Dementia is a worldwide concern. Its global prevalence is increasing. At present, there is no medication licensed to prevent or delay the onset of dementia. Inflammation has been suggested as a key factor in dementia pathogenesis. Therefore, medications with anti‐inflammatory properties could be beneficial for dementia prevention.
To evaluate the effectiveness and adverse effects of aspirin and other non‐steroidal anti‐inflammatory drugs (NSAIDs) for the primary or secondary prevention of dementia.
We searched ALOIS, the specialised register of the Cochrane Dementia and Cognitive Improvement Group up to 9 January 2020. ALOIS contains records of clinical trials identified from monthly searches of several major healthcare databases, trial registries and grey literature sources. We ran additional searches across MEDLINE (OvidSP), Embase (OvidSP) and six other databases to ensure that the searches were as comprehensive and up‐to‐date as possible. We also reviewed citations of reference lists of included studies.
We searched for randomised controlled trials (RCTs) and controlled clinical trials (CCTs) comparing aspirin or other NSAIDs with placebo for the primary or secondary prevention of dementia. We included trials with cognitively healthy participants (primary prevention) or participants with mild cognitive impairment (MCI) or cognitive complaints (secondary prevention).
Data collection and analysis
We used standard methodological procedures according to the Cochrane Handbook for Systematic Reviews of Interventions. We rated the strength of evidence for each outcome using the GRADE approach.
We included four RCTs with 23,187 participants. Because of the diversity of these trials, we did not combine data to give summary estimates, but presented a narrative description of the evidence.
We identified one trial (19,114 participants) comparing low‐dose aspirin (100 mg once daily) to placebo. Participants were aged 70 years or older with no history of dementia, cardiovascular disease or physical disability. Interim analysis indicated no significant treatment effect and the trial was terminated slightly early after a median of 4.7 years’ follow‐up. There was no evidence of a difference in incidence of dementia between aspirin and placebo groups (risk ratio (RR) 0.98, 95% CI 0.83 to 1.15; high‐certainty evidence). Participants allocated aspirin had higher rates of major bleeding (RR 1.37, 95% CI 1.17 to 1.60, high‐certainty evidence) and slightly higher mortality (RR 1.14, 95% CI 1.01 to 1.28; high‐certainty evidence). There was no evidence of a difference in activities of daily living between groups (RR 0.84, 95% CI 0.70 to 1.02; high‐certainty evidence).
We identified three trials comparing non‐aspirin NSAIDs to placebo. All three trials were terminated early due to adverse events associated with NSAIDs reported in other trials.
One trial (2528 participants) investigated the cyclo‐oxygenase‐2 (COX‐2) inhibitor celecoxib (200 mg twice daily) and the non‐selective NSAID naproxen (220 mg twice daily) for preventing dementia in cognitively healthy older adults with a family history of Alzheimer’s disease (AD). Median follow‐up was 734 days. Combining both NSAID treatment arms, there was no evidence of a difference in the incidence of AD between participants allocated NSAIDs and those allocated placebo (RR 1.91, 95% CI 0.89 to 4.10; moderate‐certainty evidence). There was also no evidence of a difference in rates of myocardial infarction (RR 1.21, 95% CI 0.61 to 2.40), stroke (RR 1.82, 95% CI 0.76 to 4.37) or mortality (RR 1.37, 95% CI 0.78 to 2.43) between treatment groups (all moderate‐certainty evidence).
One trial (88 participants) assessed the effectiveness of celecoxib (200 mg or 400 mg daily) in delaying cognitive decline in participants aged 40 to 81 years with mild age‐related memory loss but normal memory performance scores. Mean duration of follow‐up was 17.6 months in the celecoxib group and 18.1 months in the placebo group. There was no evidence of a difference between groups in test scores in any of six cognitive domains. Participants allocated celecoxib experienced more gastrointestinal adverse events than those allocated placebo (RR 2.66, 95% CI 1.05 to 6.75; low‐certainty evidence).
