eMedicine Specialties > Neurology > Behavioral Neurology and Dementia

Alzheimer Disease in Individuals With Down Syndrome: Treatment & Medication

Author: Norberto Alvarez, MD, Assistant Professor, Department of Neurology, Harvard Medical School; Consulting Staff, Department of Neurology, Boston Children's Hospital
Contributor Information and Disclosures

Updated: Jan 10, 2008

Treatment

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 . I ndeed, 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

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).

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.


Tacrine (Cognex)

Indicated in early stages of dementia; centrally acting, reversible cholinesterase inhibitor that slows degradation of ACh produced by remaining cholinergic neurons; these effects in turn increase ACh concentrations in cerebral cortex.
Use is very limited because of adverse effects.

Adult

10 mg PO qid; increase by 40 mg/d with adjustments q6wk; not to exceed 160 mg/d

Pediatric

Disease state not seen in children

Inhibits hepatic microsomal enzyme CYP450 and potentiates theophylline and cimetidine effects; increases toxicity of cholinesterase inhibitors, succinylcholine, or cholinergic agonists; antagonized by cigarette smoke; concomitant administration of NSAIDs may cause GI bleeding

Documented hypersensitivity; history of jaundice (>3 mg/dL bilirubin) associated with tacrine

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 bladder outlet obstruction, sick sinus syndrome, cardiovascular disease, peptic ulcer, and asthma; increased serum transaminases may occur


Donepezil (Aricept)

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

Initially 5 mg/d PO hs; may increase up to 10 mg qhs after 4-6 wk

Pediatric

Disease state not seen in children

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


Rivastigmine (Exelon)

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

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

Disease state not seen in children

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


Galantamine (Razadyne)

Indicated in AD. Recent studies showed some benefits in vascular dementia and vascular dementia combined with AD.

Adult

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

Disease state not seen in children

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

Documented hypersensitivity; severe renal dysfunction (ie, <10 mL/min CrCl)

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


Rivastigmine transdermal patch (Exelon patch)

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

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

Not indicated

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

Anti-Parkinson agents

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


Selegiline (Eldepryl)

An irreversible MAOI that has been used experimentally in treating AD; acts as a "suicide" substrate for the enzyme where MAO converts it to an active moiety that combines irreversibly with active site or enzyme's essential FAD cofactor; blocks breakdown of dopamine; in parkinsonism, extends duration of action from each dose of L-dopa; often allows for L-dopa dose reduction; because of greater affinity for type B than for type A active sites, can serve as a selective inhibitor of MAO type B at recommended dose; however, at doses >10 mg/d, significant MAO-A inhibition may occur; no evidence that additional benefit is obtained from doses >10 mg/d.
A large double-blind placebo-control study failed to showed any benefit in slowing the progression of the disease.
No studies in DS have been reported.

Adult

Initially 5 mg PO qd, increased gradually up to 10 mg/d

Pediatric

Disease state not seen in children

At least 3-5 wk should lapse between discontinuation of fluoxetine and initiation of MAOIs to prevent fatal interactions that have been reported with MAO type A inhibitors; in general, avoid administering MAOIs concomitantly with opioids; severe agitation, hallucinations, and death have occurred with concomitant administration with meperidine

Concomitant use of opioids (eg, meperidine); concurrent administration of SSRIs; antidepressants can probably be used, although concerns exist regarding rare interactions

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

Adverse effects include nausea, dizziness, and syncope

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.


Alpha-tocopherol (vitamin E, Vita-Plus E, E-Complex-600)

Protects polyunsaturated fatty acids in cell membranes from attack by free radicals.
No studies published using vitamin E in DS. One study involving persons with DS is in progress.
A double-blind, placebo-controlled trial with 2000 IU of vitamin E suggested that vitamin E delayed admission to nursing home, functional decline, and death but did not affect cognitive decline in persons with moderate-to-severe AD.
Vitamin E 2000 IU/d is considered standard therapy for persons with AD; however, a government panel recommended a lower dose of no more than 1000 IU because of the possibility of coagulation disorders.

