Alzheimer's disease, the most common form of dementia, is a progressive disorder characterized by widespread neuronal loss, betaamyloid deposits in the cerebral blood vessels, development of neuritic plaques and the presence of neurofibrillary tangles. These changes, occurring in the association area of the cerebral cortex, the hippocampus and the middle and temporal lobes, are accompanied by decreased concentrations of the neurotransmitter acetylcholine.
O'Hara and associates discuss recent findings and treatments of patients with Alzheimer's disease. The primary symptom is a decline in memory and cognition that leads to marked impairment in daily functioning. Changes in personality and behavior changes (e.g., agitation, hallucinations, delusions) may also occur as the disease progresses. The duration of illness is approximately seven to 10 years from the time of diagnosis, with the later stages requiring total custodial care.
Diagnostic criteria for Alzheimer's disease include onset between 40 and 90 years of age, no disturbance of consciousness, dementia evidenced by objective standards, gradual and progressive deficits in two or more areas of cognition (one of which is memory), absence of organic cause for the deficits and deficits that do not occur exclusively during an episode of delirium. The diagnosis of possible Alzheimer's disease is made when only one progressive, severe cognitive deficit is identified, and other organic causes are absent. Some confusion exists between the memory loss associated with possible Alzheimer's disease and the memory loss associated with mild cognitive impairment; however, the latter diagnosis typically involves milder memory loss and the absence of functional impairment.
Because early intervention may prolong functioning in patients with Alzheimer's disease, identifying risk factors has become more important. Identified risk factors include a family history of dementia with other possible, but less well-documented risk factors, including female sex, poor nutrition, atherosclerotic vascular disease, head injury, depression, engaging in fewer social activities and lower occupational attainment.
The mainstay of treatment options is acetylcholinesterase inhibitors, which increase the duration of acetylcholine action in synapses. Tacrine, the earliest drug in this group, has only limited benefit and a poor side effect profile, including hepatotoxicity. Donepezil is a highly selective acetylcholinesterase inhibitor that significantly improved cognitive scores (during phase 2 and 3 clinical trials), with a better side-effect profile. A newer acetylcholinesterase inhibitor, rivastigmine, has a good side effect profile but requires more time for dosage titration than donepezil. Estrogen therapy increases acetylcholine concentrations and has antioxidant activity, but proof of its ability to reduce the risk of Alzheimer's disease has been inconclusive. Anti-inflammatory drugs, including cyclooxygenase-2 inhibitors and steroids, are under investigation. Antioxidants, including selegiline, vitamin E and Ginkgo biloba have demonstrated some benefit in improving cognition and delaying progression of the disease, but the outcome measures used have been variable, making treatment recommendations difficult.
The authors conclude that donepezil is the most useful treatment in patients with Alzheimer's disease and should be prescribed to patients with mild or moderate dementia at a starting dosage of 5 mg per day, with an increase to 10 mg after 10 weeks. The duration of treatment and definition of the patients who will benefit most are unclear. The efficacy of other treatments needs to be further documented. Antipsychotic agents may be helpful in controlling behavior problems such as agitation and aggression, although adverse side effects may occur. Ongoing research is focusing on the further role of cholinesterase inhibition, muscarinic agonists, the effect of reducing beta-amyloid, identifying which patients benefit most from pharmacologic treatment, and understanding the interaction between genetic variables and psychosocial risk factors for the disease.
editor's note: As this article implies, one of the most important reasons to make the diagnosis of Alzheimer's disease in patients with early onset dementia is the availability of donepezil, because it causes few side effects and can significantly delay the onset of moderate to severe dementia. It is much less effective when given later in the course of the disease. Performing a Mini-Mental State examination of patients with suspected dementia and ruling out other organic or psychologic causes are essential parts of family practice.—r.s.