitive symptoms of the disease. The most successful approach has been to reduce the naturally occurring breakdown of acetylcholine. Acetylcholine is normally degraded through an enzyme known as acetylcholinesterase (AChE). Inhibition of AChE results in increased acetylcholine levels because of reduced degradation.9

Donepezil, rivastigmine, galantamine, and tacrine are FDA-approved CEIs for the treatment of mild-to-moderate cognitive impairment.11 In 2010, the FDA also approved donepezil for use in moderate-to-severe AD. These drugs are considered symptomatic treatments because they potentially improve symptoms without modifying the course of the disease. They're also prescribed “off-label” to treat memory disorders in other conditions, including vascular dementia, Lewy body dementia, and mild cognitive impairment.12 All CEIs work by reducing the inactivation of acetylcholine and, thus, potentiate the cholinergic neurotransmitter, which in turn produces a modest improvement in memory and goal-directed thought; however, CEIs don't reverse the degenerative process.

Limited data also suggest that CEIs may delay placement in long-term-care facilities, reduce caregiver stress, and play a modest role in decreasing behavioral and psychological symptoms of AD.12 In long-term use, they may slow the progression of memory loss and diminish apathy, depression, hallucinations, anxiety, euphoria, and purposeless motor behaviors. Functional autonomy has been reported to be less well preserved.13

As a class, the CEIs may take up to 6 weeks before any improvement in baseline memory or behavior is apparent, and they may take months before any stabilization in the degenerative course of the disease is evident.10 The most common adverse reactions associated with CEIs are gastrointestinal in nature because of the peripheral inhibition of AChE. Central inhibition of AChE may contribute to nausea, vomiting, weight loss, and sleep disturbances. Rare, but life-threatening or dangerous adverse reactions of CEIs include seizures and syncope.12,13 All CEIs can be lethal if overdosed.11 Discontinuing CEIs may lead to notable deterioration in memory and behavior, which may not be restored when the drug is restarted or another CEI is initiated.11

Memantine HCl: The FDA has also approved memantine HCl for treatment of moderate-to-severe AD. Memantine HCl is an N-methyl-D-aspartate (NMDA) noncompetitive glutamate receptor antagonist. It produces its effect through the blockade of NMDA receptors, thereby reducing a cellular event called excitotoxicity. Studies have shown that enhancement of the excitatory effects of the neurotransmitter glutamate may play a role in the pathogenesis of AD.1416 When the patient is receiving a CEI indicated for the mild-to-moderate stages of AD, memantine may be prescribed in conjunction with the CEI in the later stages of the disease.11

Combining CEIs and memantine HCl: The evidence regarding combined use of CEIs with memantine is better than the evidence regarding switching between agents or combining two CEIs, although more data are needed.12 Both memantine and CEIs are approved for moderate AD, so clinicians have a choice of which agent to start therapy, based on factors such as ease of use, patient preference, cost, and safety. In judging treatment response, clinicians should always: seek information from a reliable informant; take into account dementia and general health fluctuations; and evaluate changes in cognition, function, and behavior. It's also important to educate the family on realistic expectations to enhance adherence to treatment. Families should be cautioned that abrupt discontinuation can occasionally lead to worsening cognition or behavior.11

The CEIs are the class of drugs with the strongest evidence supporting their efficacy in treating the cognitive symptoms of mild-to-moderate AD. They should be considered as part of the care for most patients with AD. Explicit education of patients and their caregivers is essential before initiating treatment with CEIs. Ongoing assessment of the benefits and risks is essential after treatment with CEIs is initiated.

