Diagnosis, Management, and Treatment of Alzheimer Disease: A Guide for the Internist Diagnosis, Management, and Treatment of Alzheimer Disease A Guide for the Internist Stephanie S. Richards, MD; Hugh C. Hendrie, MB, ChB A lzheimer disease (AD) is a diagnosis of inclusion based on patient history, physical ex- amination, neuropsychological testing, and laboratory studies; however, there is no de- finitive diagnostic test for AD. Early recognition of AD allows time to plan for the future and to treat patients before marked deterioration occurs. Effective treatment requires moni- toring of symptoms, functional impairment, and safety, and the use of multiple treatment modalities including pharmacotherapy, behavioral management, psychotherapies, psychosocial treatments, and support and education for families. Pharmacotherapeutic agents available for AD only provide symp- tomatic relief. The cholinesterase inhibitors, tacrine and donepezil, are effective in improving cogni- tion, delaying nursing home placement, and improving behavioral complications in some patients. Other cholinesterase inhibitors are in development, as are other cholinomimetic agents such as muscarinic and nicotinic receptor agonists. Symptomatic treatments are available for the psychiatric manifestations of AD. Anti-inflammatories, antioxidants, neurotrophic factors, and other agents are promising new treatments for the future. Arch Intern Med. 1999;159:789-798 Alzheimer disease (AD) is one of a group of neurodegenerative disorders that fre- quently cause dementia. Dementia is char- acterized by a progressive cognitive de- cline leading to social or occupational disability occurring in a state of clear consciousness. Specifically, AD is characterized clini- cally not only by an impairment in cogni- tion but also by a decline in global func- tion, a deterioration in the ability to perform activities of daily living, and the appear- ance of behavioral disturbances. When AD was originally described by Alois Alzhei- mer in 1907,1 it was considered to be a rela- tively uncommon disorder. However, sub- sequent clinical and neuropathological studies identified the characteristic AD pa- thology of senile plaques and neurofibril- lary tangles as the most common cause of dementia in the elderly. With the aging of our population, the management and treat- ment of AD is likely to become one of the major public health problems facing our society in the next century. Our knowl- edge of the pathophysiology and natural his- tory of the disease has increased greatly over the past decade, yet the definitive cause remains unclear and a cure has been elu- sive. Nevertheless, we now have avail- able effective pharmacological and psy- chosocial interventions to alleviate the symptoms and suffering of patients with AD and their families. The purpose of this article is to discuss the epidemiology, pre- sentation, diagnosis, and pharmacologi- cal management of the disorder. EPIDEMIOLOGY The prevalence of dementia in the United States in individuals aged 65 years or older is about 8%, with these rates doubling if those with milder forms of dementia or cognitive impairment are included. Rates of dementia are very much age depen- dent, doubling every 5 years from 1% to 2% at ages 65 to 70 years, to 30% and higher after the age of 85 years. Alzhei- mer disease is by far the most common of the dementing disorders in the United This article is also available on our Web site: www.ama-assn.org/internal. From the Department of Psychiatry, Indiana University School of Medicine, Indianapolis. REVIEW ARTICLE ARCH INTERN MED/ VOL 159, APR 26, 1999 789 ©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ by a Carnegie Mellon University User on 04/05/2021 States, accounting for 65% to 75% of cases.2-5 COST The calculated economic cost of the management and treatment of AD is staggering. The combined direct costs, including medical and long- term care and lost productivity, and indirect costs, including resource loss and family care, approach $100 billion per year.6 In addition, there is also the immeasurable emotional cost to families who suffer tremen- dously watching their affected loved ones slowly lose their identity. RISK FACTORS Our knowledge of putative genetic risk factors for AD has increased dramatically over the past decade. There is now evidence that certain types of early-onset, autosomal dominant AD are associated with gene mutations on chromosome 21, chromosome 14, and chromo- some 1.7-9 These findings are im- portant for determining pathologic mechanisms but account for only a small proportion (about 2%) of all cases of AD.10 The presence of the APOEe4 al- lele on chromosome 19 has been as- sociated with a considerably greater risk for developing the more com- mon, late-onset form of AD.8,11,12 The effect appears to be dose depen- dent. The presence of a single e4 al- lele increases the risk of AD by 2- to 4-fold, whereas possessing the double e4 allele increases the risk from 4- to 8-fold. It must be remem- bered that possessing the e4 allele is neither necessary nor sufficient for the development of AD. Therefore, APOE genotyping is not recom- mended as a predictive test for AD in asymptomatic individuals.13 How- ever, experts disagree on the utility of APOE genotyping as a diagnos- tic test. It may be useful for confir- mation in some patients with de- mentia when a diagnosis of AD is unclear, although the presence of 1 or 2 copies of the APOE e4 allele still does not make the diagnosis cer- tain and absence of the e4 allele does not preclude a diagnosis of AD. APOE genotyping, when used in patients with a clinical diagnosis of AD, may increase the specificity of the diagnosis.14 Research on other risk factors for AD is relatively new. To date, only age, family history of demen- tia, and Down syndrome consis- tently have been shown to be asso- ciated with AD. However, high education and ingestion of estro- gen, nonsteroidal anti-inflamma- tory drugs, and vitamin E may be protective. It is likely in the future that risk factor models involving ge- netic and environmental interac- tions will emerge. DIAGNOSTIC PROCESSES AND DIFFERENTIAL DIAGNOSIS As AD is both a clinical and a neu- ropathological entity, the defini- tive diagnosis of AD can be made only with a brain biopsy or an au- topsy. One of the major clinical ad- vances in the diagnosis of AD has been the promulgation of diagnos- tic criteria for possible and prob- able AD by a select group spon- sored by the National Institute of Neurological and Related and Com- municative Disorders and Stroke– Alzheimer’s Disease and Related Dis- orders Association (Table).15 Using these criteria, the clinical diagnosis of AD has been confirmed at au- topsy in close to 90% of cases. It has been stated that AD is a diagnosis of exclusion. This is only partially cor- rect. While it is essential for the phy- sician to evaluate other possible causes of memory loss, a positive di- agnosis of probable AD can be made based on a characteristic history from a spouse or a knowledgeable informant together with a physical and neurologic examination. The differential diagnosis for AD in- cludes a broad range of other causes of dementia and nondementing metabolic or psychiatric illnesses. Among the more important nondementing causes of dementia are delirium and depression. De- lirium is common in elderly sub- jects, particularly in inpatient set- tings and in nursing homes. Unlike delirium in children, which is an acute disorder, delirium in the el- derly can be subacute at onset, stretch- ing over weeks or even months, char- Criteria for Clinical Diagnosis of Probable Alzheimer Disease* Criteria include Dementia established by clinical examination and cognitive test (Mini-Mental State Examination or Blessed