Adult

2000 IU PO qd has been used in the treatment of AD (daily requirement is 10-30 mg/d)

Pediatric

Disease state not seen in children

Increases effect of PO anticoagulants; mineral oil decreases absorption when used concomitantly; delays absorption of iron

Pregnancy

A - Fetal risk not revealed in controlled studies in humans

Precautions

May induce vitamin K deficiency; large doses have been associated with necrotizing enterocolitis

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.


Memantine (Namenda, Axura)

Indicated for moderate-to-severe Alzheimer disease. NNMDA antagonist. NMDA receptor stimulation in the CNS by glutamate (an excitatory amino acid) is hypothesized to contribute to Alzheimer symptoms.

Adult

5 mg PO qd initially; gradually titrate to a 20-mg/d target dose using following dosage regimen (allow >1 wk between each dosage increase): 5 mg PO bid; then, 5 mg PO qam and 10 mg PO qpm; then, 10 mg PO bid

Pediatric

Disease state not seen in children

Coadministration with drugs causing alkaline urine (eg, sodium bicarbonate, carbonic anhydrase inhibitors) may decrease clearance by 80%; thus, accumulation and toxicity may occur; coadministration with other NMDA antagonists (eg, amantadine, ketamine, dextromethorphan) may increase toxicity risk; concurrent use with other drugs renally eliminated via tubular secretion (eg, hydrochlorothiazide, triamterene, cimetidine, ranitidine, quinidine, nicotine) may alter plasma levels of either drug

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Common adverse effects include dizziness (7%), headache (6%), and constipation (5%); predominantly excreted renally; no data support use in severe renal impairment

More on Alzheimer Disease in Individuals With Down Syndrome

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Differential Diagnoses & Workup: Alzheimer Disease in Individuals With Down Syndrome
Treatment & Medication: Alzheimer Disease in Individuals With Down Syndrome
Follow-up: Alzheimer Disease in Individuals With Down Syndrome
Multimedia: Alzheimer Disease in Individuals With Down Syndrome
References
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Further Reading

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Keywords

Alzheimer's disease, Alzheimer's, AD, dementia, Alzheimer dementia, presenile dementia, dementia presenilis, primary neuronal degeneration, primary senile dementia, trisomy 21, trisomy 21 syndrome, Down's syndrome, DS, mental retardation

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Contributor Information and Disclosures

Author

Norberto Alvarez, MD, Assistant Professor, Department of Neurology, Harvard Medical School; Consulting Staff, Department of Neurology, Boston Children's Hospital
Norberto Alvarez, MD is a member of the following medical societies: American Academy of Neurology, American Epilepsy Society, and Child Neurology Society
Disclosure: Nothing to disclose.

Medical Editor

Robert A Hauser, MD, Professor, Departments of Neurology, Pharmacology, and Experimental Therapeutics, Director, Parkinson's Disease and Movement Disorders Center, University of South Florida and Tampa General Healthcare
Robert A Hauser, MD is a member of the following medical societies: American Academy of Neurology and Movement Disorders Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Richard J Caselli, MD, Professor, Department of Neurology, Mayo Medical School, Rochester, MN; Chair, Department of Neurology, Mayo Clinic of Scottsdale
Richard J Caselli, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American Medical Association, American Neurological Association, and Sigma Xi
Disclosure: Nothing to disclose.

CME Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
Disclosure: Nothing to disclose.

Chief Editor

Howard A Crystal, MD, Professor, Departments of Neurology and Pathology, State University of New York Downstate; Consulting Staff, Department of Neurology, University Hospital and Kings County Hospital Center
Howard A Crystal, MD is a member of the following medical societies: American Academy of Neurology and American Neurological Association
Disclosure: Pfizer Honoraria Speaking and teaching; Myriad Honoraria Consulting

 
 
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