AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

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• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
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Background

Alzheimer disease (AD) is the most common form of dementia. It is a progressive degenerative disease of the brain, strongly associated with advanced age. However, it should not be considered a part of the normal aging process. AD is characterized by a relentless progression of symptoms associated with defined neuropathologic changes.

Individuals with trisomy 21, or Down syndrome (DS), develop a clinical syndrome of dementia that has almost identical clinical and neuropathologic characteristics of AD as described in individuals without DS. The main difference is the early age of onset of AD in individuals with DS. These patients present with clinical symptoms in their late 40s or early 50s.

The neuropathology of AD in persons with DS closely resembles the pathology of AD in individuals without DS and is superimposed on developmental abnormalities such as reduced dendritic arborizations, decreased number of spines, spine atrophy, and abnormalities of spine orientation in pyramidal neurons.

Pathophysiology

The reason AD is more frequent in individuals with DS is not known. All recognized mutations for AD are associated with increased deposition of amyloid beta, a peptide fragment from 39 to 43 amino acids long, which are products of the catabolism of the amyloid precursor protein (APP) molecule. The discovery that the APP gene is on the 21st chromosome led to the hypothesis that the early and universal development of AD pathology is due to a third copy of the APP gene. Nonetheless, many steps in the amyloid cascade hypothesis remain unproven.

Epidemiologic and brain imaging studies of patients with AD without DS have led to observations that patients with limited education or diminished baseline cognitive abilities are at increased risk for AD. These data have led to the cognitive reserve hypothesis, which suggests that patients with better baseline cognitive abilities can tolerate more AD pathology and neuronal loss than patients with worse baseline cognitive abilities. Because most patients with DS are mentally retarded and have limited baseline cognitive ability, the cognitive reserve hypothesis would suggest that patients with DS are at increased risk to develop AD.

Frequency

United States

Several studies document that most if not all individuals with DS develop AD. This is unrelated to the degree of mental retardation; AD is not more prominent in individuals with mental retardation from other causes. Due to better clinical management, most persons with DS now reach the age of 40 years. Thus, the frequency of AD is likely to increase.

The percentage of people with DS and AD varies in some of the epidemiologic studies presented. A review of these studies showed that 10-25% of patients had AD when aged 40-49 years, 20-50% had AD when aged 50-59 years, and 60-75% had AD when older than 60 years.

International

No particular geographic distribution exists. A similar clinical picture has been described in other countries.

Mortality/Morbidity

The disease is responsible for the sharp decline in survival in DS patients older than 45 years.

Race

No documentation exists that race influences prevalence.

Sex

In patients without DS, the influence of sex on the incidence and prevalence of AD remains controversial. Some, but not all, studies suggest that the prevalence is higher in women than men. Few studies have evaluated the influence of sex on AD in patients with DS and the results have been contradictory.

Age

• Age and the presence of trisomy 21 are the most important factors in disease development.
• The neuropathologic findings related to AD have been described in all DS individuals older than 35 years.
• Early clinical signs and symptoms are observed at the end of the fifth decade to the beginning of the sixth decade of life. Mean age at the time of clinical diagnosis is 51 ± 6 years.

CLINICAL

Section 3 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
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History

• This progressive neurodegenerative disorder affects multiple components of the central nervous system (CNS). The clinical signs and symptoms are an expression of continuous progressive neuronal dysfunction and death.
• One of the most sensitive and specific symptoms of Alzheimer disease (AD) in people without Down syndrome (DS) is a decline in the patient's ability to perform cognitive tasks related to employment, shopping, or household finance. When individuals with DS are employed or performing complex tasks with certain degree of personal autonomy, noticing early signs of the disease might not be difficult. Because most individuals with DS have mental retardation, a history of decline in high level premorbid cognitive abilities is usually difficult to document.
• On average, approximately 1-2 years elapse between the early signs of the disease and the confirmation of the diagnosis.
• In the author's research, typically the first symptoms, most often identified retrospectively, are observed when the patient is aged 50 years (range 36-62.5 y), and the diagnosis is confirmed at age 52.6 years (range 37-62 y). Death occurs at a mean age of 60.11 years (range 46.7-69.8 y). The author's research has also shown that the duration of the disorder from first symptoms to death is 9.10 years (range 6.9-11.10 y), and duration from diagnosis to death is 8.2 years (range 5-12.4 y).
• The main symptoms are confusion, disorientation, and wandering. In most instances, these early signs are not recognized and commonly are misdiagnosed.
• Longitudinal studies showed a progression of cognitive decline with subtle memory loss as early symptoms, which are associated with deficits in visuospatial organization.
• Behavioral changes
• • In the early stage of the disease, behavioral changes are the most common sign. These changes are usually considered an exaggeration of long-standing behavioral traits. For example, refusal to follow certain orders or to do chores at home may be perceived as stubbornness.
  • Since the early changes are subtle, only those familiar with the individual recognize these changes. Such changes include change in daily routine, change in sleeping or eating habits, inability to make clothing decisions, getting lost in familiar environments, and inability to remember the names of familiar people.
  • One of the potentially early signs of AD in highly functional DS individuals is the inability to perform job duties.
• Visual deficiencies
• • Impairment in visual perception as a consequence of central processing dysfunction has been described in the early stage of AD in individuals with DS who have a relatively high level of intelligence.
  • Central processing dysfunction is more difficult to delineate in patients with DS who have severe mental retardation.
  • These central changes are magnified by peripheral visual disorders (eg, cataracts, myopia, astigmatism), which frequently are present in people with DS.
  • The visual deficiencies may be responsible for individuals getting lost in familiar environments, not being able to perform activities that require visuomotor coordination, increased frequency of accidents and falls, and difficulty in learning new tasks.
• Impaired learning ability is usually present in the early stages of the disease but is difficult to demonstrate in people with a moderate (or more severe) degree of mental retardation.
• Other indications of early deterioration include loss of language and other communication skills, impairment of social and adaptive skills, and progressive loss of activities of daily living (ADL) (eg, personal hygiene, dining skills, bathroom skills).
• Middle stage
• • ADL markedly deteriorate. The patient may depend totally on others for activities such as dressing, eating, walking, and toilet needs.
  • Communication skills are reduced markedly. Speech and language, if present, are not used efficiently.
  • Behavioral problems are exaggerated, and psychotic behavior may be displayed. Social activities are reduced to a minimum.
• Advanced stage
• • Patients are almost at a vegetative level.
  • They totally depend on others and interact minimally with the environment.