Dementia Scale) and confirmed by neuropsychological tests Deficits in $2 areas of cognition Progressive worsening of memory and other cognitive function No disturbance of consciousness Onset between ages 40 and 90 years Absence of systemic disorder or brain disease that could account for progressive cognitive deficits The diagnosis is supported by Progressive deterioration of specific cognitive functions such as language (aphasia), motor skills (apraxia), and perception (agnosia) Impaired activities of daily living Altered behavior Family history of similar disorders Normal lumbar puncture, normal electroencephalogram or nonspecific changes, progressive cerebral atrophy on computed tomography Features consistent with the diagnosis Plateaus in the course of progression Associated symptoms including depression, insomnia, incontinence, delusions, illusions, hallucinations, catastrophic outbursts, sexual disorders, or weight loss Neurologic signs including increased muscle tone, myoclonus, or gait disorder Seizures (in advanced stage) Computed tomography normal for age Features that make the diagnosis uncertain or unlikely Sudden, apoplectic onset Focal neurologic findings such as hemiparesis, sensory loss, visual field deficits, and incoordination (early in the course) Seizures or gait disturbance (at the onset or early in the course) *From the National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer’s Disease and Related Disorders Association Work Group.15 ARCH INTERN MED/ VOL 159, APR 26, 1999 790 ©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ by a Carnegie Mellon University User on 04/05/2021 acterized by apathy rather than agitation, and vague paranoid symp- toms rather than vivid hallucina- tions. Thus, delirium in the elderly can often be misdiagnosed. Com- mon causes of delirium include in- fection (particularly urinary tract in- fections), hypoglycemia, electrolyte abnormalities (such as those accom- panying dehydration), hepatic dys- function, renal insufficiency, endo- crine dysfunction (particularly thyroid abnormalities), and medi- cations (especially anticholinergic agents, benzodiazepines, hista- mine2 antagonists, and narcotics), all of which are eminently treatable. De- lirium and dementia can coexist. In fact, dementia predisposes to the de- velopment of delirium with even modest metabolic insults. Severe depression in the el- derly is often accompanied by com- plaints of memory loss and the pres- ence of mild cognitive deficits on neuropsychological testing. In de- pression, the subjective complaints of cognitive impairment often ex- ceed the neuropsychological defi- cits, and the primary problem seems to be one of motivation or lack of ef- fort. Depression and dementia can coexist, however. Among the dementing disor- ders, vascular dementia follows AD as the second most common form.16 The vascular dementias usually, but not always (eg, Binswanger dis- ease), have a relatively acute onset temporally related to a vascular event such as transient ischemic attack or stroke and have a more fluctuating course than AD. Focal neurologic signs or symptoms usually accom- pany them. Cerebrovascular changes can also coexist with AD path- ology, and this combination can adversely affect the dementing process.17 Other neurodegenerative dis- orders that can cause dementia in- clude Parkinson disease, Hunting- ton disease, Pick disease, and dementia with Lewy bodies. Parkin- son disease and Huntington dis- ease are characterized by extrapy- ramidal signs, which usually predate the cognitive decline. Pick disease is one of the frontal lobe dementias and usually presents with behavioral dis- inhibition, poor insight, and lan- guage deficits early in the course of the illness. Memory and construc- tional praxis are relatively spared early on. Frontal and temporal lobe atrophy is usually evident on com- puted tomography. Dementia with Lewy bodies is a progressive demen- tia characterized by detailed recur- rent visual hallucinations, parkin- sonism, and fluctuations of alertness and attention.18 Other common fea- tures include frequent falls, syn- cope, systematized delusions, and neuroleptic sensitivity. Autopsy se- ries findings demonstrate cortical Lewy bodies in 20% to 30% of de- mentia cases and there may be over- lap with AD.18 A long history of heavy use of alcohol can also cause dementia. Creutzfeld-Jakob disease is an example of an infectious cause of de- mentia caused by prions. Creutzfeld- Jakob disease is characterized by relatively sudden onset and rapid progression with myoclonic jerks, pyramidal frontal motor signs, vi- sual agnosia, and death within months. Other neurologic disorders less commonly associated with demen- tia include normal pressure hydro- cephalus, subdural hematoma, brain tumor, posttraumatic brain injury, and posthypoxic damage. DIAGNOSTIC EVALUATION A diagnostic evaluation for demen- tia involves a complete history, neu- ropsychological examination (eg, the Mini-Mental State Examination [MMSE]),19 physical examination, and selected laboratory studies and neuroimaging.20 The history should be obtained from a reliable in- formant. In this regard, attention should be paid to change in cogni- tion and functioning relative to pre- vious performance, mode of onset of impairment (insidious onset is char- acteristic of AD), progression of illness (slow gradual decline is typi- cal of AD), and duration of impair- ment (it is important to repeatedly ask if there were any earlier signs that may have indicated a change). One should ask about all cognitive do- mains and give examples of early signs. For example, when asking about memory impairment, one could ask if the patients have diffi- culty remembering what day it is, what they ate for the previous meal, or if they have trouble keeping ap- pointments. Be aware that patients and families often make excuses for memory problems. For the lan- guage domain, one could ask if the patients have trouble finding the right word for things or call some- thing by the wrong name, mispro- nounce words, or if they feel that they have more trouble expressing themselves verbally. For praxis, it would be appropriate to ask if they have trouble figuring out how to use machines that they knew how to use before (microwave, washing ma- chine, or lawn mower) or if they have trouble with any skills (crafts or hobbies) in which they previ- ously engaged. For agnosia, deter- mine if they have trouble recogniz- ing common objects such as a telephone, toaster, or broom. Diffi- culty with executive functioning manifests as trouble with complex tasks such as preparing a meal or managing finances. In addition to in- quiring about cognitive function, it is critical to inquire about the use of prescription and over-the-counter medications, alcohol, and illicit drugs and their temporal relation- ship to any cognitive changes. The instrument used most commonly for assessing cognitive function is the MMSE. This instru- ment is a nonspecific screen for cog- nitive function and has some limi- tations. The MMSE is not sensitive for detecting cognitive impairment in individuals with higher levels of education or high levels of premor- bid functioning. Conversely, those with low levels of education or mi- nority cultural backgrounds may score low on the test without hav- ing impairment. However, the MMSE is especially useful when re- peated regularly to follow illness pro- gression. A complete physical and neu- rologic examination is indicated. Fo- cal neurologic signs may suggest vascular dementia or some other neurologic disorder, and parkinson- ism suggests Parkinson disease or dementia with Lewy bodies disease depending on the time course of symptoms relative to the cognitive impairment. Results of the neuro- logic examination are