Pharmacological interventions for cognitive decline in people with Down syndrome
People with Down syndrome are vulnerable to developing dementia at an earlier age than the general population. Alzheimer's disease and cognitive decline in people with Down syndrome can place a significant burden on both the person with Down syndrome and their family and carers. Various pharmacological interventions, including donepezil, galantamine, memantine and rivastigmine, appear to have some effect in treating cognitive decline in people without Down syndrome, but their effectiveness for those with Down syndrome remains unclear.
To assess the effectiveness of anti‐dementia pharmacological interventions and nutritional supplements for treating cognitive decline in people with Down syndrome.
In January 2015, we searched CENTRAL, ALOIS (the Specialised Register of the Cochrane Dementia and Cognitive Improvement Group), Ovid MEDLINE, Embase, PsycINFO, seven other databases, and two trials registers. In addition, we checked the references of relevant reviews and studies and contacted study authors, other researchers and relevant drug manufacturers to identify additional studies.
Randomised controlled trials (RCTs) of anti‐dementia pharmacological interventions or nutritional supplements for adults (aged 18 years and older) with Down syndrome, in which treatment was administered and compared with either placebo or no treatment.
Data collection and analysis
Two review authors independently assessed the risk of bias of included trials and extracted the relevant data. Review authors contacted study authors to obtain missing information where necessary.
Only nine studies (427 participants) met the inclusion criteria for this review. Four of these (192 participants) assessed the effectiveness of donepezil, two (139 participants) assessed memantine, one (21 participants) assessed simvastatin, one study (35 participants) assessed antioxidants, and one study (40 participants) assessed acetyl‐L‐carnitine.
Five studies focused on adults aged 45 to 55 years, while the remaining four studies focused on adults aged 20 to 29 years. Seven studies were conducted in either the USA or UK, one between Norway and the UK, and one in Japan. Follow‐up periods in studies ranged from four weeks to two years. The reviewers judged all included studies to be at low or unclear risk of bias.
Analyses indicate that for participants who received donepezil, scores in measures of cognitive functioning (standardised mean difference (SMD) 0.52, 95% confidence interval (CI) ‐0.27 to 1.13) and measures of behaviour (SMD 0.42, 95% CI ‐0.06 to 0.89) were similar to those who received placebo. However, participants who received donepezil were significantly more likely to experience an adverse event (odds ratio (OR) 0.32, 95% CI 0.16 to 0.62). The quality of this body of evidence was low. None of the included donepezil studies reported data for carer stress, institutional/home care, or death.
For participants who received memantine, scores in measures of cognitive functioning (SMD 0.05, 95% CI ‐0.43 to 0.52), behaviour (SMD ‐0.17, 95% CI ‐0.46 to 0.11), and occurrence of adverse events (OR 0.45, 95% CI 0.18 to 1.17) were similar to those who received placebo. The quality of this body of evidence was low. None of the included memantine studies reported data for carer stress, institutional/home care, or death.
Due to insufficient data, it was possible to provide a narrative account only of the outcomes for simvastatin, antioxidants, and acetyl‐L‐carnitine. Results from one pilot study suggest that participants who received simvastatin may have shown a slight improvement in cognitive measures.
Due to the low quality of the body of evidence in this review, it is difficult to draw conclusions about the effectiveness of any pharmacological intervention for cognitive decline in people with Down syndrome.
Nuala Livingstone, Jennifer Hanratty, Rupert McShane, Geraldine Macdonald
Plain language summary
Medications for cognitive decline in people with Down syndrome
People with Down syndrome often experience cognitive decline (a deterioration in memory, language, thinking and judgment that are greater than normal age‐related changes) at a younger age and in greater numbers than the general population. Various medicines have been shown to improve, or at least slow down the progression of these symptoms in people without Down syndrome.
Do adults (18 years and older) with Down syndrome benefit from treatment with medicine to prevent cognitive decline, compared with other adults with Down syndrome who receive either fake medicine (placebos) or no medicine?