Physical

The clinical evolution of physical symptoms is similar to that observed in individuals with AD but without DS.

• Motor disorders
• • Motor disorders become obvious in the middle and advanced stage of the disease.
  • Motor disorders are associated with a progressive gait disorder and in some patients, a parkinsonian syndrome.
  • In very advanced stages, the patient is confined to bed with marked rigidity and little voluntary movement.
• Eating/swallowing disorders
• • In the author's research, eating disorders with progressive dysphagia and frequent choking may be observed at the beginning of the disease but are more obvious in the middle stage.
  • Aspiration pneumonia is a frequent complication.
  • Changes in the diet and type of food may help ameliorate the dysphagia; in some patients, tube feeding may be necessary.
• Epileptic seizures
• • In the author's research, epileptic seizures of the tonic-clonic type have been described. These occur approximately 2.4 years (range 7 mo to 6.1 y) after the disease presents.
  • Usually generalized tonic-clonic seizures are infrequent; if present, they typically can be controlled with antiepileptic medication.
• Myoclonus occurs more frequently than tonic-clonic seizures.  The myoclonus may be  stimulus sensitive and can be induced by light or a simple touch.  In the advanced stages, myoclonus may be constantly present.
• The following information is from the author's personal experience with institutionalized DS individuals. These data may help those who plan services for individuals with DS and AD.
• • Communication/speech disorder: Early indication of the impairment was observed after an average of 1.4 years (range 0-4 y; "0" implies the presence of symptoms at the time of first evaluation), and total loss of function occurred approximately 4.5 years (range 2.5-6.8 y) after confirmation of diagnosis.
  • ADL: Early indication of failure was observed at an average of 5 months (range 0-1.8 y), and total loss of function occurred 4.5 years (range 1.5-6.5 y) after confirmation of diagnosis.
  • Ambulation: Early signs of deterioration were observed after 1.1 years (range 0-3.7 y), and total loss of ambulation occurred 4.6 years (range 2.5-7.4 y) after confirming the diagnosis.
  • Leisure activities: Early indications of deterioration were observed after 10 months (range 0-2.9 y), and total loss of the ability to participate in leisure activities was seen after an average of 4.1 years (range 1.5-6.5 y).
• The following is the author's account of disease evolution in an individual who was observed from disease onset. This example demonstrates the complexity of the medical issues involved.
• • A male, born in 1930, was admitted to an institution for individuals with mental retardation in 1939. He died in the institution in 1991.
  • Diagnosis of DS was confirmed by chromosomal analysis.
  • Clinical presentation before the beginning of AD was as follows:
  • • No behavioral problems; was pleasant and congenial
    • Followed simple commands and understood simple orders
    • Walked independently and also was independent in ADL
    • Normal diet
    • Performed housework and showered well
    • Good leisure skills and active social program; participated in dances and outdoor trips and sang with the radio
    • Understood that he had to leave the building when a fire alarm sounded
    • Score on Vineland Adaptive Behavior Scale in 1975, when aged 45 years, was 4.9 years; remained the same when he was aged 49 years
  • The following is a yearly description of his symptoms as he developed AD:
  • • 1981 (age 51 y): First symptoms were disorientation, confusion, and behavior changes. He refused to accept that the program activity in which he was involved was over. He refused to return to his residence. He was found wandering the grounds crying and yelling in a state of confusion.
    • 1982 (age 52 y): He showed increased forgetfulness and had emotional problems and periods of agitation manifested by verbal outbursts and throwing of objects.
    • 1983 (age 53 y): ADL needed consistent prompting. He was still capable of showering and changing clothes daily. Leisure skills were unchanged. He exhibited 3 incidents of major aggression and agitation. His score on the Vineland Adaptive Behavior Scale decreased to 3 years.
    • 1984 (age 54 y): He demonstrated poor participation in social activities due to frequent sleeping; ADL needed increased assistance, although he remained independent. A choking episode was observed.
    • 1985 (age 55 y): Regression steadily continued. Disorientation, confusion, wandering, forgetfulness, and sleeping increased. Behavior deteriorated; he would undress in the dining room and at work. ADL also regressed, and he needed more help; however, he remained independent. He frequently was found wandering outside his residence and unable to find his way. Occasionally, he could not find his bedroom. The score on the Vineland Adaptive Behavior Scale decreased to 2.1 years.
    • 1986 (age 56 y): The patient exhibited photomyoclonic response; he had myoclonic seizures and difficulty walking. ADL regressed further; he still could eat and drink but had to be reminded constantly to do so. He was transferred to a safer and more restrictive environment.
    • 1987 (age 57 y): Generalized tonic-clonic seizures appeared. He became aggressive, and his gait deteriorated markedly, but he was still able to walk. He occasionally needed a wheelchair. He fed himself using adaptive equipment. Toilet training was scheduled, but a few accidents occurred.
    • 1988 (age 58 y): He became lethargic. Inappropriate behavior became frequent. He no longer was able to walk independently or feed himself. He frequently lost sphincter control. He could not tolerate bus rides into the community. He still enjoyed music and expressed pleasure by smiling and laughing.
    • 1989 (age 59 y): He developed aspiration pneumonia. He was totally dependent for ADL. He required a wheelchair, and his social interaction became very poor. He developed urinary incontinence.
    • 1990 (age 60 y): He suffered from frequent bouts of pneumonia. He no longer was able to swallow and was fed through a nasogastric tube; a feeding tube (percutaneous endoscopic gastronomy) was placed. Incontinence required the use of diapers. He had minimal interaction with his surroundings and slept most of the time. Occasionally, he conveyed pleasure and displeasure by laughing or crying.
    • 1991 (age 61 y): He showed minimal response to environmental stimulation and slept most of the time.

