Longevity Briefs: Could Common Painkillers Prevent Dementia?

Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

There are currently no curative or preventative treatments for dementia – the best that modern medicine can do is to slow down the progression of the disease. However, we know that a large proportion of dementia cases are preventable through lifestyle modifications. One way to reduce the risk of dementia may be to limit inflammation, which research suggests may play a crucial role in neurodegeneration within the brain. We already have safe and effective drugs for suppressing inflammation, so could these pre-existing drugs hold untapped potential to prevent dementia?

Non-steroidal anti-inflammatory drugs (NSAIDs) are a common class of anti-inflammatory drugs that include ibuprofen and aspirin. In animal studies, NSAIDs have been found to reduce amyloid-β plaque formation (a hallmark of Alzheimer’s disease), but human studies have yielded inconsistent results. Much of this inconsistency probably comes down to variable dosing and patients not receiving NSAIDs for long enough for them to have an effect. In this study, researchers set out to resolve some of these problems by investigating the long-term effects of NSAID use on dementia risk.

The discovery:

Researchers analysed data from 11,745 dementia-free participants with an average (mean) age of 66.2 years. They followed them up for an average of 14.5 years and tracked their use of NSAIDs from pharmacy records that included treatment duration and dose. They then categorized participants into four groups based on this data: non-use, short-term (<1 month), intermediate-term (1–24 months), and long-term (>24 months) use. This duration was measured cumulatively, so participants did not need to be taking NSAIDs for 24 consecutive months to be categorized as long-term users, for example.

After controlling for confounding factors, researchers found that long-term NSAID use (>24 months) was associated with a statistically significant reduction in all-cause dementia and Alzheimer’s risk. Specifically, those taking NSAIDs for more than 24 months were 12% less likely to get dementia and 21% less likely to get Alzheimer’s compared with those who did not take NSAIDs. A higher cumulative dose of NSAIDs was not associated with reduced dementia risk – only long treatment duration. The apparent risk reduction also didn’t seem to be explained by reductions in amyloid-β, as when the researchers categorized NSAIDs into those that were shown to reduce amyloid and those that were not, they found that non amyloid-lowering NSAIDs actually had a stronger association with risk reduction. They also found that long-term NSAID use was only associated with reduced dementia risk in those without the APOE-ε4 allele, a gene variant that greatly increases Alzheimer’s risk.

Interestingly, short-term and intermediate-term use were actually associated with a small but statistically significant increase in risk of 4%.

The implications:

This study suggests that prolonged use of NSAIDs may reduce dementia risk, while shorter term use is associated with slightly increased risk. This benefit appears to be linked to duration, not dose, meaning that intensive (but shorter term) use of NSAIDs does not achieve the same effect as longer term treatment. It also suggests that these apparent benefits can be attributed in part to the effects of NSAIDs independent of reductions in amyloid plaque. In other words, it is likely that long-term protection against inflammation in the brain played a role.

So, should everyone be on long term NSAID treatments? Definitely not – long-term NSAID use is associated with relatively common and potentially severe gastrointestinal, renal and cardiovascular side effects. However, the fact that they seem to reduce dementia risk should prompt further investigation into targeting inflammation as a way of preventing dementia. The most effective ways to prevent inflammation naturally include exercise, an anti-inflammatory diet (which generally means one rich in plants and fish) and avoidance of inflammatory stimuli like pollution.

Finally, we should note that since this study was observational in nature, it’s not possible to conclude that the relationships here were fully causative. Even though the researchers attempted to control for confounding factors, they still could have played some role. For example, people who are taking long-term NSAIDs but get severe side effects will stop taking them, as will those who start taking other drugs that interact with NSAIDs. This means that studying people on long-term NSAIDs selects for a population that may actually be healthier than short-term users in some ways, and therefore less likely to develop dementia.