usually essen- tially normal in early AD. ARCH INTERN MED/ VOL 159, APR 26, 1999 791 ©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ by a Carnegie Mellon University User on 04/05/2021 Laboratory evaluation should include tests for complete blood cell counts, electrolytes, blood chemis- tries, liver functions, thyrotropin lev- els, vitamin B12 levels, and a sero- logic test for syphilis. Other tests should be obtained as indicated by the history such as erythrocyte sedimentation rate (autoimmune disease), heavy metal screen (indus- trial exposure), human immunode- ficiency virus (with human immu- nodeficiency virus risk factors), and toxicology screen (suspected use of illicit drugs). An electroencephalo- gram reveals nonspecific changes and is rarely indicated except to di- agnose Creutzfeld-Jakob disease, a disease associated with a character- istic periodicity on the electroen- cephalogram, or hepatic encepha- lopathy with characteristic triphasic waves. A neuroimaging study may be obtained in a complete workup to rule out neurologic disease, which may contribute to cognitive decline, but is not required for diagnosis un- less warranted by unusual findings. A computed tomographic scan of the head without contrast is usually suf- ficient to rule out cerebrovascular dis- ease, subdural hematoma, normal pressure hydrocephalus, or brain tu- mor. Magnetic resonance imaging is more expensive but is better for vi- sualizing small subcortical lacunae and mesial temporal lobe atrophy (in coronal slices). However, there is a tendency to overread vascular changes (periventricular and subcor- tical white matter hyperintensities) on magnetic resonance imaging. Single proton emission computed to- mography may be helpful in atypi- cal, difficult, or early cases. In AD, there is a characteristic hypoperfu- sion in the temporal and parietal lobes. In vascular dementia, there are more patchy changes. Pick disease is marked by frontal and temporal lobe perfusion defects. Single pro- ton emission computed tomogra- phy may be most useful in distin- guishing AD from vascular dementia and frontotemporal dementia, but should be used selectively and only as an adjunct to clinical evaluation and computed tomography.21 Posi- tron emission tomography has the advantage of greater sensitivity and spatial resolution but at a much higher price, and while it is a better tool for research purposes, it has lim- ited clinical application. Single pro- ton emission computed tomogra- phy is simpler to perform, less expensive, and has greater poten- tial in the clinical setting than posi- tron emission tomography.22 Detailed neuropsychological testing is also helpful in character- izing the pattern of cognitive im- pairment. It is also more sensitive than a screening instrument such as the MMSE in detecting early impair- ment in highly educated individu- als. It also provides a quantitative measure, which affords the ability to follow disease progression over time. If the diagnosis remains un- clear after a complete evaluation, there are several options. Repeat- ing the cognitive testing in 6 months will determine if there is progres- sive cognitive decline during the in- tervening period. More complete neuropsychological testing may also be helpful. Consultation with a spe- cialist, either a neurologist or geri- atric psychiatrist, is warranted. IMPORTANCE OF EARLY DIAGNOSIS Early diagnosis of AD is important for many reasons. Patients may present with nonspecific physical complaints that may prompt exten- sive and costly diagnostic workups and unnecessary treatments. Early recognition allows the possibility of treating with agents that can slow the cognitive decline at a point where there is still minimal impairment. Early diagnosis also allows the patient and the family time to plan for the future such as developing advanced directives and appoint- ing durable power of attorney while competence is not yet an issue. The practitioner can educate the pa- tient and the family regarding dis- ease progression and prognosis, provide support, and monitor judg- ment and safety issues so that the patient can continue independent or community dwelling as long as possible. Unfortunately, AD is frequently not diagnosed at this early stage de- spite visits to the primary care phy- sician. There are many reasons for this delay in diagnosis. Patients and families often underreport symp- toms, families attribute symptoms to normal aging and compensate for functional impairment, and social skills are maintained, masking any impairment during a short, fo- cused office visit. Even when cog- nitive testing is performed, individu- als with dementia may score in the “normal” range on the MMSE. Re- sults of laboratory tests are normal in AD so a diagnostic workup will not reveal any abnormalities. There is a need to improve early recognition of AD in the primary care setting and to avoid delays in diagnosis. Practitioners should screen for functional and cognitive decline and any concerns should prompt a full dementia workup. TREATMENT OF AD IN THE PRIMARY CARE SETTING The successful treatment of AD in- volves multiple treatment modali- ties targeting various aspects of the illness and its consequences for the patient and the family. Again, it is important to stress the necessity for accurate diagnosis of AD and early recognition to provide the best pos- sible treatment. While there is no cure for AD, there are approaches to improving cognition and possibly delaying the progression of the ill- ness, and there are efficacious treat- ments for the psychiatric and be- havioral manifestations. Another important aspect of treatment is helping the patient and the family with the legal aspects, supporting the family through caregiving, and assisting with decisions about long- term care placement. Providing reg- ular appointments for maintenance and surveillance is necessary to meet the goals of minimizing ex- cess disability and ensuring safety and security. PHARMACOLOGICAL TREATMENT OF AD There are several conceptual ap- proaches to the treatment of AD. The first approach is to treat symptom- atically. This includes treating the cognitive impairment, decline in glo- bal function, deterioration in the ability to perform activities of daily living, and behavioral distur- ARCH INTERN MED/ VOL 159, APR 26, 1999 792 ©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ by a Carnegie Mellon University User on 04/05/2021 bances. This approach reflects the current state of treatment. Another approach is to slow disease progres- sion or delay onset of disease. Even- tually, it may be possible to be able to prevent the development of AD or even repair neuronal damage af- ter onset of disease. These latter ap- proaches are currently being inves- tigated at a basic science level. The only currently available therapeu- tic agents are targeted at specific symptoms of AD. Cognitive Impairment Cholinesterase Inhibitors.