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Alzheimer disease: Time to improve its diagnosis and treatment

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CURRENT AND FUTURE TREATMENTS

Five drugs have been approved for treating Alzheimer disease: four cholinesterase inhibitors approved for mild to moderate disease and a glutamate N-methyl D-aspartate (NMDA) antagonist approved for moderate to severe disease.

Cholinesterase inhibitors for mild to moderate disease

The cholinesterase inhibitors tend to stabilize memory during the first year of treatment, and they may make the subsequent decline more gradual. The four current drugs have similar efficacy, so the choice is usually based on tolerability and ease of use.

Tacrine (Cognex) is rarely used because it must be taken four times a day, it can cause gastrointestinal adverse effects, and it can raise hepatic enzyme levels.

Donepezil (Aricept) is the drug most often prescribed because it can be taken once daily, a major benefit in older patients with memory loss. Also, its starting dose (5 mg) is a therapeutic dose. Donepezil was also recently approved for the treatment of severe Alzheimer disease on the basis of positive results in trials in patients with moderate to severe disease.35,36

Galantamine (Razadyne) comes in an extended-release formulation that can be taken once daily.

Rivastigmine (Exelon) is taken twice a day with food to reduce the risk of gastrointestinal adverse effects. It is also now available as a daily patch, which has a more favorable adverse-effect profile than oral rivastigmine.37

Memantine for moderate to severe disease

Memantine (Namenda), an NMDA antagonist, is approved for moderate to severe Alzheimer disease. The approval was based on a trial in which patients with advanced Alzheimer disease who received memantine monotherapy showed less decline in cognition and function after 6 months than those who received placebo,38 and another trial in which patients who received the combination of donepezil plus memantine showed more benefit than with donepezil alone.39

A treatment strategy

Recent guidelines recommend starting treatment with a cholinesterase inhibitor soon after Alzheimer disease is diagnosed and titrating the dose, as tolerated, to the high end of the therapeutic range.40 Once patients decline to the moderate stage of the illness, usually with an MMSE score of 10 to 20, memantine should be added and titrated upward to 10 mg twice a day. The medications should be continued as long as they are tolerated and the clinician feels there is some evidence they are helping.

The main benefit of the cholinesterase inhibitors in clinical trials is an attenuation of decline over time rather than an improvement in cognitive or behavioral symptoms. This should be considered when judging whether there has been a positive effect. It is also important to discuss this point with patients and their families, who may expect improvement rather than relative stability. Benefits of these drugs in later stages of the illness usually involve better recognition and engagement with family members and people around them and less severe behavioral disturbances, making care easier.36,41–43

Will drug therapy help in mild cognitive impairment?

Currently, no drugs are approved by the US Food and Drug Administration for patients with mild cognitive impairment, and the use of cholinesterase inhibitors in this population may not be reimbursed.

Six trials of cholinesterase inhibitors for mild cognitive impairment have been completed.44–47 On the whole, donepezil, rivastigmine, and galantamine had no effect on the primary end points in these trials, but they had some effects on some secondary ones.

In the Alzheimer Disease Cooperative Study,44 donepezil had no effect on the rate of progression from mild cognitive impairment to Alzheimer disease over the entire 3 years of the study, but it did reduce the rate in the first year of treatment. Moreover, the subgroup with one or two ApoE4 alleles benefitted over the entire 3 years.

A 24-week trial of donepezil in patients with mild cognitive impairment45 had negative results with regard to the selected study end points (two standardized tests), but there was evidence of cognitive benefit with donepezil on secondary measures such as the Alzheimer’s Disease Cognitive Assessment Scale-Cognitive Subscale,48 a widely used cognitive measure in Alzheimer disease trials, and in patients’ self-assessment of their memory.

One should discuss the risks and benefits of cholinesterase treatment with patients with mild cognitive impairment in whom underlying Alzheimer disease is strongly suspected.

Addressing behavioral problems

Behavioral problems are often the most disturbing symptoms in dementia, often leading to higher levels of care.

Apathy is the most common behavioral symptom in Alzheimer disease, increasing with disease severity.49 There is no approved treatment for these apathetic symptoms, though methylphenidate (Ritalin) and modafanil (Provigil) are being tested in small clinical trials.

Depression and irritability are common and may respond well to low doses of serotonin reuptake inhibitors.

Agitation and psychosis are distressing and are likely to overwhelm the caregiver’s ability to cope. Recent studies have raised concern about the safety and efficacy of atypical neuroleptics in patients with dementia and suggest that these drugs be used with careful monitoring.50

A safe, calm, predictable environment

Patients with Alzheimer disease function best in an environment that is safe, calm, and predictable, and their caregivers require ongoing support and education to develop realistic expectations throughout the course of the illness.

Behavioral treatments for problematic behaviors for which supportive evidence exists include reduction of environmental stressors and behavioral management of problematic behaviors.51–53 Such interventions typically include carefully observing and recording the problematic behavior, including its antecedents and situations under which it is most likely to occur, and then modifying the physical and interpersonal environment and schedule to reduce its occurrence.51

A challenge to the use of behavioral interventions in dementia is that the patient’s cognitive functioning is gradually declining, and this may require adjustments of interventions with time and in response to new behaviors that emerge.51 Referral to a behavioral specialist such as a geriatric psychiatrist may be helpful in managing disruptive and hard-to-treat behavioral problems.

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