Causes

• For patients with or without DS, age is the most important risk factor for AD.
• See Alzheimer Disease for a discussion of risk factors for sporadic and autosomal dominant AD.
• A few case studies suggest that persons with DS and atypical karyotypes (partial trisomies, mosaicism, translocations) may have a lower risk of AD than patients with full trisomy.
• Other chromosome 21 genes, such as the gene coding for superoxide dismutase-1 (SOD-1), may be involved. The increased activity of this enzyme may result in increased production of hydroxy radicals, which may accelerate the progression of the disease. SOD-1 activity has been reported to be increased in people with DS.
• In patients without DS, the APOE epsilon 4 allele is associated with increased risk of AD, and the epsilon e2 allele may be protective. Among patients with DS, several studies have demonstrated that the epsilon e2 allele may be protective. Data that the e4 allele increases risk in patients with DS is less compelling than it is for patients without DS. 
• Small head circumference, a small brain, low level of intelligence, and a history of head trauma have also been related to a higher incidence of AD. However, none of these factors have been evaluated in individuals with DS.
• Factors that may decrease risk (eg, Mediterranean diet, active life style) or increase risk (eg, cardiac and cerebrovascular disease, small head circumference) of AD in patients without DS have not been evaluated in patients with DS.

DIFFERENTIALS

Section 4 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Depression
Other psychiatric disorders
Computed tomography in neurovascular diseases
Dementia in Parkinson disease
Dementia in progressive supranuclear palsy
Multi-infarct dementia

WORKUP

Section 5 of 11  

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• Workup
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• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• The workup is no different than that recommended for patients with dementia who do not have Down syndrome (DS). Excluding treatable forms of dementia is important.
• • Liver function tests
  • Renal function tests
  • Electrolytes
  • Blood glucose
  • CBC
  • Folic acid
  • Vitamin B-12
  • Possibly tests for syphilis and HIV (Among patients without DS, these tests are not recommended as part of routine evaluation but only when clinically indicated.)
  • Thyroid stimulating hormone (TSH) and thyroxine (T-4) levels (likely to be abnormal due to high incidence of immune-dependent hypothyroidism in patients with DS)
• Although the APOE epsilon 4 allele is associated with increased risk of AD, its use as a diagnostic tool in patients without DS is generally not recommended. At present, there is no role for this testing in patients with DS.
• Lumbar puncture is indicated in evaluation of dementia without DS when conditions that could be diagnosed by examination of the cerebrospinal fluid (such as fungal meningitis) are reasonable diagnostic possibilities. Most of the time such conditions are so unlikely that lumbar puncture is rarely performed as part of routine medical care in the evaluation of dementia. These same criteria should be used when considering lumbar puncture in patients with dementia and DS.

