What is the role of acetyl cholinesterase inhibitors in the treatment of Alzheimer disease (AD) in Down syndrome (DS)?

Updated: Nov 13, 2019
  • Author: Norberto Alvarez, MD; Chief Editor: Jasvinder Chawla, MD, MBA  more...
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Answer

Four acetyl cholinesterase inhibitors (tacrine, donepezil, rivastigmine, and galantamine) have been approved by the US Food and Drug Administration (FDA) for treatment of AD in patients without DS. Tacrine is no longer used because its potential liver toxicity necessitates frequent blood monitoring. These drugsare 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 the available data have not convincingly demonstrated that these drugs influence the overall progression of the disease. Nonetheless, industry-sponsored studies have shown that AD patients without DS who were treated with these medications may require nursing home placement 1 year later than patients who were not so treated.

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 AD 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. A meta-analysis showed that memantine monotherapy might have a beneficial effect on persons with AD (DS not included), [113] but other studies do not confirm these results. [114]

Several studies in patients without DS suggest that both the cholinesterase inhibitors and memantine may be effective in treating secondary symptoms of AD (eg, agitation). Given that both groups of medications usually have fewer side effects than neuroleptics do, a trial of a cholinesterase inhibitor or memantine to control secondary symptoms of AD before neuroleptic therapy may be warranted.

Few clinical trials of the cholinetransferase inhibitor donepezil have been performed in patients with DS and AD. Results have been negative or have consisted of modest benefits that were not sustained for more than a few months. [115, 116, 117, 118, 119, 109, 110]

A Cochrane review of the use of donepezil in persons with DS found a modest and statistically nonsignificant benefit in persons with DS and AD who were able to tolerate the adverse effects of the medication. [111]

A small study involving 3 individuals with DS showed that donepezil treatment resulted in urinary incontinency in 2. [116]

Some improvement in cognitive functions with donepezil was reported in another small study involving 4 individuals with DS. [118]

In a 24-week, double-blind, placebo-controlled, parallel-group involving 30 persons with DS and mild-to-moderate AD, with an average age in the placebo group of 55 years (range, 45-62 y) and 53 years (range, 40-69 y) in the treatment group, there was a nonsignificant reduction in deterioration as measured by the Dementia Scale for Mentally Retarded Persons, Severe Impairment Battery, and the Adaptive Behavioral Scale. The tolerance for donepezil was good. [120]

Boada Rovira et al (2005) in an open crossover study involving 14 individuals with DS older than 40 years and diagnosed with possible or probable dementia receiving 5 mg of donepezil during the first month of treatment and 10 mg for the next 5 months found improvement in cognition and social activities in the first 3 months of the donepezil-phase of the study, but no difference with the control group at the end of the study.

Improvement in daily activity was observed with a low dose of donepezil (3 mg/day) in a group of 21 women with DS (aged 32-58 y; mean, 45.6 y) and severe cognitive impairment. [121] In this study, donepezil treatment was beneficial for DS patients in the early part of the treatment phase and was never reduced throughout the trial. Most of the patients had IQs below 20, suggesting that donepezil treatment could be beneficial even for severely impaired patients.

Regarding rivastigmine, a retrospective study [46] involving of 17 patients with DS and AD receiving a starting dose of 1.5 mg twice daily and gradually increased up to 12 mg/day over 8 weeks showed that individuals treated with rivastigmine had less of a decline, over 24 weeks, in global functioning and adaptive behavior when compared with an untreated group; however the difference was not statistically significant.

A Cochrane review of the use of rivastigmine in people with DS found 4 studies addressing this issue, but 3 were excluded because they did not meet the standards requested, and 1 was awaiting assessment. The conclusion was that there was no evidence that rivastigmine is useful in this population. [122]

A Cochrane review of the use of galantamine failed to find any study in this population. [123]

A more recent meta-analysis of the use of these medications in persons with DS again failed to show benefits of donepezil and memantine. Also, participants who received donepezil were significantly more likely to experience an adverse event. [124]


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