genetic predisposition and environmentalinfluences is probably responsible.
One of these influences may be subclinical ischemia,because patients with high blood pressure andelevated cholesterol levels tend to have anincreased risk for Alzheimer’s disease.
Neurofibrillary tangles are made up partly ofa protein called tau,which links togetherto form filaments.The density ofthese fila-ments within neurons in the brain is directly related to the severity ofdementia.It isunclear why tangles form,but different al-leles ofa gene are known to create forms of tau that are more likely to tangle.
It is alsounclear whether tangles are linked to plaqueformation.The ultimate effect ofthe tangles,however,is compromise ofmicrotubularfunction,with eventual destruction oftheneuron.Involvement ofcholinergic neurons causeslevels ofacetylcholine within synapses todecline.Levels ofacetylcholinesterase alsodrop,perhaps to compensate for the loss of acetylcholine.Activity ofanother cholin-esterase enzyme (butyrylcholinesterase)increases,and a significant portion ofacetyl-choline is metabolized by this enzyme as thedisease progresses.Eventually,the neuron isdestroyed.
he financial and social costs of Alzheimer’s disease are stagger-ing.In the United States,the dis-ease accounts for about $100 bil-lion per year in medical andcustodial expenses,with the average patientrequiring an expenditure ofabout $27,000 per year for medical and nursing care.In addition,80 percent ofcaregivers report stress,andabout 50 percent report depression.
Thisarticle reviews the pathophysiology of Alzheimer’s disease,evidence for the efficacy ofvarious pharmacologic treatments,andguidelines for the use ofdrug therapy inpatients with this devastating disease.
Two microscopic changes occur in the brainin Alzheimer’s disease:senile plaques developbetween neurons,and neurofibrillary tanglesdevelop within neurons.These changes arethought to be intricately related to the cause,development,and course ofthe disease.Researchers have speculated that inflamma-tion around plaques destroys neighboringneurons.Plaques,which are composed of
-amyloid polypeptides,seem to form as aresult ofdisorders in processing
-amyloidand its precursor protein.A combination of
Alzheimer’s disease is characterized by the development of senile plaques and neurofibril-lary tangles, which are associated with neuronal destruction, particularly in cholinergic neu-rons. Drugs that inhibit the degradation of acetylcholine within synapses are the mainstayof therapy. Donepezil, rivastigmine, and galantamine are safe but have potentially trouble-some cholinergic side effects, including nausea, anorexia, diarrhea, vomiting, and weightloss. These adverse reactions are often self-limited and can be minimized by slow drug titra-tion. Acetylcholinesterase inhibitors appear to be effective, but the magnitude of benefitmay be greater in clinical trials than in practice. The drugs clearly improve cognition, but evi-dence is less robust for benefits in delaying nursing home placement and improving func-tional ability and behaviors. Benefit for vitamin E or selegiline has been suggested, but sup-porting evidence is not strong. Most guidelines for monitoring drug therapy in patients withAlzheimer’s disease recommend periodic measurements of cognition and functional ability.The guidelines generally advise discontinuing therapy with acetylcholinesterase inhibitorswhen dementia becomes severe. (Am Fam Physician 2003;68:1365-72. Copyright© 2003American Academy of Family Physicians.)
Pharmacologic TreatmentofAlzheimer’s Disease:An Update
VINCENT W.DELAGARZA,M.D.,West Virginia University School ofMedicine,Morgantown,West Virginia
Richard W. Sloan,M.D., R.PH.,coordina-tor of this series, ischairman of theDepartment of Family Medicine at York (Pa.)Hospital and clinical associate professor infamily and community medicine at the Mil-ton S. Hershey Med-ical Center, Pennsylva-nia State University,Hershey, Pa.See page 1241 for definitions of strength-of-evidence levels.
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