Improving Treatment Options for Alzheimer's Disease

An identity thief of the worst kind, Alzheimer's disease (AD) evokes unparalleled fear. This insidious, progressive neurodegenerative condition slowly robs victims of personality, memory, self-sufficiency, decorum, and the ability to communicate. It traumatizes victims as they realize they are "losing it." It finds family members economically and physically strapped, and unprepared for the emotional impact of a relative's blank stare.

Fear among elders is valid: 90% of AD cases occur in people 65 years and older, and nearly half of elders over age 85 are afflicted. Their poor long-range prognosis is death; approximately 50% of victims die within 8 years of diagnosis (Table 1^1,2). Until recently, the limited treatment options were pharmacologically similar. Today, 5 FDA-approved agents target different sites, offering some choice.

Stages and Symptoms

AD symptoms are categorized into 3 stages: mild, moderate, and severe. Many patients remain undiagnosed, partly due to stereotypes about aging, until they progress to the moderate stage with its dramatic changes. In this stage, patients experience serious cognitive deficits:

• Inability to recognize the purpose of everyday objects (eg, comb, keys)
• Inappropriate dress
• Confusion when given commands
• Marked inability to communicate clearly

Patients in the severe stage are completely disoriented, lose daily living skills, and have little or no motor coordination. Unresponsive, uncommunicative, bed-ridden, incontinent, and helpless, these patients often die quickly because of their increased susceptibility to myriad comorbid conditions and complications.

Pathophysiology

The 2 core characteristics of AD are structural brain abnormalities: amyloid plaques, dense insoluble protein deposits, and cellular material that form around the neurons of the brain, consisting primarily of beta-amyloid; and neurofibrillary tangles, a disarray and tangling of the microtubules of nerve cells. Are these abnormalities causes or by-products of the disease? No one knows. Autopsy results and pre-death cognitive testing reveal considerable variation between degree of brain pathology and overt symptoms; brain pathology does not correlate closely with symptoms.^3,4 Additionally, research has confirmed that brain pathology precedes symptoms for at least a decade, if not longer.² Although a genetic link exists, most geneticists believe that additional factors bring forth the manifestation of AD.⁴

The Cholinergic Hypothesis

Acetylcholine is essential for normal cognitive functioning. In normal neural transmission, acetylcholine interacts with postsynaptic and presynaptic nicotinic and muscarinic receptors, and it is metabolized by acetylcholinesterase and butyrycholinesterase. Normally, small acetylcholine declines occur over years, but AD is associated with up to a 90% decline. The plaques and tangles of AD correlate with cholinergic deterioration, so research has focused primarily on enzyme inhibition to prevent acetylcholine metabolism.^3,5

Drug Therapy

Of the 5 approved drugs, 4 are cholinesterase inhibitors for mild-to-moderate symptoms: tacrine, donepezil, rivastigmine, and galantamine (Table 2^3,6). All inhibit acetylcholinesterase, butyrycholinesterase, or both. Maximum benefits usually require higher doses. Of the 4, tacrine is considered second-line because it elevates liver enzyme levels in 40% of patients and requires biweekly blood testing during dose escalation and routine testing thereafter.⁴

"Start low and go slow" is essential for cholinesterase inhibitors. Their transient, centrally mediated side effects generally occur during dose escalation. Adhering to a 4-week titration schedule reduces adverse events. For example, 12% of patients experienced diarrhea with a 1-week titration of galantamine, compared with 6% with a 4-week titration.⁵ Administering the drug with food often reduces side effects.

Memantine

Memantine, approved in October 2003, is the first drug for moderateto- severe AD. An N-methyl-D-aspartate antagonist (NMDA), memantine blocks glutamate action. Glutamate acts on NMDA receptors and regulates calcium movement. The destruction of brain cells in AD may increase glutamate levels. Excess glutamate overstimulates other cells, which are further damaged by excess calcium.⁷ Decreasing glutamate attenuates cell damage.

Memantine-treated patients in clinical trials improved significantly both on cognitive measures and in daily living skills.⁸

Initial dosing of memantine is 5 mg daily, with a target dose of 20 mg daily. The dose may be increased in 5-mg increments over 1 week, and doses exceeding 10 mg should be divided into 2 doses. Memantine may be taken with or without food, and common side effects include dizziness (7%), headache (6%), and constipation (6%).^8,9

Switching Drugs

Clinicians rarely switch AD drugs because treatment options are limited. They often believe that failure to respond to one cholinesterase inhibitor implies unlikely success with another. Additionally, they may interpret poor response as disease progression. Research suggests otherwise. Nonresponders to donepezil, for example, have improved on rivastigmine. Also, tolerability varies among cholinesterase inhibitors; one study found that 75% of patients who could not tolerate donepezil tolerated rivastigmine.⁵ Prior to switching, some practitioners recommend a washout period of 1 week.⁵

Some clinicians are using memantine in combination with a cholinesterase inhibitor. Cholinesterase inhibitors improve behavioral symptoms and reduce the need for antipsychotic and antidepressant medications, which themselves can interfere with cognition.⁵ The addition of memantine offers continued benefits as patients progress from the moderate to the severe stage. With no practice guideline available, clinicians should assess candidates for combination therapy carefully.

Counseling Patients

Families and patients need a realistic expectation of treatment response. Treatment does not prevent further degeneration, and it will not restore pre-illness functioning. Improvement may be equivalent to reversal of a 1-year decline, and noticeable differences may take several weeks.⁶ Monitoring side effects is critical. A daily log to record side effects and a patient's reactions may help clinicians individualize doses.

The Future

Numerous investigational agents are targeting different pathways in AD. Even modest prevention efforts could have enormous impact. Delaying symptom onset by 5 years would decrease incidence (and related costs) by 50%.¹ Perhaps within the next 20 years, researchers will be able to restrain or detain this identity thief.

Dr. Zanni is a health-systems consultant and a former commissioner of mental health for the District of Columbia. Ms. Yeznach Wick is a senior clinical research pharmacist at the National Cancer Institute, National Institutes of Health. The opinions expressed are those of the authors and not necessarily those of any government agency.

For a list of references, send a stamped, self-addressed envelope to: References Department, Attn. A. Stahl, Pharmacy Times, 241 Forsgate Drive, Jamesburg, NJ 08831; or send an e-mail request to: astahl@mwc.com.