In January 2015, we, a team of Cochrane researchers, searched for all medical studies that investigated the effect of any medicine or nutritional supplement on cognitive decline in adults with Down syndrome. We found nine relevant randomised controlled trials (this design produces the most reliable results) that we could include in this overview. These studies tested:
‐ donepezil, a medicine used to treat Alzheimer's disease (four studies);
‐ memantine, a medicine used to treat Alzheimer's disease (two studies);
‐ simvastatin, a (statin) medicine used to prevent heart disease (one study);
‐ a mixture of antioxidants, including forms of vitamins C and E, and alpha‐lipoic acid (one study); and
‐ acetyl‐L‐carnitine, a dietary supplement that has previously been used to treat dementia (one study).
Five of the studies focused on adults aged 45 to 55 years and four focused on adults aged 20 to 29 years. Seven studies were conducted in either the USA or UK, one took place in Norway and the UK, and one study was conducted in Japan.
The nine studies we found examined the effects of five medicines that are, or have been, used to prevent cognitive decline. All the studies compared the medicine being tested with a placebo (a tablet or capsule that looked and tasted like the medicine, but which contained no medicine).
Generally, those who received the medicine did no better than those who received the placebo in any of the areas assessed in the studies. The areas assessed included general functioning (including memory and thinking, speech, mood and behaviour); cognitive functioning (including memory, following what’s going on around you); adaptive behaviours (being able to do day‐to‐day tasks); or behaviour problems (such as being irritable or aggressive).
The only medicine to show any positive effect was the statin, simvastatin. Preliminary findings from a very small study showed that simvastin had some benefit on improving memory compared to placebo.
In the four donepezil studies, those participants given donepezil reported more headaches, dizziness, and nausea than participants given placebo. In the two memantine studies, there was no difference between participants given memantine or placebo for reports of headaches, dizziness, and nausea.
Quality of the evidence
Although the included studies were well conducted, most involved small numbers of participants and for many of the areas assessed we could not combine results from two or more studies. Overall, the quality of this evidence is low. We cannot be certain whether any of these medicines are effective. Running more trials with more people over a longer period of time would allow us answer this question with greater certainty.
We could not find any trials that investigated many of the medicines used to prevent cognitive decline, and so research is needed to explore the effectiveness of these medications in the Down syndrome population.
Nuala Livingstone, Jennifer Hanratty, Rupert McShane, Geraldine Macdonald
Implications for practice
Due to the low sample size of the included studies in this review, it is difficult to state with certainty the implications for the continued practice of pharmacological interventions for cognitive decline in people with Down syndrome. Donepezil may be associated with a lack of any clear benefit, as well as a risk of adverse events. There is limited and inconclusive evidence for memantine, antioxidants and acetyl‐L‐carnitine. The results from Cooper 2012 suggest there may be a positive trend for participants receiving simvastatin, but this suggestion is based only on preliminary results from a small feasibility study. There are no data available to consider the impact of galantamine, rivastigmine, piracetem, or DYRK1A inhibitors for cognitive decline in people with Down syndrome.
Implications for research
This review highlights the need for further research in this area. More RCTs are needed before any conclusions can be drawn about the effectiveness of any pharmacological intervention for treating cognitive decline in people with Down syndrome. Future research should also provide clear details regarding the inclusion criteria for participants, and in particular, the level of dementia they consider eligible and ineligible for their studies. It is also important to consider the reasons why this review identified so few eligible RCTs, and why these RCTs have such small sample sizes. This could be a reflection of the fact that it is difficult to conduct research in this population. Scoping of potential sample size should be an important priority for commissioning of future research in this area. Furthermore, future research should consider the choice of outcomes to be measured carefully. For example, only two of the included studies reported global functioning, which some consider a more reliable measure of outcome in this population than cognitive function. In addition, researchers must ensure that any measurement tools selected are likely to be completed by participants, sufficiently sensitive to detect relevant changes, harmonised so that meta‐analysis can be undertaken and sufficiently powered.