—Alzhei- mer disease is in part a disorder of cholinergic functioning. Degenera- tion of basal forebrain cholinergic sys- tems is a hallmark feature of AD and appears to be associated with cogni- tive deficits, functional impairment, and behavioral disturbances. One strategy for ameliorating the symp- toms of AD is to enhance choliner- gic neurotransmission. Acetylcho- linesterase inhibitors are the best studied and the only currently avail- able agents for the symptomatic treat- ment of AD. Acetylcholinesterase in- hibitors delay the degradation of acetylcholine at the synaptic cleft, thus potentiating cholinergic neuro- transmission. The only 2 agents currently available for the treatment of AD are the cholinesterase inhibitors ta- crine and donepezil. Both agents in- hibit acetylcholinesterase in a dose- dependent manner. Both are effective in improving performance on a test of cognitive function and global per- formance in patients with mild to moderate AD.23-29 Cognitive im- provements are, on average, mod- est and may not be clinically rel- evant in many patients. However, some patients demonstrate a dra- matic improvement in cognitive scores that is readily observable in daily functioning. Some cholinester- ase inhibitors are also associated with improvement in behavioral symp- toms, including depression, psycho- sis, and agitation, even in the ab- sence of profound cognitive change.30 However, this is based on an open- label study. Cholinesterase inhibi- tors are also associated with a delay in nursing home placement.31 Meth- odological limitations of this study in- clude the open-label, nonrandom- ized, and nonblinded design. Studies of acetylcholinesterase inhibitors have generally shown an initial improvement in cognitive scores beginning early in the treat- ment course with a subsequent de- cline at a rate similar to untreated patients with AD.32 When the medi- cation is stopped, cognitive function- ing declines to nontreatment levels. This is consistent with the hypoth- esis that cholinesterase inhibitors pro- vide symptomatic relief without al- tering the disease course. The long- term effects or continued benefit of cholinesterase inhibitors will be- come clearer in clinical practice. One neuroimaging study33 demonstrated increased regional cerebral blood flow in the parietal lobe, which per- sisted up to 14 months with contin- ued treatment. Treatment with tacrine re- quires a lengthy dose titration begin- ning with 10 mg orally 4 times daily and increasing by 10 mg 4 times daily every 6 weeks as tolerated to a maxi- mum of 160 mg/d. Only doses of 120 to 160 mg/d are significantly more ef- ficacious than placebo. However, dose titration is frequently limited by ad- verse effects to the gastrointestinal tract or hepatic transaminase eleva- tions. Transaminase activity (ala- nine and aspartate aminotransfer- ase) must be monitored weekly until a steady dose has been achieved for 6 weeks, after which monitoring ev- ery 3 months is sufficient. If trans- aminase activity levels rise to more than 5 times the upper limit of nor- mal, treatment with tacrine should be discontinued. Transaminase eleva- tions are usually asymptomatic and reversible and patients may be rechal- lenged after transaminase normaliza- tion (see package insert for details). Donepezil has replaced ta- crine as the first choice “cognitive enhancer” owing to ease of admin- istration, less titration, greater tol- erability, relative lack of hepa- totoxic side effects, and absence of monitoring requirements. Donepe- zil is selective for acetylcholinester- ase and is longer acting than ta- crine. It is metabolized via the hepatic cytochrome P450 system and is highly plasma protein bound. Donepezil is administered in once- daily dosing and requires less ex- tensive titration. Dosing is initiated at 5 mg/d and may be increased to 10 mg/d in 1 month. It is well tol- erated and the most common ad- verse effect is gastrointestinal tract distress (nausea, vomiting, and di- arrhea). Other cholinesterase inhibi- tors are in development and are expected to reach the market soon. Metrifonate is a prodrug for the long-acting cholinesterase inhibi- tor, 2,2-dichlorovinyl dimethyl phosphate. Its pharmacokinetic profile permits once-daily dosing. Early studies demonstrate improve- ment in cognitive scores and global function compared with placebo, with few adverse effects.34-36 Rivastig- mine is a central nervous system– selective, pseudo-irreversible, car- bonate-selective cholinesterase inhibitor.37 Dosing is 2 or 3 times daily and extensive titration is re- quired. It is well tolerated at the lower doses with predominantly adverse ef- fects on the gastrointestinal tract. Heptylphysostigmine is a derivative of physostigmine with a long dura- tion of inhibition.38 Several other agents are also in development. Other Cholinergic Agents.— An- other strategy targeting the cholin- ergic system is specific cholinergic receptor agonists. Muscarinic ace- tylcholine postsynaptic m1 recep- tors are relatively intact in AD, while the m2 presynaptic receptors are de- creased. Agents that target the post- synaptic m1 receptors are being de- veloped. There is some evidence suggesting that these agents may also slow disease progression, but most have not been well tolerated at thera- peutic doses. Xanomeline is a selec- tive m1 and m4 agonist that has demonstrated moderate efficacy in improving cognitive performance, but even greater efficacy in decreas- ing psychotic symptoms and agita- tion.39 However, adverse events to xanomeline were associated with high discontinuation rates prima- rily because of adverse effects on the gastrointestinal tract and syncope. Other cholinergic agonists in de- velopment include milameline, SB202026, AF 102B, and ENS-163. Stimulation of presynaptic nico- tinic receptors increases the release of acetylcholine and may be associ- ARCH INTERN MED/ VOL 159, APR 26, 1999 793 ©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ by a Carnegie Mellon University User on 04/05/2021 ated with cognitive improvement in selected domains. Therefore, nico- tinic acetylcholine receptor ago- nists also appear promising. Disease-Altering Treatment Strategies One target for disease-altering treat- ments is apoptosis or programmed cell death. Mechanisms that are im- plicated in neuronal degeneration are the inflammatory response and oxi- dative stress. The inflammatory re- sponse contributes to cell death in part by triggering release of free radicals. An accumulation of free radicals in turn damages cell membranes and triggers the neurodegenerative cas- cade. In addition, components of the inflammatory response are found in association with senile plaque forma- tion. Anti-inflammatory agents may be protective against AD; in epide- miological studies, the use of anti- inflammatory drugs is associated with a decreased risk of AD. Prednisone is currently under investigation for the treatment of AD.40 Antioxidants may also be protective against cell death. In one clinical trial,41 alpha- tocopherol (vitamin E) and selege- line hydrochloride (L-deprenyl), a se- lective monoamine oxidase–type B inhibitor that acts as an antioxidant, demonstrated efficacy in delaying ad- verse events. Methodological limita- tions of this study include poor ran- domization whereby baseline scores on the MMSE were higher in the placebo group, requiring adjust- ment for this in the analysis. Chelat- ing agents may also work via an an- t i o x i d a n t m e c h a n i s m . O t h e r monoamine oxidases are currently under investigation. Neurotropic factors may have a modulating effect on neuronal structural integrity and neurotrans- mitter function. Estrogen acts as a neurotropic factor and may be pro- tective in decreasing the incidence or delaying the onset of AD and en- hancing response to cholinesterase inhibitors.42,43 It is currently being investigated as a treatment for AD. Other neurotrophic factors under in- vestigation include nerve growth fac- tor and other agents that enhance its effect.44 Other treatment strategies in- volve blocking the abnormal phos- phorylation of tau proteins, prevent- ing amyloid deposition, blocking amyloid toxicity, and lowering APOE e4 levels. Ganglioside GM1 and phosphatidylserine have mem- brane effects that may interfere with the disease process. Other poten- tial treatment under investigation in- clude ergot alkaloids (ergoloid me- sylates and nicergoline45), nootropics (piracetam, oxiracetam, prami- racetam, and aniracetam), and vinca alkaloids. These agents have mul- tiple putative mechanisms of ac- tion including cholinergic and do- paminergic