One trial (1457 participants) assessed the effectiveness of the COX‐2 inhibitor rofecoxib (25 mg once daily) in delaying or preventing a diagnosis of AD in participants with MCI. Median duration of study participation was 115 weeks in the rofecoxib group and 130 weeks in the placebo group. There was a higher incidence of AD in the rofecoxib than the placebo group (RR 1.32, 95% CI 1.01 to 1.72; moderate‐certainty evidence). There was no evidence of a difference between groups in cardiovascular adverse events (RR 1.07, 95% CI 0.68 to 1.66; moderate‐certainty evidence) or mortality (RR 1.62, 95% CI 0.85 to 3.05; moderate‐certainty evidence). Participants allocated rofecoxib had more upper gastrointestinal adverse events (RR 3.53, 95% CI 1.17 to 10.68; moderate‐certainty evidence). Reported annual mean difference scores showed no evidence of a difference between groups in activities of daily living (year 1: no data available; year 2: 0.0, 95% CI –0.1 to 0.2; year 3: 0.1, 95% CI –0.1 to 0.3; year 4: 0.1, 95% CI –0.1 to 0.4; moderate‐certainty evidence).
There is no evidence to support the use of low‐dose aspirin or other NSAIDs of any class (celecoxib, rofecoxib or naproxen) for the prevention of dementia, but there was evidence of harm. Although there were limitations in the available evidence, it seems unlikely that there is any need for further trials of low‐dose aspirin for dementia prevention. If future studies of NSAIDs for dementia prevention are planned, they will need to be cognisant of the safety concerns arising from the existing studies.
Plain language summary
Aspirin and other non‐steroidal anti‐inflammatory drugs for the prevention of dementia
The purpose of this review was to investigate if aspirin and other non‐steroidal anti‐inflammatory drugs (NSAIDs) could help in the prevention of dementia.
Dementia is a worldwide healthcare concern. At present, there is no medicine that is proven to delay or prevent the onset of dementia. The biology of dementia is still poorly understood. However, there are reasons to believe that inflammation may be partly responsible for some of the brain changes seen in dementia. There are many medicines that have anti‐inflammatory properties, including aspirin and NSAIDs that are often sold as pain killers. We wanted to see if these medicines had any effect on developing dementia. These medicines have a few potential side effects, including heart attack and bleeding, so we also assessed for any harmful effects of the medicines.
We searched for relevant studies that had been published up to January 2020. We found four trials that met the inclusion criteria for this review (23,187 people). One trial was undertaken in the USA and Australia and three in the USA only. The trials included different populations. One was of aspirin in healthy people with no history of dementia, cardiovascular disease or physical disability. The other three were of NSAIDs other than aspirin and were conducted in healthy people with a family history of Alzheimer’s disease, people with self‐reported memory loss and people with mild cognitive impairment (a slight but noticeable and measurable decline in cognitive abilities, including memory and thinking skills). All of the included studies had limitations. The study of aspirin was stopped early due to ineffectiveness. The three studies of other NSAIDs (celecoxib, naproxen and rofecoxib) were stopped early due to concerns around the safety.
Key results and quality of the evidence
The aspirin study found that low‐dose aspirin (100 mg daily) did not prevent dementia in healthy older people, but resulted in higher rates of death and major bleeding compared to placebo (pretend tablet). We were very confident in this result. The NSAID studies did not find any evidence of a difference between the NSAIDs and placebo in terms of reducing the numbers of people developing dementia. In fact, in one of the studies, more people developed dementia in the NSAID group. One of the included NSAIDs studies reported more stomach bleeding and another reported other stomach problems, such as pain, nausea and gastritis. Other side effects were similar between groups. We were moderately confident in most of the results on NSAIDs.
This review found no evidence to support the use of either aspirin or other NSAIDs for the prevention of dementia and, in fact, there was some suggestion that they may cause harm. The studies had limitations, but, given the concerns over safety, further studies of low‐dose aspirin for dementia prevention seem unlikely. If future studies of NSAIDs for dementia prevention are planned, then these will need to be mindful of the safety concerns arising from the studies included in this review and from other studies of the same medicines.