Imaging Studies

• Imaging studies are useful to exclude other causes of dementia, including subdural collections, tumors, and multiple infarcts. Once the diagnosis is established, repeat imaging is indicated when the course of progression is not consistent with AD (such as very rapid deterioration).
• Brain CT scan
• • CT scan studies comparing young individuals with DS (19-34 y) and a comparable group of healthy individuals without mental retardation found no significant differences between the 2 groups in white or gray matter volumes or ventricular volumes.
  • Quantitative studies with CT scan and MRI demonstrated that young adults with DS have no ventricular dilatation, no atrophy, and no consistent malformation that could explain the mental retardation. However, small brain size was reported consistently. This is probably an expression of small stature and a small cranial vault.
  • Bilateral symmetric basal ganglia calcification is a frequent finding in people with DS (see Media files 1-3); in fact, it exceeds the prevalence in the general population. However, the relationship with the clinical presentation of AD in DS is unclear.
  • The results were different when people with DS and cognitive deficiencies were compared with individuals without cognitive deficiencies. In individuals with DS and cognitive deficiencies, cerebral atrophy and ventricular enlargement that suggested brain atrophy were reported consistently (see Media files 4-6).
  • In advanced cases, atrophy was generalized. However, regional differences can exist with greater involvement of the temporal horns. The relationship between enlargement of the temporal horns of the lateral ventricles and dementia in elderly DS patients has been a consistent feature.
• Brain MRI
• • MRI studies have shown several developmental findings in persons with DS—reduction in the whole brain volume (including cerebellum) and gray and white matter of the brain, decrease in the volume of the hippocampus, focal reductions in the volume of the frontal and occipital lobes, and relative preservation of the temporal lobe but decreased volume of the planum temporale and the superior temporal gyrus.
  • MRI studies might show a decrease in the volume structures of the temporal lobe (hippocampus and adjacent medial temporal lobe) in patients with DS without dementia. A significant atrophy of the corpus callosum, an indication of neocortical atrophy, more obvious in the splenium, was also demonstrated in persons with DS before the development of AD.
  • MRI findings in symptomatic individuals are similar to those of CT scan and reveal progressive atrophy of the brain with enlargement of the ventricular system.
  • Volumetric analysis of selective areas of the brain is a research tool not available from routine MR studies.
  • Results of studies suggest that CT scan and MRI can differentiate nondemented and demented older individuals with DS.
• Brain positron emission tomography (PET)
• • Schapiro et al found that PET did not demonstrate any difference between healthy people with DS and individuals without mental retardation.¹
• • Studies with xenon-133 inhalation technique, which evaluates the cortical cerebral blood flow, showed no abnormalities in young, healthy people with DS.
  • Significant differences were observed in individuals with DS and dementia; the greatest reduction occurred in the parietal-temporal association neocortex.
  • PET is not considered a routine test for AD in individuals with DS.

Other Tests

• Generally, the methods used for testing the non-DS population (eg, Mini Mental Status Examination) are unreliable. Additionally, many people with DS cannot be evaluated by standard neuropsychologic tests.
• • Several tests have been designed that are more appropriate. Generally, these tests emphasize a change in function as measured by a decline in activities of daily living (ADL) such as eating, dressing, and bathing.
  • A simple tool developed at Wrentham Developmental Center is included in this chapter (see Alzheimer Functional Assessment Tool). The information can be obtained by interviewing relatives or caregivers. This tool, based on ADL, is appropriate for the follow-up care of individuals with DS and Alzheimer disease (AD). A decline in functions documented through this tool can also be used as a diagnostic test; however, this tool was not intended to be used as a diagnostic test.
  • The Dementia Scale for Down Syndrome (DSDS) can be a useful screening tool. In individuals in the middle or latter stage of the disease, the DSDS showed a high correlation between the diagnosis of AD and the findings. The correlation was not as good in the early stage of the disease.
  • The Dementia Questionnaire for Mentally Retarded Persons is a diagnostic screening test that can be completed by caregivers. Is as effective as the DSDS.
• Electroencephalogram
• • Patients with DS have a high baseline prevalence of seizures and the prevalence increases further as patients develop AD. It is prudent to obtain an EEG in the baseline evaluation of a patient with DS and dementia.
• Dementia screening tests marketed to consumers are of questionable usefulness in patients with DS and of no value in patients with DS.

Procedures

• During the course of the disease, patients may need placement of gastrostomy or jejunostomy tubes for enteral feeding.

TREATMENT

Section 6 of 11  

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Medical Care

Four acetylcholinesterase inhibitors (tacrine, donepezil, rivastigmine, and galantamine) have been approved by the FDA for treatment of AD in patients without DS. Tacrine is almost never used because potential liver toxicity requires frequent blood monitoring. All 4 drugs are approved for mild-to-moderate dementia. Donepezil remains the only cholinesterase inhibitor also approved for treatment of patients with severe dementia. Memantine, a partial N-methyl-D-aspartate (NMDA) antagonist, is approved for the treatment of moderate-to-severe AD.  

The efficacy of the cholinetransferase inhibitors in AD in patients without DS is modest and data is not convincing that these drugs influence the overall progression of the disease. Nonetheless, industry-sponsored studies have shown that AD patients without DS on these medications may require nursing home placement one year later than patients not treated with these medications.

Cholinetransferase inhibitors might be expected to produce the same results in persons with DS. However, AD in patients with DS is often diagnosed at a later stage than in patients without DS. Most studies of cholinesterase inhibitors were conducted in patients with mild-to-moderate disease and efficacy in patients with severe disease is less well established.

The efficacy of memantine is also modest. Indeed, its effect size is only half that of the cholinetransferase inhibitors. Memantine also does not slow the progression of disease. Some believe its efficacy is due to decreasing baseline noise in information processing associated with excess glutamate.

Several studies in patients without DS suggest that both the choliensterase inhibitors and memantine may be effective in treating secondary symptoms of AD such as agitation. As both groups of medications usually have fewer side effects than neuroleptics, a trial of a cholinesterase inhibitor or memantine to control secondary symptoms of AD before neuroleptics may be warranted. 

Few double-blind, placebo controlled clinical trials of cholinetransferase inhibitors in patients with DS and AD have been performed. Results have been negative or of modest benefit that was not sustained for more than several weeks.  