properties, as well as effects on protein processing and cel- lular metabolism. However, stud- ies to date involving these agents have shown them to be generally ineffective. FUNCTIONAL IMPAIRMENT Alzheimer disease is associated with a gradual decline in global function- ing. Instrumental activities of daily living are the first to deteriorate. These include managing finances, shopping, cooking, cleaning, and maintaining an independent life- style. Basic activities of daily living include bathing, toileting, dress- ing, and feeding oneself. Eventu- ally, patients with AD become un- able to perform even these basic tasks. Functional impairment of- ten prompts changes in levels of care from independent living to more ac- tive involvement of family to living with a family member or assisted liv- ing, and often eventually to skilled care or a nursing home. Effective treatment for func- tional decline is the same as for cog- nitive impairment. The cholinester- ase inhibitors have been shown to delay outcomes of functional de- cline and are the only currently avail- able treatment. PSYCHIATRIC MANIFESTATIONS OF AD Psychiatric manifestations are com- mon in AD and occur in almost all patients at some point in their ill- ness. Behavioral disturbance is the most common symptom and oc- curs in up to 90% of patients with dementia. 4 6 Behavioral distur- bance, especially agitation and wan- dering, is associated with greater cognitive impairment, is the symp- tom most likely to emerge during the course of treatment, and is the most persistent.47 It is the symptom that is the most troubling to families and caregivers and is the most common reason for institutionalization in long-term care facilities and for re- ferral to specialists. Psychosis is the next most common psychiatric manifestation and includes delu- sions, most commonly paranoid and misidentification delusions, and hal- lucinations, with visual more com- mon than auditory hallucinations. Delusions are associated with greater cognitive and functional impair- ment and show moderate persis- tence over time.47 Psychosis may also be associated with more rapid cog- nitive decline. Depressive symp- toms are present in up to 86% of pa- tients with AD, with about 10% to 20% having a diagnosable depres- sive disorder.48 Depressive symp- toms are less likely to emerge dur- ing the course of AD than psychosis and behavioral disturbance, and are the least persistent.47 Comorbid de- pression is associated with greater cognitive impairment, greater level of disability, and higher rates of in- stitutionalization, mortality, and functional impairment.49 Effective treatment of the psy- chiatric manifestations of AD can im- prove quality of life for patients and their families, decrease caregiver bur- den, decrease health care utiliza- tion, and delay institutionalization. Treatment can also significantly de- crease the risk of harm to the pa- tients and their caretakers. Nonpharmacological treat- ment approaches should be at- tempted first before pharmacologi- cal treatments. Environmental manipulation or simple behavioral techniques may be helpful. In this regard, creating a safe and consis- tent environment with moderate stimulation, contrasting colors, and pictures for directions and signs may be useful. A structured routine and consistent environment as free from change as possible also can help eliminate confusion. Additionally, it may be desirable to provide familiar personal objects such as pictures and momentos, as well as cues for orien- tation like calendars and clocks. Com- ARCH INTERN MED/ VOL 159, APR 26, 1999 794 ©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ by a Carnegie Mellon University User on 04/05/2021 munication should be clear and simple. Behavioral interventions such as validation and not correcting mis- statements can ease anxiety. Pa- tients should be encouraged to be ac- tive participants in their care and in decision making. Emotion- oriented psychotherapy, supportive psychotherapy, interpersonal psycho- therapy, and reminiscence therapy may be beneficial in individual cases. Stimulation-oriented therapy such as music, art, and pet therapy and exer- cise may be helpful for others. Because the psychopathology changes over the natural course of the illness, treatments must be moni- tored and periodically reevaluated for continued appropriateness. Since depressive symptoms are not per- sistent over time, short-term anti- depressant treatment is probably in- dicated. Psychotic symptoms are moderately persistent and long- term antipsychotic use is associ- ated with significant morbidity and adverse effects, so antipsychotics should be tapered if possible. Be- cause behavior disturbance is more persistent, long-term treatment is likely necessary. TREATMENT OF DEPRESSION IN AD Recognition of depression in AD may be complicated by an overlap of symptoms between the 2 disor- ders and failure to meet strict crite- ria for a depressive disorder. Any patient with dementia with signifi- cant depressive symptoms such as sleep, appetite, or energy distur- bance, depressed mood or irritabil- ity, anhedonia, social withdrawal, excessive guilt, a passive death wish or suicidal ideation, or agita- tion should be considered for treat- ment of depression even if failing to meet criteria for a depressive disorder.50 There are limited data on the treatment of depression in AD,51,52 so treatment strategies are extrapo- lated from the treatment of depres- sion in elderly patients without de- mentia. In general, starting doses are half those normally used in adults and titration is at smaller incre- ments and slower, to allow for the decreased rate of metabolism. Effec- tive doses in patients with AD may be lower than in adults or may be the same as in younger patients. Selective serotonin reuptake inhibitors (SSRIs) are first-line agents because they are the best tolerated, do not have cognitive adverse effects, and may even improve cognitive function inde- pendent of antidepressant effects.53 The choice of an SSRI is dependent on pharmacokinetics and adverse- effect profiles.54 Sertraline has few interactions with the cytochrome P450 system and little anticholin- ergic activity, so it is a good first choice SSRI for the patient with AD. Fluoxetine, with its long half- life and active metabolite, make it less desirable in the elderly unless noncompliance is a problem; the long half-life allows for adequate levels to be maintained even when doses are missed. Paroxetine is the m o s t a n t i c h o l i n e r g i c o f t h e SSRIs and, theoretically, may have more adverse effects on cognition. Fluvoxamine has a relatively short half-life and the twice-daily dosing may impair compliance. The start- ing dose of SSRI therapy should be half that normally used in adults (ie, 25 mg of sertraline or 10 mg of fluoxetine). The most common adverse effects with the SSRIs are transient headache, nausea and vomiting, diarrhea, anxiety, rest- lessness, psychomotor agitation, insomnia, and lethargy. Several atypical antidepres- sants are available. Venlafaxine in- hibits both serotonin and norepi- nephrine reuptake without having anticholinergic adverse effects. Most common adverse effects are nau- sea, anxiety, insomnia, dizziness, constipation, and sweating.55 Bupro- pion has an atypical and not well- understood mechanism of action.56 It is a weak norepinephrine uptake inhibitor but is a stronger inhibitor of dopamine uptake. The dopamin- ergic effect may be beneficial in some patients and may be stimulating and particularly effective for apathy. Bu- propion is generally well tolerated with most common adverse effects being insomnia, anxiety, headache, tremor, nausea, dry mouth, and con- stipation as well as a dose-related in- crease in risk of