An estimated 5.4 million individuals of all ages in the United States have Alzheimer disease (AD).1 This figure includes 5.2 million people ages 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

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Cochrane Reviews recently reported that there is no evidence for treatment of AD with the substances cited above, which families may have heard or read about in the media.2 There is insufficient evidence regarding lecithin, light therapy, melatonin, thiamine, and physical activity to improve cognitive function and/or sleep disturbances in patients with AD. However, there is 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

Pharmacologic treatment

New diagnostic criteria have redefined the stages of AD: preclinical phase, mild cognitive impairment, and Alzheimer disease dementia. A description of the role of biomarkers is included in the discussion of each stage disease (see Diagnostic guidelines for AD).3 The major biomarkers to measure the presence or progress of AD are the biomarker for beta-amyloid accumulation seen on positron emission tomography (PET) amyloid imaging and the biomarkers for neuronal degeneration or injury evidenced by elevated total and phosphorylated cerebrospinal fluid (CSF) tau, seen in CSF assays. Amyloid biomarkers become abnormal when individuals are asymptomatic, usually 10-20 years before symptoms appear. Neurodegeneration also becomes prevalent at a later point, and as AD worsens, the neurodegenerative biomarker measures worsen too. 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 examination, is indicated for diagnosing the more advanced stages of mild cognitive impairment and AD dementia. The biomarkers may, however, be used to complement the diagnosis in the later stages of the disease. A definitive diagnosis can be made without the use of biomarkers for clinicians who may not have access to methods of measuring biomarkers in the later stages of the disease.3

Figure. Pathologic tissue changes in AD

Consensus clinical guidelines for the management of AD present the available evidence on the effectiveness of the U.S. Food and Drug Administration (FDA)-approved pharmacologic therapies for dementia that address cognition, global functioning, behavior/mood, and quality of life that affects activities of daily living (for example, bathing and mobility).3-9 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 people with dementia. The authors of the document state that there are circumstances in which it is appropriate.4-10

Overall, the benefits of symptomatic treatments for AD are modest, and some authors argue that the magnitude of this benefit, though 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 considers 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 (Aricept, Aricept ODT), rivastigmine (Exelon, Exelon patch), galantamine (Razadyne, Razadyne ER), and tacrine (Cognex) 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 are 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. CEIs do not, however, 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 (GI) 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

Donepezil: Donepezil is a piperidine derivative that reversibly inhibits AChE.15 It is very well absorbed after oral administration and reaches peak plasma concentration (Cmax) in 3 to 4 hours. Elimination half-life of donepezil is approximately 70 hours, allowing once-daily administration. Donepezil binds to plasma proteins in a proportion of 96% and is metabolized by isoenzyme 2D6 and 3A4 of cytochrome P450.15 The usual daily dosing range is 5 to 10 mg administered at bedtime. A 23 mg tablet is also available however, side effects have been reported to occur more frequently at doses higher than 10 mg. Donepezil is also available in 5 and 10 mg orally disintegrating tablets.12 Its favorable adverse reaction profile appears to correlate with its lack of inhibition of cholinesterase in the GI tract.16 A disadvantage of donepezil is that it may be associated with more sleep disturbances than other CEIs. It has also been infrequently associated with bradydysrhythmias, especially in people with underlying cardiac disease. A few patients taking donepezil experience syncope.16

Rivastigmine: Rivastigmine is a carbamate derivative that reversibly inhibits both AChE and butyrylcholinesterase.11,15 Rivastigmine is well absorbed after oral administration and reaches Cmax in 1 hour. Its elimination half-life is approximately 1 to 2 hours. It binds to proteins in a proportion of 40% and is excreted in the urine. Cytochrome P450 isoenzymes are not involved in the metabolism of rivastigmine, hence minimizing drug-drug interactions.15 Rivastigmine appears to have somewhat more peripheral activity than donepezil and, thus, is more likely to cause GI distress.

Although generally well tolerated, recommended dosages may need to be decreased in the initial period of treatment to limit adverse effects in the GI and central nervous systems. The starting dose of rivastigmine is 1.5 mg twice a day, which can be gradually titrated to the maximal dose of 6 mg twice a day. The minimal effective dose is 3 mg twice a day.16,17

A transdermal form of rivastigmine became available in 2008.19,20 Transdermal rivastigmine allows titration to the highest and most therapeutic doses of the medication while minimizing adverse reactions. This is achieved by slowly releasing the medication into the circulatory system as demonstrated by a Cmax of 8 hours by the transdermal route. The starting dose of transdermal rivastigmine is 4.6 mg/24 hours (5 cm2 patch) and the effective and maximal dose is 9.5 mg/24hours (10 cm2 patch).5,20