Several other classes of drugs have been tested in AD without DS. Neuroinflammation may have a role in the pathogenesis of AD, but clinical trials with anti-inflammatory drugs have failed to show consistent efficacy. Data suggest that free radicals may contribute to neurodegeneration in AD, but clinical trials have not consistently shown efficacy of antioxidants. Several phase III clinical trials of drugs that decrease the amount of beta-amyloid in the brain are ongoing. Trials with active immunization of patients with Abeta were halted because 7% of patients developed encephalitis. How effective immunization was in slowing progression in this trial is controversial. 
A phase III trial with passive immunization is ongoing.

Trials with drugs that decrease amyloid Abeta1-42 by other mechanisms are also ongoing.

Epidemiologic data had suggested that postmenopausal women taking estrogen were at decreased risk for developing AD. However, a clinical trial testing this hypothesis among women older than age 65 with a family history of AD was halted because the women treated with estrogen appeared to have increased risk for dementia. Data suggest that estrogen may have a protective role if started in younger women at the onset of menopause; studies are ongoing.  

Psychotropic medications

Typical and atypical neuroleptics are often used to treat agitation, aggression, and hallucinations in patients with AD without DS. A black box warning from the FDA warns about the use of atypical neuroleptics in patients with dementia. Nonetheless, most experts still occasionally use atypical neuroleptics, such as quetiapine, with the least extrapyramidal side effects in treating AD patients with agitation. Physicians need to inform patients' families that they are prescribing such medications despite the black box warning.

Other medications

Small trials have examined using antiseizure medications such as valproate, carbamazepine, and lamotrigine for treatment of agitation in AD. Results have been inconsistent. 

Surgical Care

• Some patients may require placement of a feeding tube.
• Some patients may need a tracheostomy.

Consultations

• Consult a neurologist and/or gerontologist for diagnosis, advice, and follow-up care.
• Consult rehabilitation specialists.
• In advanced stages, consult an ethics specialist regarding decisions for resuscitation and/or hospice care.

Diet

• No particular diet is required. As the disease progresses, dysphagia may become a prominent feature and changes in food texture usually are recommended. A dietitian's help may be needed at this stage.
• In advanced stages, limited intake may be associated with severe weight loss. At this point, consider a feeding tube.

Activity

A good comprehensive plan for individuals with AD should include a variety of physical and social activities.

MEDICATION

Section 7 of 11  

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The following medications have been recommended or used in individuals with Alzheimer disease (AD). Donepezil is the only drug investigated in individuals with Down syndrome (DS).

Drug Category: Cholinesterase inhibitors

The nucleus basalis of Meynert degenerates in AD, leading to a deficiency in CAT that result in deficient production of ACh in the cerebral cortex. This cholinergic deficiency is associated with behavioral changes, mainly memory dysfunction, observed in AD. Inhibitors of AChE, the enzyme that metabolizes ACh, may improve symptoms of AD. These drugs do not have clinically significant drug-drug interactions. These drugs can exacerbate stomach ulcers, asthma, and cardiac arrhythmias.

Drug Name	Donepezil (Aricept)
Description	Noncompetitively inhibits centrally active AChE, which in turn may increase concentrations of ACh available for synaptic transmission in CNS; indicated in mild forms of AD. The only drug with clinical trials in persons with DS.
Adult Dose	Initially 5 mg/d PO hs; may increase up to 10 mg qhs after 4-6 wk
Pediatric Dose	Disease state not seen in children
Contraindications	Documented hypersensitivity
Interactions	Agents that affect CYP450, CYP2D6, and CYP3A4 enzymes may affect rate of elimination; antagonizes anticholinergic medications; effects of succinylcholine, cholinesterase inhibitors, or cholinergic agonists are increased when administered concurrently; monitor for GI bleeding when using concomitantly with NSAIDs
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Caution in sick sinus syndrome, other supraventricular cardiac conduction disorders, or asthma

Drug Name	Rivastigmine (Exelon)
Description	Indicated in mild-to-moderate dementia. Competitive and reversible inhibitor of acetylcholinesterase. While mechanism of action unknown, may reversibly inhibit cholinesterase, which may in turn increase concentrations of ACh available for synaptic transmission in CNS and enhance cholinergic function. Effect may lessen as disease process advances and fewer cholinergic neurons remain functionally intact. There is no evidence that acetylcholinesterase inhibitors alter the course of underlying dementia.
Adult Dose	Initially 1.5 mg PO bid; if tolerated, increase by 1.5 mg bid q2wk; usual range, 6-12 mg; not to exceed 12 mg/d; take with meals
Pediatric Dose	Disease state not seen in children
Contraindications	Documented hypersensitivity
Interactions	May reduce effects of anticholinergics; increases effects of cholinergic agonists and neuromuscular blockers; risk of bradycardia increases when administered concurrently with beta-blockers without ISA, calcium channel blockers diltiazem or verapamil, or digoxin
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	May cause significant nausea, vomiting, anorexia, and weight loss (occurs frequently during titration phase, and in women); if significant adverse effects occur, patient should discontinue treatment for several doses, then restart at same or next lower dose; if treatment stopped for several days, initiate treatment at lowest daily dose; caution in history of peptic ulcer disease, concurrent NSAID use, sick sinus syndrome, urinary obstruction, pulmonary conditions such as COPD or asthma, and bradycardia or supraventricular conduction conditions