seizures. Mirtazap- ine is an a2-antagonist and serotonin type 2 and type 3 (5HT2 and 5HT3) receptor antagonist and may be ef- fective in treating refractory pa- tients. However, it is sedating and causes weight gain in some pa- tients.57 Nefazodone is a serotonin reuptake inhibitor and 5HT2A recep- tor antagonist. It is administered in twice-daily dosing and the most common adverse effects are leth- argy, dizziness, and dry mouth.58 T r i c y c l i c a n t i d e p r e s s a n t s should be used only if better toler- ated agents are ineffective or in de- pression severe enough to warrant inpatient psychiatric hospitaliza- tion. Tertiary tricyclic antidepres- sants (imipramine and amitripty- line) should never be used in patients with AD because of the an- ticholinergic effects. Nortriptyline is the tricyclic antidepressant of choice because of fewer anticholinergic ef- fects. Serum levels and electrocar- diogram should be monitored at steady state before each dose in- crease with target levels of 50 to150 ng/mL. Adverse effects include or- thostatic hypotension, which places patients at risk for falls and hip frac- tures, cardiac conduction delays, and anticholinergic effects such as uri- nary retention, constipation, cogni- tive impairment, and delirium. S p e c i f i c t a r g e t s y m p t o m s should be identified and moni- tored through the course of treat- ment to determine treatment re- sponse and to guide dose titration. Cognition should also be moni- tored with a simple instrument such as the MMSE. Treatment should be reevaluated periodically as depres- sive symptoms may decrease with natural disease progression. If symp- toms are adequately controlled and there is no history of recurrent ma- jor depression, consider tapering the antidepressant in 6 months. Be pre- pared to reinstitute treatment if any depressive symptoms reemerge. TREATMENT OF PSYCHOSIS IN AD Choice of antipsychotic is deter- mined by the adverse-effect profile. The low-potency agents, such as chlorpromazine, have significant an- ticholinergic adverse effects while the high-potency agents, such as halo- peridol, have significant extrapyra- midal adverse effects causing parkin- ARCH INTERN MED/ VOL 159, APR 26, 1999 795 ©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ by a Carnegie Mellon University User on 04/05/2021 sonism; both can predispose to falls. The newer atypical agents (risperi- done, olanzapine, quetiapine, and clozapine) or midpotency agents such as perphenazine are preferred because of fewer adverse effects. Haloperidol has demonstrated efficacy for psychosis and behav- ioral disturbance in dementia and was considered the criterion standard agent. However, its use is limited by extrapyramidal adverse effects even at relatively low doses, and it also causes cognitive deterioration.59 R i s p e r i d o n e h a s d e m o n - strated efficacy in psychosis and agi- tation in AD.60 Even relatively low doses can produce the disabling ex- trapyramidal syndrome in older pa- tients. Other potential adverse ef- fects include postural hypotension and sedation. Olanzapine and queti- apine, the newest atypical antipsy- chotic agents, have not yet been well studied in this population. Clozap- ine has demonstrated efficacy in el- derly patients with psychosis but, owing to the risk of agranulocyto- sis and need for weekly blood moni- toring, it is not a first-line agent in AD. It should be reserved for patients who develop significant extrapyramidal syndrome or who remain refractory to other antipsy- chotics. Clozapine is a low-potency agent and is associated with ortho- static hypotension and sedation. There are no data on the long- term benefits of antipsychotics al- though the long-term risks are well un- derstood. Antipsychotic use should be reevaluated periodically (every 3-6 months) to determine continued ne- cessity. Dose tapering should be at- tempted if symptoms are under ad- equate control. If symptoms reemerge during drug taper, an effective dose should be reinstituted. The most se- rious long-term risk is tardive dyski- nesia, which occurs at a much higher rate in elderly patients. Estimates of the risk of tardive dyskinesia in the el- derly begin at 29% in the first year and increase to 40% after 10 years of an- tipsychotic exposure.61 The Omnibus Reconciliation Act regulations for nursing home care require frequent reevaluation of continued use of an- tipsychotics and other psychotropic medications. Dose reductions should be attempted at least twice per year to determine continued necessity. TREATMENT OF AGITATION IN AD The diagnostic evaluation of agi- tated behavior should begin with a thorough medical evaluation to search for a treatable cause such as urinary tract infection, fracture, decubitus, constipation, or reaction to a medi- cation or drug interaction. The un- derlying medical problem should be treated or the offending medication discontinued. Once a physical ill- ness has been ruled out, the under- lying psychopathology should be determined and treated appropri- ately.62 Agitation may be associated with underlying depression, anxi- ety, psychosis, or delirium. If there is no underlying problem and the agi- tation is an isolated disturbance, an- tipsychotics are the most effective treatments. In a meta-analysis of an- tipsychotic trials,63 antipsychotics were significantly more effective than placebo in reducing agitation, but there was a modest effect size, with only 18% of patients benefiting from antipsychotics over placebo. No an- tipsychotic was better than any other. Other treatment strategies for which there is limited evidence of efficacy in- clude buspirone, carbamazepine, val- proate, trazodone, propranolol, and lithium. Benzodiazepines are gener- ally not useful for agitation and may produce paradoxical reactions (in- creased agitation and disinhibition) and cause sedation, falls, ataxia, amnesia, and delirium. Cholinergic agents such as the cholinesterase in- hibitors and cholinergic agonists may also be effective for the behavioral dis- turbances. Theoretically, the behav- ioral complications may be due in part to altered cholinergic function, ex- plaining why cholinomimetics can improve behavior. There is evidence that the cholinesterase inhibitors such as donepezil, tacrine, and metrifo- nate and the muscarinic agonist xanomeline can improve psychosis and behavioral disturbance in AD.30,39 TREATMENT OF INSOMNIA IN AD Insomnia or sleep-wake cycle dis- turbance is common in AD and oc- curs in up to 20% to 40% of pa- tients. This can cause significant distress to family caregivers who are awakened at night and may have to be vigilant to prevent wandering away from home or self-injury of the patient. Insomnia often occurs con- currently with other symptoms. Treatment of insomnia and sleep- wake cycle disturbance is not well studied in AD. Effective strategies in- clude trazodone and zolpidem ad- ministered at bedtime. Chloral hy- drate and benzodiazepines should only be used for short-term treat- ment. The benzodiazepine tria- zolam should be avoided due to am- nesia. Diphenhydramine should be avoided because of anticholinergic effects. CAREGIVER DISTRESS Treatment of a patient with AD in- variably also involves treatment of the family, especially the primary caregiver. The emotional, physical, and often financial stresses associ- ated with caring for a relative with AD are enormous. Thus, it should come as no surprise that up to 50% of caregivers suffer from “caregiver burnout.” This may take the form of depression, anxiety, isolation, sub- stance abuse, or physical illness. In- dividual and family counseling and support as well as involvement in support groups can avoid or delay nursing home placement by almost 1 year.64 These family intervention strategies are most effective