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Ongoing assessment and management

Although significant results can be obtained with different CEIs and memantine HCl, the disease will inevitably progress to an advanced stage despite treatment, at which point the discontinuation of symptomatic pharmacologic therapy should be considered. Indicators that a patient has reached this stage include inability to ambulate or to recognize family members. A standardized rating scale such as the Functional Assessment Staging Test (FAST), the Global Deterioration Scale, or the Clinician's Interview-Based Impression can be used in determining decline in functional status. With the FAST scale, for example, advancement to level 7b or 7c might be an indicator for discontinuation of symptomatic drug therapy.17

Discussion with family members is essential when making decisions to terminate treatment. Consideration must be given to clinical evidence that suggests that withdrawal of these medications likely accelerates cognitive and functional decline. Some families elect to continue treatment even when the medications are no longer efficacious in the advanced stage. Although there are research advances in medications that address memory problems, more research is needed in the pharmacologic management of behavioral symptoms and sleep disturbances in persons with AD and other dementias.

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Nonpharmacologic interventions

Although there's limited evidence from clinical trials, nonpharmacologic interventions have been reported to treat memory problems, behavioral symptoms, and sleep issues in patients with AD.2 Nonpharmacologic treatment such as use of aromatherapy can often reduce the amount of psychotropic and antipsychotic drugs.18 These drugs have been known to cause adverse reactions such as extrapyramidal symptoms, delirium, falls, hip fractures, pressure ulcers, and insomnia that further compromise the health of persons with AD.19 Cochrane Reviews reported four randomized controlled trials on aromatherapy; only one had usable data. The analysis of this one small trial did show a significant effect in favor of aromatherapy on measures of agitation and neuropsychiatric symptoms.2

Memory problems: Gingko and ginseng (Panax species) are the most common herbs used to enhance memory and prevent cognitive decline, but there has been controversy about the usefulness and safety of these herbs in the treatment of cognitive decline.20 Cochrane Reviews found that there was no convincing evidence to support use of gingko and ginseng with patients with AD.2 Lemon balm (Melissa officinalis extracts), rosemary (Rosmarinus officinalis), and sage (Salvia lavandulaefolia officinalis) appear to be more promising in managing memory problems when tested on young adults and normal older adults, and there could be benefits in adults with AD, but more research is needed.21

Behavioral symptoms: Operant and classical conditioning to reduce behavioral symptoms in persons with AD includes strategies such as consistent positive reinforcement for appropriate behaviors while ignoring negative behaviors. In one study, exercise was used to replace wandering behaviors with meaningful activities (such as housework and reminiscence using person-centered care) and may have produced a more positive social environment. The researchers stressed that the evidence didn't provide a clear rationale for group treatments, and interventions should be structured and individualized based on the patient's history.22

Multisensory stimulation environment programs (such as Snoezelen) consist of social interaction, recreation, and leisure activities, along with changes to the environment, including use of controlled lighting, aromatherapy, mirrors, tactile stimuli, or music. Many studies were pilot studies; more clinical trials are needed to substantiate the effectiveness of these types of programs.23 The effectiveness of a walking exercise program is being tested to treat behavioral symptoms in person with AD. Although walking may appear to be a simple intervention, the researchers stress that implementing the treatment requires a well-thought-out and structured plan.24

Sleep problems: Nighttime awakenings by persons with AD are a common cause of sleep/wake disturbances in family caregivers.25 Aromatherapy has been tested to manage sleep disturbances; studies included the use of essential oils such as rosemary, chamomile, sandalwood, or lavender. Aromatherapy is noninvasive, can be administered at low cost, appears to have few adverse reactions, and can be administered in many ways: orally, through inhalation, baths, massage, compresses, creams, oils, mouthwash, or suppositories.2628

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Assisting families and caregivers

The number of people diagnosed with dementia is increasing, and family caregivers are seeking interventions to prevent more memory loss and manage the illness. FDA-approved pharmacologic interventions have been developed to address memory problems, but pharmacologic interventions aren't consistently effective to address behavioral symptoms and sleep problems. Unfortunately, medications often become ineffective as the disease progresses or result in adverse reactions. Many nonpharmacologic interventions may be less costly and can be used to manage behaviors and sleep problems simultaneously with lower doses of pharmacologic treatment, which may result in fewer adverse reactions. Although complementary and alternative medicine treatments are advertised in the media and many people are using them, most have little knowledge of safe amounts and how to use them. The nurse can assist patients and families by providing the latest evidence regarding use and safety.

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