Drug Name	Galantamine (Razadyne)
Description	Indicated in AD. Recent studies showed some benefits in vascular dementia and vascular dementia combined with AD.
Adult Dose	Initially, 4 mg PO bid for 1 mo; if well tolerated, increase by 4 mg PO bid qmo; not to exceed 12 mg bid; take with meals
Pediatric Dose	Disease state not seen in children
Contraindications	Documented hypersensitivity; severe renal dysfunction (ie, <10 mL/min CrCl)
Interactions	Coadministration with other cholinesterase inhibitors (eg, succinylcholine) may increase toxicity; CYP450-2D6 or -3A4 inhibitors (eg, cimetidine, ketoconazole, ritonavir, paroxetine, erythromycin) may decrease elimination and increase serum levels
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Decrease dose in moderate renal insufficiency or moderate-to-severe hepatic impairment; caution in asthma; may cause bradycardia or AV block; syncope may occur with doses >24 mg/d; cholinergic adverse effects are dose related

Drug Name	Rivastigmine transdermal patch (Exelon patch)
Description	Competitive and reversible acetylcholinesterase inhibitor. While mechanism of action unknown, may reversibly inhibit cholinesterase, which may, in turn, increase concentrations of acetylcholine available for synaptic transmission in CNS and thereby enhance cholinergic function. Effect may lessen as disease process advances and fewer cholinergic neurons remain functionally intact. Available as 5-cm2 patch containing 9 mg (releases 4.6 mg/24 h) and 10-cm2 patch containing 18 mg (releases 9.5 mg/24 h). Indicated for dementia of Alzheimer disease and for dementia associated with Parkinson disease.
Adult Dose	Apply patch to upper or lower back, upper arm, or chest Initiating patch therapy (not switching from oral therapy): 4.6 mg/24 h patch (5 cm2) applied qd initially; if well tolerated and after minimum of 4 wk, increase to 9.5 mg/24 h patch (10 cm2) applied qd Switching from oral administration to patch therapy: Apply first patch on day following last oral dose Total daily oral dose <6 mg/d: Switch to 4.6 mg/24 h patch Total daily oral dose 6-12 mg/d: Switch to 9.5 mg/24 h patch
Pediatric Dose	Not indicated
Contraindications	Documented hypersensitivity
Interactions	May reduce effects of anticholinergics; increases effects of cholinergic agonists and neuromuscular blockers; risk of bradycardia increases when administered concurrently with beta-blockers without ISA, the calcium channel blockers diltiazem or verapamil, and digoxin
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Apply patch to clean, dry, and hairless area of back, upper arm, or chest; area where patch is applied must be free of powder, oil, moisturizer, lotion, or other substances that would keep patch from adhering properly to skin; also, apply to areas free of cuts, rashes, or other irritation; may cause significant nausea, vomiting, anorexia, and weight loss if taken in doses higher than recommended; if significant adverse effects occur, patient should discontinue treatment for several doses, then restart at lowest dose; extrapyramidal symptoms may occur or be exacerbated (especially tremor); caution in history of peptic ulcer disease, sick sinus syndrome, urinary obstruction, pulmonary conditions (eg, COPD, asthma), and bradycardia or supraventricular conduction conditions

Drug Category: Anti-Parkinson agents

These agents increase availability of dopamine and extend its duration of action.

Drug Category: Antioxidants

Free radicals, which may damage cell membranes and tissues, are natural byproducts of metabolic processes, especially oxidative metabolism. Eliminating free radicals is hypothesized to prevent neuronal damage.

Drug Category: N-methyl-D-aspartate antagonists

Newest class of agents indicated for AD. May be used alone or combined with acetylcholinesterase inhibitors. Glutamate stimulates 70% of excitatory synapses. The dysfunction of this excitatory system may result in continuous excitation in the neurons and may result in neuronal damage and death. This excitatory neuronal death may be related to the stimulation of the glutamate receptor N-methyl-D-aspartate (NMDA). Blocking this receptor may prevent the excitatory damage that results from excessive glutamate release.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Inpatient Care

• Inpatient care is not necessary except when the patient presents with acute medical complications.
• In the advanced stage of the disease, institutionalization may be required.

Further Outpatient Care

• Most services are provided in the outpatient setting.
• Consult a team that is experienced in managing Alzheimer disease (AD) patients with Down syndrome (DS).

Transfer

• When the severity of the dementia creates dangerous situations, individuals with AD need to be transferred from their usual living conditions. The ideal situation is to obtain support from the family or to arrange for caretakers at home so that the patient is maintained in a familiar and friendly environment as long as possible.

Complications

• Good nursing care is needed to avoid complications (eg, decubitus ulcers, aspiration pneumonia, deterioration of gastroesophageal reflux, fractures, dysphagia, urinary tract infections, accidents).

Prognosis

• As no treatment is available for the primary disease, prognosis is poor.

Patient Education

• Discuss issues related to diagnosis and prognosis with the family and caregivers early in the course of the disease.
• Establishing rapport with a team that specializes in the management of AD is useful.
• Caregivers are an important component in the care of persons with AD. In most instances, caregivers are family members. Several recent studies showed that caregivers endure a significant burden that might result in physical and emotional disorders. A good program for the treatment of persons with AD, with or without DS, should include education for and protection of the caregivers. A program consisting of 2 sessions of individual therapy for the caregiver of a person with AD (usually the spouse), 4 sessions of family counseling, support group participation, and continuous availability of phone counseling for the caregiver resulted in a 28.3% reduction in nursing home placement and a delay of almost a year and a half in the admission to a nursing home when that was needed. These positive results were achieved without a negative impact on caregiver well being.
• For excellent patient education resources, visit eMedicine's Dementia Center. Also, see eMedicine's patient education articles Alzheimer Disease and Alzheimer Disease in Individuals With Down Syndrome.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Alzheimer Functional Assessment Tool

This tool was developed by the Alzheimer team at Wrentham Developmental Center, Massachusetts and was designed to record key information on the status of patients with Alzheimer disease and to assist in making decisions concerning the patient's program and residential placement.

