Alzheimer's disease currently affects about 4 million people in the United States. This neurodegenerative disease causes selective neuronal loss in brain regions involved in memory, language, personality, and cogni- tion. The earliest symptom of Alzheimer's disease is usually the insidious onset and progression of memory loss. Initially, this memory loss can be difficult to differen- tiate from common age-associated benign forgetfulness. However, patients with age-associated benign forgetful- ness are aware of the deficit and their activities of daily living are minimally impaired.
I. Pathogenesis
A. Age is the major risk factor for development of
Alzheimer's disease. The incidence of Alzheimer's disease increases with age, doubling every 5 years between ages 60 and 85. Limited education and a history of head trauma may also be factors in development of disease.
B. The presenilin 1 gene is the most common site of
mutations responsible for early-onset Alzheimer's disease. Genetic testing should be restricted to patients with early-onset Alzheimer's disease and a strong family history of dementia.
C. Onset of dementia symptoms after age 60 occurs
II. Diagnosis
Criteria for diagnosis of Alzheimer's disease
Dementia established by clinical examination and docu- mented by the Mini-Mental State Examination or similar examination
Deficits in two or more areas of cognition (ie, language, memory, perception)
Progressive worsening of memory and other cognitive function; as disease progresses, patient experiences impairment in activities of daily living and altered behav- ioral patterns
No disturbance of consciousness
Onset between ages 40 and 90, but most often after age 65
Absence of other systemic disorder or brain disease that may account for deficits in memory and cognition
A. Computed tomographic scanning and magnetic
resonance imaging often show generalized and hippocampal atrophy in patients with Alzheimer's disease. These tests are not sensitive enough to establish a diagnosis. Imaging is useful in exclud- ing a diagnosis of stroke, tumor, or hydrocephalus.
B. Delirium should be excluded and coexisting condi-
tions that worsen dementia by reviewing medica- tions, screening for depression, and ruling out nutritional deficiencies, diabetes mellitus, uremia, alterations in electrolytes and thyroid disease.
III. Treatment of Cognitive Deficits in Alzheimer's Disease
A. Cholinesterase Inhibitors. Treatment with
cholinesterase inhibitors can provide modest improvement of symptoms, temporary stabilization of cognition, or reduction in the rate of cognitive decline in mild to moderate Alzheimer's disease. Approximately 20 to 35 percent exhibit a seven-point improvement on neuropsychologic tests (5 to 15 percent benefit). These agents raise acetylcholine levels in the brain by inhibiting acetylcholinesterase.
Cholinesterase Inhibitors for the Treatment of Mild-to-Moderate Alzheimer's Disease
Drug Dosage Side effects Specific
cautions Donepezi l (Aricept) Initial dos- age is 5 mg once daily; if necessary, dosage can be in- creased to 10 mg once daily after 4 to 6 weeks.
Mild side ef- fects, including nausea, vomit- ing, and diar- rhea; effects can be re- duced by tak- ing with food. Initial increase of agitation in some; agita- tion subsides after a few weeks. Possible in- teractions with cimetidine (Tagamet), theophylline, warfarin (Coumadin), and digoxin (Lanoxin) Rivastigm ine (Exelon) Initial dos- age of 1.5 mg bid (3 mg per day) is well toler- ated; dos- age can be increased as tolerated to maximum of 6 mg twice daily (12 mg per day). Nausea, vomit- ing, diarrhea, headaches, dizziness, ab- dominal pain, fatigue, mal- aise, anxiety, and agitation; these effects can be re- duced by tak- ing rivastigmine with food. Weight loss Interacting drugs include amino- glycosides and procainamide (Procanbid). Galantam ine (Reminyl) Initial dos- age is 4 mg bid (8 mg per day) for 4 weeks; dosage is then in- creased to 8 mg twice daily (16 mg per day) for at least 4 weeks. An increase to 12 mg twice daily (24 mg per day) should be considered.
Mild side ef- fects, including nausea, vomit- ing, and diar- rhea; these effects can be reduced by taking galantamine with food. No apparent association with sleep dis- turbances (which can occur with other cholinergic treatments) Contraindi- cated for use in patients with hepatic or renal im- pairment Tacrine (Cognex) Initial dos- age is 10 mg four times daily (40 mg per day) for 4 weeks. High incidence of side effects, including gas- trointestinal problems. Hepatotoxicit y is a prob- lem; hence, liver tests should be performed.
1. Donepezil (Aricept) is given once daily, begin-
ning with a dosage of 5 mg per day, which can be increased to 10 mg per day (max) after four weeks. Donepezil is not hepatotoxic. Adverse effects are mild (eg, nausea, vomiting, and diarrhea) and are reduced when taken with food. An initial increase in agitation may occur, which subsides after the first few weeks. Donepezil produces improvements of cognitive and global function with mild-to-moderate Alzheimer's disease.
2. Rivastigmine (Exelon) is initiated in a dosage
of 1.5 mg twice daily. The dosage is increased by 1.5 mg twice daily (3 mg per day) as toler- ated, every four weeks, to a maximum of 6 to 12 mg per day. No laboratory monitoring is required. Adverse effects include nausea, vomiting, diarrhea, weight loss, headaches, dizziness, abdominal pain, fatigue, malaise, anxiety, and agitation. Rivastigmine has been is effective in temporarily slowing cognitive decline, improving function, and reducing behavioral and psychopathologic symptoms in mild-to-moderate Alzheimer's disease.
3. Galantamine (Reminyl) starting dosage is 4
mg twice daily, taken with morning and evening meals. After four weeks, the dosage is in- creased to 8 mg twice daily. An increase to 12 mg twice daily may be considered. The most common side effects are nausea, vomiting, and diarrhea, which can be minimized by titrating the dosage gradually and taking the medication with meals. Improvement of cognitive and functional outcomes and behavioral symptoms has been demonstrated.
4. Tacrine (Cognex) is a second-line agent
because, unlike the newer cholinesterase inhibitors, tacrine causes elevation of liver enzyme levels; thus, biweekly liver tests are necessary.
5. Beneficial response to a cholinesterase inhibi-
tor can be determined from the physician's global assessment of the patient, the primary caregiver's report, a neuropsychologic assess- ment or mental status questionnaire, or evi- dence of behavioral or functional changes. Observation for six to 12 months is usually necessary to assess potential benefit.
B. Vitamin E intake of 2,000 IU daily of may slow the
progression of functional symptoms.
C. N-methyl-D-aspartate (NMDA) receptor antago- nists
1. Glutamate is the principle excitatory amino acid
neurotransmitter in cortical and hippocampal neurons. One of the receptors activated by glutamate is the N-methyl-D-aspartate (NMDA) receptor, which is involved in learning and memory.
2. Memantine (Axura, Ebixa) is an NMDA recep-
tor antagonist. In patients with mild-to-moder- ate vascular dementia (mini mental status examination scores 12 to 20), memantine significantly improves cognitive abilities. There were no serious side effects with therapy. This may represent a promising avenue for the treatment of vascular dementia.
IV.Comorbid conditions. Depression is common in
older adults, including those with Alzheimer's disease. Selective serotonin reuptake inhibitors, such as citalopram (Celexa) and sertraline (Zoloft), appear to be effective and have few side effects; thus, they are the agents of choice for the treatment of depression. References, see page 282.