Painkillers and risk of Alzheimer’s

“Regular use of painkillers 'could cut Alzheimer's risk by a quarter'” is the headline in the Daily Mail today. A study has found that regular use of ibuprofen, aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) reduces the risk of developing the disease. The newspaper goes on to warn that “doctors say they cannot advise people to start taking over-the-counter pain remedies to ward off dementia”, as there are also side effects, such as an increased chance of bleeding, which need to be considered. Also, it is not known how the drugs protect the brain.

This review of six different studies involved almost 14,000 people, of whom more than a quarter had taken one of the NSAID group of drugs, for varying lengths of time from an average of one to five years. Researchers had previously thought that a sub-group of NSAIDs, known as the SALAs, that selectively lower levels of the peptide Aβ42 – a certain type of deposit found in the brain of Alzheimer's patients – might be more effective at preventing Alzheimer’s disease. However, the SALA drugs, which include the commonly used drugs diclofenac and ibuprofen, were no more effective than the other non-SALAs, such as naproxen or aspirin.

Where did the story come from?

Dr Christine Szekely from the Johns Hopkins Bloomberg School of Public Health and colleagues from elsewhere around the US carried out this research. The study was supported by several grants from the National Institutes of Health and the National Institute on Ageing. It was published in the peer-reviewed medical journal: Neurology .

What kind of scientific study was this?

This was a pooled analysis of data from six prospective cohort studies. The researchers contacted the authors of all the studies they knew which had collected data on Alzheimer’s using recognised scoring criteria and related this to details of NSAID and aspirin use, including drugs bought directly over the pharmacy counter (without prescription). All the data on drug use had to have been collected before the patient was diagnosed with dementia. The six studies they found were all from the USA or Canada and the researchers excluded seven other studies because the data had been collected after the diagnosis of dementia or the data on drugs bought directly had been excluded. Four investigators from the individual “primary” trials declined to take part in the review study.

The researchers extracted the details of medication use from the study reports and counted the number of new diagnoses of Alzheimer’s disease that were made during each study. They also calculated the “person-years” for each study, by adding together the total number of years each person was in the study. This allowed them to report the results as a rate: the number of new people diagnosed with Alzheimer’s per person-years in the study. They adjusted the rates to take into account age, sex and education level of the participants.

What were the results of the study?

The researchers report that they looked at 13,499 initially dementia-free participants who together provided 70,863 person-years of data. Amongst these people, 820 developed a new diagnosis of Alzheimer’s disease.

The users of NSAIDs (of any type) showed a 23% reduced risk of Alzheimer’s compared with non-users, and this reduction was significant. When the researchers looked individually at the SALA users and non-SALA users compared with those who did not use any NSAID they found similar but non-significant reductions in risk (13% and 25% respectively). 

To look at any differences between the effects of SALA and non-SALA drugs, the researchers excluded the 573 NSAID users who reported taking both a SALA and non-SALA drug. When they did this, there was an 18% reduction in risk of Alzheimer’s for those who used SALA only and a 40% reduction for non-SALA use only, both of these were statistically significant. For people who used both NSAIDs types there was a 13% reduction, which was not statistically significant. The 40.7% of participants who used aspirin also showed a reduced risk of Alzheimer’s, even when they used no other NSAIDs. By contrast, there was no association with the use of paracetamol.

What interpretations did the researchers draw from these results?

The researchers conclude that in their study NSAID use reduced the risk of Alzheimer’s disease. However, there was no apparent advantage for this outcome in the subset of users of NSAIDs shown to selectively lower the peptide Aβ42 – SALAs, suggesting that all conventional NSAIDs, including aspirin, have a similar protective effect in humans.

What does the NHS Knowledge Service make of this study?

This study has collected data from some large prospective studies of NSAID drug use. The results have shown no difference between the subgroups of users of each drug type. Such evidence of no difference may be because there really is no difference or it could be because the studies were not sufficiently large or similar enough to detect a difference if one existed. Some limitations to the individual studies and the methods of this review should be considered;

• Although the researchers say that the studies were similar enough to allow pooling of the results, there were some differences in the way the studies collected data and defined the current use of NSAIDs. Three studies assessed current use, one assessed current use plus use over the previous two weeks, one assessed use over the prior two years and one defined use as current or former use of four or more doses per week for one month or longer. These differences may have affected the reliability of combining the results of each study into a summary measure.
• There may have been problems for some patients in the early stages of Alzheimer’s disease in recalling previous NSAID use and this may have affected the results.
• It is unclear how the four studies that were not included in the analysis because the investigators declined to contribute, may have affected the results had they been included.
• The researchers included studies in which they were aware that data had been collected on Alzheimer’s using recognised scoring criteria and which had been related to details of NSAID and aspirin use. They obtained results by contacting known study authors, but may have missed other published studies that investigated similar outcomes. These may have been identified through a more thorough systematic search of the literature using electronic databases.

In general, this large review of observational data suggests that there is no advantage for the SALA group of drugs over those known as non-SALA drugs for the prevention of Alzheimer’s disease. Practically, even though there was a reduction in Alzheimer’s shown for all of the NSAID drugs, the drugs should not be used in the hope that they prevent dementia. This was a review of selected studies and it is important to balance the risk from bleeding against any benefits, which may yet be proven in randomised trials.