Interview the staff on all shifts who work directly with the patient. Find out the patient's behavior and overall ADL. The patient's abilities (skills, problems, other considerations) are described in the "description of skills" section of the summary sheet. Perform this assessment at the time of diagnosis of AD and every 6 months or when a significant change in status is observed.

• Alzheimer Functional Assessment Tool 
• • Date:
  • Name:
  • Activities of daily living:
  • Description of skills:
  • Toileting:
  • Dining:
  • Walking/motor:
  • Bathing:
  • Dressing:
  • Personal/oral hygiene:
  • Environmental awareness:
• Scoring for Alzheimer Functional Assessment Tool
• • Toileting
  • 1. Can use bathroom in familiar and unfamiliar environments independently
    2. Goes to the toilet independently or asks staff to assist; may need reminders to use toilet paper and wash hands
    3. Has occasional toileting accidents; needs verbal reminders
    4. Needs staff to take to the bathroom on a schedule; remains continent 90% of the time
    5. Needs staff to take to the bathroom on a schedule; remains continent 50% of the time or less
    6. No bowel or bladder control; may require frequent changing or special clothing (eg, pads, diapers)
  • Dining
  • 1. Can prepare simple food (eg, sandwich, toast); can set table and clean up after meal; uses knife and fork to cut food; may or may not use adaptive equipment to eat independently
    2. Can use fork and spoon to eat independently but needs food to be cut
    3. Eats independently with the help of adaptive equipment
    4. Can use fork and spoon to eat independently but may need occasional prompts to start or continue eating; may finger feed; needs food to be cut
    5. Needs physical assistance to complete the meal
    6. Develops swallowing problems; needs change in consistency of food or thick drinks
    7. Completely dependent; may need specialized feeding program
  • Walking/motor
  • 1. Independent ambulation; able to walk steadily; able to start, stop, and change direction without falling; able to walk fast or run; ascends and descends stairs; capable of leaving premises without assistance
    2. Independent ambulation for short distances; walks up and down the stairs one step at a time by holding rails; able to leave premises without assistance
    3. Independent but cannot negotiate stairs; unable to leave premises without assistance
    4. Can walk without support but requires supervision; may be unsteady; requires supportive measures at times
    5. Needs assistance (another person to hold, walker) to walk; "cruises" around using structures such as furniture and walls as support; unable to leave premises independently
    6. Needs wheelchair but can move independently
    7. Needs an adapted wheelchair and cannot move independently; needs to be pushed
  • Bathing
  • 1. Can independently carry out an appropriate bathing routine (disrobing, washing, drying, and dressing)
    2. Can carry out an appropriate bathing routine with occasional reminders to do a step or wash more thoroughly
    3. Needs verbal prompts to initiate and/or complete some steps in the bathing process (due to subtle confusion and/or fear); continuous staff supervision at shower time not necessary; may use toiletries inappropriately
    4. Requires continuous staff supervision at shower time to ensure complete bathing and safety (eg, problems due to confusion and/or fear); hand-over-hand assistance may be necessary at times; alternatives to showering or a specialized program may be recommended due to fear of showering; safe use of hot and cold water needs to be monitored
    5. Primarily passive during bathing; requires some form of assistance for all steps; may be able to stand and move a body part when given a verbal or touch cue; fear of water may be present
    6. Physically and cognitively unable to participate actively in bathing process; may respond to stimulation during bathing with vocalizations or changes in facial expressions
  • Dressing (skills and appropriate dress)
  • 1. Dresses independently or with physical assistance due to handicap; can choose appropriate clothing (for weather or activity of the day) and cares for own clothing (eg, places dirty clothes in hamper, hangs clothing, stores properly)
    2. Occasionally needs reminders to dress appropriately ("It's cold out today") and to care for clothes ("Remember where your dirty socks go?")
    3. Dresses with minimal assistance or verbal prompts
    4. Dresses inappropriately for weather (layers clothing and/or puts clothing on inappropriately); may undress at an inappropriate time and/or place; may benefit from adaptive clothing to retain dressing skills; makes no attempt to care for own clothing
    5. Needs assistance in dressing (50% or more of task) and may be resistive; may assist when compliant (eg, puts arm through sleeve)
    6. Lies passively during dressing; does not respond to dressing or undressing
  • Personal/oral hygiene (hair brushing, teeth brushing, sanitary pad, shaving)
  • 1. Able to perform all personal hygiene tasks
    2. Able to perform all personal hygiene tasks within regular routines; may show difficulty in performing tasks if routine is changed (eg, hospitalized, moved)
    3. Able to perform all personal hygiene tasks but requires occasional reminders from staff to complete the task
    4. Able to perform personal hygiene tasks but requires frequent reminders from staff to complete the task; may need staff guidance (verbal and point cues) in some parts of some tasks (ie, may forget steps); may still be proficient in one area and lose ability in another area
    5. Requires staff supervision (verbal and point cues) to complete some personal hygiene tasks and staff assistance (light, moderate physical cues) to complete others
    6. May still be able to perform some steps of some personal hygiene tasks with staff assistance but depends on staff to meet other personal hygiene needs
    7. Depends on staff to meet all personal hygiene needs
  • Environmental awareness
  • 1. Cognizant and responsive, in a relevant way, to familiar and unfamiliar people and other environmental stimuli
    2. Generally responsive to familiar and unfamiliar people and situations but seems self-absorbed and/or confused most of the time
    3. Cognizant and responsive in a relevant way to familiar people and situations but shows a delayed or inappropriate response to unfamiliar people and situations
    4. Cognizant and responsive to stimuli, but response is often inappropriate, even in familiar situations
    5. Mostly awake but seems self-involved, showing little or inconsistent response to the environment
    6. Sometimes awake but shows little interest in surroundings; sleeps at other times
    7. Sleeps most of the day; needs to be aroused repeatedly to maintain interaction