in the early to middle stages of the illness, again reinforcing the need for early illness recognition. Respite ser- vices can also provide a source of re- lief to family members so that they can have some time for taking care of themselves and renewing social relationships with others. The Alz- heimer’s Association is an excel- lent source of information on local services such as support groups and respite care. Families should be re- ferred to their local chapter for ad- ditional support. CONCLUSIONS Alzheimer disease is the most com- mon cause of dementia and will af- fect a growing number of people as the US population ages. It is now clear that AD is both diagnosable and treatable. Because most patients with AD are treated in the primary care ARCH INTERN MED/ VOL 159, APR 26, 1999 796 ©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ by a Carnegie Mellon University User on 04/05/2021 setting, it is important for primary care practitioners to be able to ac- curately diagnose and effectively treat AD. The primary care practi- tioner has multiple roles in the treat- ment of AD. The primary care prac- titioner must accurately diagnose AD and distinguish it from depression, delirium, and other causes of de- mentia. This practitioner must also be prepared to treat the cognitive im- pairment, treat the behavioral dis- turbances, refer to a specialist when there is uncertain diagnosis or dif- ficult-to-manage psychiatric mani- festations, provide education and support to the patient and their fam- ily, help maintain safety in the com- munity, and address long-term care issues. Early recognition is important to begin pharmacological therapy at the point in the illness when it can be most effective and to provide edu- cation about progression of the ill- ness, help families and patients an- ticipate the course of the illness, and discuss planning for the future. Alz- heimer disease is a diagnosis of in- clusion based on history and clini- cal presentation. A full laboratory and neuroimaging workup is not necessary in every case to rule out other causes of dementia. Cognitive impairment may im- prove in the short-term with the cho- linesterase inhibitors tacrine and donepezil. New cholinesterase in- hibitors such as metrifonate and cho- linergic agents such as specific mus- carinic and nicotinic agonists will be available soon. Vitamin E and selege- line may slow disease progression. Other disease-altering strategies are currently being investigated includ- ing estrogen, nonsteroidal anti- inflammatory drugs, and neuro- trophic factors. Behavioral disturbances includ- ing depression, psychosis, and agi- tation are common in AD and are treatable with antidepressants, an- tipsychotics, and other psycho- tropic medications, as well as with acetylcholinesterase inhibitors. The natural course of behavior distur- bance changes with progression of the illness, so patients require re- peated regular reassessment of treat- ment and alteration as appropriate. Treatment of a patient with AD also involves treatment of the fam- ily. This includes providing educa- tion and support, referral to the Alz- heimer’s Association and other support networks, evaluating care- giver burnout, helping assess and maintain safety in the community, and helping families deal with the le- gal issues and with long-term care when and if appropriate. Primary care physicians are not alone in treating patients and their families with dementia and AD. Spe- cialists should be consulted in atypi- cal or complex cases.50 Neurologic consultation is important for pa- tients with parkinsonism, focal neu- rologic signs and atypical presenta- tions, or course of illness. Geriatric psychiatrists should be consulted for difficult-to-treat behavioral or psy- chiatric manifestations. Psycholo- gists can provide behavior manage- m e n t , f a m i l y c o u n s e l i n g , a n d functional evaluations. Neuropsy- chologists can help clarify uncer- tainties in diagnosis and ascertain cognitive and functional impair- ment. Other supports include so- cial workers, attorneys, commu- nity support agencies, area councils on aging, and the Alzheimer’s As- sociation. Accepted for publication July 15, 1998. This study was supported by a grant from Bayer Pharmaceuticals, West Haven, Conn. We thank Francine Bray for her help in the preparation of the manu- script. Reprints: Hugh C. Hendrie, MB, ChB, Department of Psychiatry, In- diana University School of Medicine, Room 298, 541 Clinical Dr, India- napolis, IN 46202-5111. REFERENCES 1. Alzheimer A. Uber eine eigenartige Erkrankung der Hirnrinde. Allemeine Zeitschr Psychiatr Psy- chisch Gericht Med. 1907;64:146-148. 2. Jorm AF, Korten AE, Henderson AS. The preva- lence of dementia: a quantitative integration of the literature. Acta Psychiatr Scand. 1987;76:465- 469. 3. Ritchie K, Kildea D, Robine JM. The relationship between age and the prevalence of senile demen- tia: a meta-analysis of recent data. Int J Epide- miol. 1992;21:763-769. 4. Skoog I, Nilsson L, Palmez B, et al. A population- based study of dementia in 85-year-olds. N Engl J Med. 1993;328:153-158. 5. Bachman DL, Wolf PA, Linn RT, et al. Incidence of dementia and probable Alzheimer’s disease in a general population: the Framingham Study. Neu- rology. 1993;43:515-519. 6. Ernst RL, Hay JW. The US economic and social costs of Alzheimer’s disease revisited. Am J Pub- lic Health. 1994;84:1261-1264. 7. Hardy J. Amyloid, the presenilins and Alzheimer disease. Trends Neurosci. 1997;20:154-159. 8. Schellenberg GD. Progress in Alzheimer’s dis- ease genetics. Curr Opin Neurol. 1995;8:262- 267. 9. Plassman BL, Breitner JCS. Recent advances in the genetics of Alzheimer’s disease and vascular dementia with an emphasis on gene-environ- ment interactions. J Am Geriatr Soc. 1996;44: 1242-1250. 10. Roses AD. Apolipoprotein E alleles as risk fac- tors in Alzheimer’s disease. Ann Rev Med. 1996; 47:387-400. 11. Farlow MR. Alzheimer’s disease: clinical implica- tions of the Apolipoprotein E genotype. Neurol- ogy. 1997;48(suppl 6):S30-S34. 12. Strittmatter WJ, Roses AD. Apolipoprotein E and Alzheimer’s disease. Ann Rev Neurosci. 1996;19: 53-77. 13. Statement on the use of Apolipoprotein E testing for Alzheimer’s disease. American College of Medi- cal Genetics/American Society of Human Genet- ics Working Group on ApoE and Alzheimer Dis- ease. JAMA. 1995;274:1627-1629. 14. Mayeux R, Saunders AM, Shea S, et al. Utility of the apolipoprotein E genotype in the diagnosis of Alzheimer’s disease. Alzheimer’s Disease Cen- ters Consortium in Apolipoprotein E and Alzhei- mer’s Disease. N Engl J Med. 1998;338:506- 511. 15. McKhann G, Drachman D, Folstein M, et al. Clini- cal diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the aus- pices of the Department of Health and Human Ser- vices Task Force on Alzheimer’s Disease. Neurol- ogy. 1984;34:939-944. 16. Morris JC. Classification of dementia and Alzhei- mer’s disease. Acta Neurol Scand Suppl. 1996; 165:41-50. 17. Snowdon DA, Greiner LH, Mortimer JA, et al. Brain infarction and the clinical expression of Alzheim- er’s disease: The Nun Study. JAMA. 1997;227: 813-817. 18. McKeith IG, Galasko K, Kosaka K, et al. Consen- sus guidelines for the clinical and pathologic di- agnosis of dementia with lewy bodies (DLB): re- port of the consortium on DLB international workshop. Neurology. 1996;47:1113-1124. 19. Folstein MR, Folstein SE, McHugh PR. “Mini- Mental State”: a practical method for grading the cognitive state of patients for the clinician. J Psy- chiatr Res. 1975;12:189-198. 20. Geldmacher DS, Whitehouse PJ. Evaluation of de- mentia. N Engl J Med. 1996;335:330-336. 21. Talbot PR, Lloyd JJ, Snowden JS, et al. A clinical role for 99mTc-HMPAO SPECT in the investiga- tion of dementia? J Neurol Neurosurg Psychia- try. 1998;64:306-313. 