Galantamine: Galantamine is a tertiary alkaloid agent that reversibly inhibits AChE.16 Galantamine also inhibits nicotinic receptors, a process that enhances actions of acetylcholine. Nicotinic modulation may also enhance the actions of other neurotransmitters by increasing the release of dopamine, norepinephrine, serotonin, gamma aminobutyric acid, and glutamate.19 Theoretically, nicotinic modulation may provide added therapeutic benefits for memory and behavior in some people with AD and may be useful for other forms of dementia, including vascular dementia, Lewy body dementia, and dementia in Down syndrome. Galantamine is rapidly absorbed after oral administration and reaches Cmax in approximately 1 hour.16 Elimination half-life is between 7 and 8 hours. It binds to plasma proteins in a proportion of 18% and is metabolized by isoenzyme 2D6 and 3A4 of cytochrome P450.16

Galantamine is available as a standard-release product and is administered twice a day. It is also commercialized as an extended-release (ER) formulation allowing once-daily dosing. The starting dose of galantamine ER is 8 mg once daily. Dose adjustments are required for patients with moderate-to-severe hepatic and renal impairment. The most common adverse reactions of galantamine are mild and transient and include dizziness, headache, nausea, vomiting, diarrhea, and anorexia.21

Tacrine : Tacrine was the first centrally acting CEI approved for the treatment of AD, and was marketed under the trade name Cognex. Tacrine is not often prescribed because it is cumbersome to titrate and use. More important, tacrine also poses the risk of hepatotoxicity.12

Memantine HCl The FDA has also approved memantine HCl (Namenda, Namenda XR) for treatment of moderate-to-severe AD. Memantine HCl is an N-methyl-d-aspartate (NMDA) noncompetitive glutamate receptor antagonist.21 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.14,15,21 Memantine is well absorbed after oral administration and reaches Cmax in 3 to 8 hours. Elimination half-life is 60 to 80 hours. It binds to proteins in a proportion of 45% and is almost completely excreted unchanged in the urine.15 Starting dose is 5 mg daily. Minimal therapeutic dose is 10 mg daily, and maximal dose is 20 mg daily.13 However, dose adjustments are required for patients with several renal impairment. Available dosage forms include 5 and 10 mg tablets, oral solution 2 mg/mL, and extended-release 7 mg, 14 mg, 21 mg, and 28 mg capsules. Memantine HCl is well tolerated, with a low incidence of adverse reactions.13 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.11,16,22

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 is needed.12 Both memantine and CEIs are approved for moderate AD, and hence 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 is 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

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 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.23

Although there is 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 aromatherapy often can reduce the amount of psychotropic and antipsychotic drugs.40 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 people with AD.26Cochrane 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

Use in 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.24Cochrane 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), however, appear to be more promising in managing memory problems when tested on young adults and normal older adults25, and there could be benefits in adults with AD, but more research is needed.

Psychosocial interventions to manage behavioral symptoms

Operant and classical conditioning to reduce behavioral symptoms in people 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 (for example, housework and reminiscence using person-centered care) and may have produced a more positive social environment. The researchers stressed that the evidence did not provide a clear rationale for group treatments, and interventions should be structured and individualized based on the patient's history.28

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.29 Many studies were pilot studies; more clinical trials are needed to substantiate the effectiveness of these types of programs.29 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.30

Sleep problems

Nighttime awakenings in people with AD are a common cause of sleep/wake disturbances in family caregivers.31Aromatherapy has been tested to manage sleep disturbances; studies included the use of essential oils such as rosemary, chamomile, sandalwood, or lavender.32-34 Aromatherapy is noninvasive, can be administered at low cost, appears to have few adverse reactions, and can be administered in many ways including through inhalation, baths, massage, compresses, creams, or oils.35-37

Koch and colleagues38 reviewed four studies, conducted in the mid 1990s, investigating aromatherapy in sleep promotion, using lavender, chamomile, and valerian. The results appeared promising in promoting sleep in people with dementia; however, the sample size was small, and valerian has been reported to be toxic for older adults.39 Researchers have also studied the use of the essential oil of lavender to help promote sleep in patients with dementia (see Aromatherapy in sleep promotion).40 O'Connor et al. stated that most psychosocial interventions used in the treatment of behavioral symptoms appear promising; however, the therapeutic effect was small and of short duration.41 They noted that treatments with moderate effect included educating staff, bed baths, muscle relaxation training, music, and aromatherapy.

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 are not 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.39 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 practitioner can assist patients and families by providing the latest evidence regarding use and safety.

Diagnostic guidelines for AD

Preclinical phase

Researchers conducted a pilot study to examine the feasibility of administering a warm lavender oil towel bath in the homes of patients with dementia who experienced sleep problems.40 The sample included six people with dementia and six caregivers.

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