Medical/Legal Pitfalls

• Individuals with Down syndrome (DS) are considered independent adults when older than 18 years.
• Instruct parents to obtain legal guardianship through the courts; otherwise, any authorization provided by the parents has no legal value. Discuss issues such as surgical procedures, placement of feeding tubes, and hospice care with the legal guardians.  

Special Concerns

• The term mild cognitive impairment (MCI) has been used to characterize a state of cognitive decline transitional between normal and dementia and is characterized by impairment in memory and other cognitive functions as demonstrated by standardized neuropsychological tests. A substantial percentage of patients with the amnestic form of MCI progress to AD within 4 years of diagnosis. The lack of adequate normative data for memory in DS in different age groups makes the concept of MCI impossible to operationalize in individuals with DS.
• The term pseudodementia is used to describe reversible cognitive impairment associated with psychiatric disease—usually depression. With treatment and amelioration of the psychiatric disease, the cognition returns to baseline. In patients without DS, many patients who develop AD have symptoms of depression in the early stages of disease, and the depression itself can impair cognitive function. Treatment of the depression (usually with SSRIs) often improves mood and sometimes cognition.  However, over the next 24-36 months, progressive cognitive impairment, not necessarily accompanied by mood disturbances, becomes clear. Data are not available on depression in patients with DS and AD.
• Hypothyroidism, observed in almost 30% of individuals with DS, may simulate dementia. Hypothyroidism is frequently present in people with DS and AD; however, treatment with hormone replacement does not change the course of the underlying disease.
• Vitamin B-12 deficiency has been reported in several individuals with DS and AD; however, replacement therapy does not change the evolution of the underlying disease.
• Persons with AD and DS present with a higher number of health comorbidities when compared with individuals with DS and no AD. The frequency of the comorbidities increase as the AD is more severe. Among the health comorbidities expected are epileptic seizures, lung diseases (mostly aspiration pneumonias), depression, visual and hearing impairment, lack of mobility, and tube feedings.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  CT scan of a man who has Down syndrome confirmed by chromosomal analysis. He has a long history of mental deterioration with progressive loss of ability to perform his usual activities. The CT scan, obtained when the patient was aged 60 years and exhibiting advanced signs of Alzheimer disease, shows several calcified areas in the basal ganglia plus diffuse cortical atrophy and enlargement of the ventricular system. The bilateral symmetric calcifications are a frequent finding in this condition.
	View Full Size Image
Media type:  CT

Media file 2:  CT scan of a man who has Down syndrome confirmed by chromosomal analysis. He has a long history of mental deterioration with progressive loss of ability to perform his usual activities. The CT scan, obtained when the patient was aged 60 years and exhibiting advanced signs of Alzheimer disease, shows several calcified areas in the basal ganglia plus diffuse cortical atrophy and enlargement of the ventricular system. The bilateral symmetric calcifications are a frequent finding in this condition.
	View Full Size Image
Media type:  CT

Media file 3:  CT scan of a man who has Down syndrome confirmed by chromosomal analysis. He has a long history of mental deterioration with progressive loss of ability to perform his usual activities. The CT scan, obtained when the patient was aged 60 years and exhibiting advanced signs of Alzheimer disease, shows several calcified areas in the basal ganglia plus diffuse cortical atrophy and enlargement of the ventricular system. The bilateral symmetric calcifications are a frequent finding in this condition.
	View Full Size Image
Media type:  CT

Media file 4:  CT scan of a 62-year-old man with Down syndrome confirmed by chromosomal analysis. This CT scan was obtained when he was showing signs of moderate-to-advanced Alzheimer disease. The CT scan shows marked, diffuse enlargement of the ventricular system and generalized atrophy of the cerebral cortex.
	View Full Size Image
Media type:  CT

Media file 5:  CT scan of a 62-year-old man with Down syndrome confirmed by chromosomal analysis. This CT scan was obtained when he was showing signs of moderate-to-advanced Alzheimer disease. The CT scan shows marked, diffuse enlargement of the ventricular system and generalized atrophy of the cerebral cortex.
	View Full Size Image
Media type:  CT

Media file 6:  CT scan of a 62-year-old man with Down syndrome confirmed by chromosomal analysis. This CT scan was obtained when he was showing signs of moderate-to-advanced Alzheimer disease. The CT scan shows marked, diffuse enlargement of the ventricular system and generalized atrophy of the cerebral cortex.
	View Full Size Image
Media type:  CT

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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