22. Waldemar G. Functional brain imaging with SPECT in normal aging and dementia: methodological, pathophysiological, and diagnostic aspects. Ce- rebrovasc Brain Metabol Rev. 1995;7:89-130. 23. Summers WK, Majowski LV, Marsh GM, et al. Oral tetrahydroaminoacridine in long-term treatment of senile dementia, Alzheimer type. N Engl J Med. 1986;315:1241-1245. 24. Davis KL, Thal LJ, Gamzu ER, et al. A double blind, placebo-controlled, multi-center study of tacrine and Alzheimer’s disease. N Engl J Med. 1992;327: 1253-1259. ARCH INTERN MED/ VOL 159, APR 26, 1999 797 ©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ by a Carnegie Mellon University User on 04/05/2021 25. Farlow M, Gracon SI, Hershey LA, et al. A 12- week, double-blind, placebo controlled, parallel- group study of tacrine in patients with probable Al- zheimer’s disease. JAMA. 1992;268:2523-2529. 26. Knapp MJ, Knopman DS, Solomon PR, et al. Con- trolled trials of high-dose tacrine in patients with Alzheimer’s disease. JAMA. 1994;271:985-991. 27. Rogers SL, Friedhoff LT. E2020 improves cogni- tion and quality of life in patients with mild-to- moderate Alzheimer’s disease: results of a phase-II trial [abstract]. Neurology. 1994;44(suppl 2): A165. 28. Rogers SL, Doody R, Mohs R. E2020 produces both clinical global and cognitive test improve- ment in patients with mild to moderately severe Alzheimer’s disease: results of a 30-week phase- III trial [abstract]. Neurology. 1996;46:A217. 29. Robert SL, Friedhoff LT. The efficacy and safety of donepezil in patients with Alzheimer’s dis- ease: results of a US multicentre, randomized, double-blind, placebo-controlled trial. Dementia. 1996;7:293-303. 30. Kauffer DI, Cummings JL, Christine D. Effect of tacrine on behavioral symptoms in Alzheimer’s dis- ease: an open label study. J Geriatr Psychiatry Neu- rol. 1996;9:1-6. 31. Knopman D, Schneider L, Davis K, et al. Long- term tacrine (Cognex) treatment: effects on nurs- ing home placement and mortality. Neurology. 1996;47:166-177. 32. Tune LE, Sunderland T. New Cholinergic thera- pies: treatment tools for the psychiatrist. J Clin Psychiatr. 1998;59:31-35. 33. Minthon L, Nillson K, Edvinsson L, et al. Long- term effects of tacrine on regional cerebral blood flow changes in Alzheimer’s disease. Dementia. 1995;6:245-251. 34. Becker RE, Colliver J, Elbie R, et al. Effects of met- rifonate, a long-acting cholinesterase inhibitor, in Alzheimer’s disease: report of an open trial. Drug Develop Res. 1990;19:425-434. 35. Becker RE, Colliver JA, Markwell SJ, et al. Double- blind, placebo-controlled study of metrifonate, an acetylcholinesterase inhibitor, for Alzheimer disease. Alzheimer Dis Assoc Disord. 1996;10:124-131. 36. Cummings JL, Cyrus PA, Bieber F, et al. Metrifo- nate treatment of the cognitive deficits of Alzhei- mer’s disease. Neurology. 1998;50:1203-1205. 37. Sramek JJ, Anand R, Wardle TS, Irwin P, Hart- man RD, Cutler NR. Safety and tolerability of ENA 713 in patients with probable Alzheimer’s dis- ease. Life Sci. 1996;58:1201-1207. 38. Asthana S, Greig NH, Hegedus L, et al. Clinical pharmacokinetics of physostigmine in patients with Alzheimer’s disease. Clin Pharmacol Ther. 1995; 58:299-309. 39. Bodick NC, Offen WW, Levey AL, et al. Effects of xanomeline, a selective muscarinic receptor ago- nist, on cognitive function and behavioral symp- toms in Alzheimer disease. Arch Neurol. 1997; 54:465-473. 40. Aisen PS, Altstiel L, Marin D, Davis K. Treatment of Alzheimer’s disease with prednisone: results of pilot studies and design of multicenter trial [ab- stract]. J Am Geriatr Soc. 1995;43:SA27. 41. Sano M, Ernesto C, Thomas RG, et al. A con- trolled trial of selegeline, alpha-tocopherol, or both, as treatment for Alzheimer’s disease: the Alzhei- mer’s Disease Cooperative Study. N Engl J Med. 1997;336:1216-1222. 42. Simpkins JW, Singh M, Bishop J. The potential role for estrogen replacement therapy in the treatment of the cognitive decline and neu- rodegeneration associated with Alzheimer’s dis- ease. Neurobiol Aging. 1994;15(suppl 2):S195- S197. 43. Schneider LS, Farlow MR, Henderson WW, et al. Effects of estrogen replacement therapy on re- sponse to tacrine in patients with Alzheimer’s dis- ease. Neurology. 1996;46:1580-1584. 44. Aisen PS, Davis KL. The search for disease modi- fying treatment for Alzheimer’s disease. Neurol- ogy. 1997;48(suppl 6):S35-S41. 45. Saletu B, Paulus E, Linzmayer L, et al. Nicergo- line in senile dementia of Alzheimer type and multi- infarct dementia: a double-blind, placebo- controlled, clinical and EEG/ERP mapping study. Psychopharmacology. 1995;117:385-395. 46. Tariot PN, Blazina L. The psychopathology of de- mentia. In: Handbook of Dementing Illnesses. New York, NY: Marcel Dekker Inc; 1993:461-475. 47. Devanand DP. Behavioral complications and their treatment in Alzheimer’s disease. Geriatrics. 1997; 52(suppl 2):537-539. 48. Wragg RE, Jeste DV. Overview of depression and psychosis in Alzheimer’s disease. Am J Psychia- try. 1989;146:577-587. 49. Rovner BW, Broadhead J, Spencer M, et al. De- pression and Alzheimer’s disease. Am J Psychia- try. 1989;146:350-353. 50. Small GW, Rabins PV, Barry PP, et al. Diagnosis and treatment of Alzheimer’s disease and related disorders: consensus statement of the American Association for Geriatric Psychiatry, the Alzhei- mer’s Association, and the American Geriatrics So- ciety. JAMA. 1997;278:1363-1371. 51. Reifler BV, Teri L, Raskind M, et al. Double-blind trial of imipramine in Alzheimer’s disease pa- tients with and without depression. Am J Psy- chiatry. 1989;146:45-49. 52. Nyth AL, Gottfries CG. The clinical efficacy of cita- lopram in treatment of emotional disturbances in dementia disorders: a Nordic multicentre study. Br J Psychiatry. 1990;157:894-901. 53. Oxman TE. Antidepressants and cognitive impair- ment in the elderly. J Clin Psychiatry. 1996;57 (suppl 5):38-44. 54. Preskorn SH. Clinically relevant pharmacology of selective serotonin reuptake inhibitors: an over- view with emphasis on pharmacokinetics and ef- fects on oxidative drug metabolism. Clin Phar- macokinet. 1997;32(suppl 1):1-21. 55. Rudolph RL, Derivan AT. The safety and tolerabil- ity of venlafaxine hydrochloride: analysis of the clinical trial database. J Clin Psychopharmacol. 1996;16(suppl 2):S54-S59. 56. Ascher JA, Cole JO, Colin J-N, et al. Bupropion: a review of its mechanism of antidepressant activ- ity. J Clin Psychiatry. 1995;56:395-401. 57. Montgomery SA. Safety of Mirtazapine: a review. Int Clin Psychopharm. 1995;10(suppl 4):37-45. 58. Goldberg RJ. Antidepressant use in the elderly: current status of Nefazodone, venlafaxine and mo- clobemide. Drugs Aging. 1997;11:119-131. 59. Devanand DP, Sackheim HA, Brown RP. A pilot study of haloperidol treatment of psychosis and behavioral disturbance in Alzheimer’s disease. Arch Neurol. 1989;46:854-857. 60. Goldberg RJ, Goldberg J. Risperidone for demen- tia-related disturbed behavior in nursing home resi- dents: a clinical experience. Int Psychogeriatr. 1997;9:65-68. 61. Sweet RA, Mulsant BH, Gupta B, et al. Duration of neuroleptic treatment and prevalence of tar- dive dyskinesia in late life. Arch Gen Psychiatry. 1995;52:478-486. 62. Rosen J, Mulsant BH, Wright BA. Agitation in se- verely demented patients. Ann Clin Psychiatry. 1992;4:207-215. 63. Schneider LS, Pollock VE, Lyness SA. A metaan- alysis of controlled trials of neuroleptic treatment in dementia. J Am Geriatr Soc. 1990;38:553-563. 64. Mittelman MS, Ferris SH, Shulman E, et al. A fam- ily intervention to delay nursing home placement of patients with Alzheimer disease: a randomized controlled trial. JAMA. 1996;276:1725-1731. ARCH INTERN MED/ VOL 159, APR 26, 1999 798 ©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ by a Carnegie Mellon University User on 04/05/2021