A study examining the relationship between the use of non-steroidal anti-inflammatory (NSAID) medication over certain time frames and the risk for dementia found that – after analysing data from 11 745 participants – using NSAIDs for longer than two years appeared to lower the risk of dementia.
While these findings from a team from The Netherlands “further contribute to the understanding of chronic inflammation as a target for additional study and intervention”, a cure for all-cause dementia as well as Alzheimer’s, remains elusive, reports MedicalNewsToday.
A leading scientist, however, believes one is out there somewhere, “but this will require new ways of doing clinical trials and significant changes in the established regulatory, statistical and operational procedures of clinical research”.
Risks
In the latest study, shorter time frames were associated with a slight increase in dementia risk, said the researchers, adding that the cumulative amount of NSAIDs did not decrease the risk.
This suggests that time of exposure matters regarding the potential benefits, they wrote in the Journal of the American Geriatrics Society, and that inflammation may be a critical piece in the development of the disease.
Their study, which sought to understand more about the long-term impact of NSAIDs on dementia risk, used data from participants in the Rotterdam Study, a current prospective population-based study in The Netherlands.
For the current analysis, they included participants who did not have baseline dementia, including 11 745 people in the final analysis based on all of their criteria. The average age was around 66.
Pharmacy records were used to examine participants’ oral NSAID use: NSAIDs were split into two categories: beta-amyloid-42-lowering or non-beta-amyloid-42-lowering.
This distinction had to do with previous data on how certain NSAIDs may affect amyloid levels in the brain, the accumulation of beta-amyloid being tied to increased dementia risk.
Participants underwent regular dementia screening. Researchers also had data on several health indicators and lifestyle factors, and had divided participant NSAID use into four main categories:
1. no use
2. short-term use (less than one month)
3. intermediate-term use, which was one month to two years
4. long-term use (more than two years).
Additional analyses used other time frames to allow for more assessment, while several different models examined the relationship between all-cause dementia and time of NSAID use and to account for different factors.
The study team also conducted several sensitivity analyses – looking at the relationship between NSAIDs and Alzheimer’s, and the association between dementia and salicylates, which are the substances found in medications like aspirin.
Follow up
There was an average follow-up time of 14.5 years, during which time, 81.3% of participants used NSAIDs.
Just under 6% used only NSAIDs without any beta-amyloid-42-lowering properties, and about 46% used a combination of non-beta-amyloid-42-lowering and beta-amyloid-42-lowering NSAIDs.
Just more than 2 000 participants developed dementia.
Short-term and intermediate-term use of NSAIDs slightly increased the risk for all-cause dementia, while long-term NSAID use decreased the risk.
The association between long-term NSAID use and reduced risk for Alzheimer’s disease was even stronger than for all-cause dementia.
The scientists also found that non-beta-amyloid-42-lowering NSAIDs appeared to lower the risk for all-cause dementia more than beta-amyloid-42-lowering NSAIDs.
They did not find an association between cumulative NSAID dose and dementia risk reduction, and also found that NSAIDs did not appear to lower the risk for all-cause dementia among participants who had the APOE-e4 allele.
The APOE-e4 allele is a form of a gene, and having it can increase a person’s risk for Alzheimer’s disease.
Vernon Williams, MD, a sports neurologist and founding director of the Centre for Sports Neurology and Pain Medicine at Cedars-Sinai Orthopaedics in Los Angeles, who was not involved in this research, said:
“This is another piece of evidence that will hopefully contribute to our understanding of dementia and opportunities to reduce risk. There are some limitations to an observational study like this, but overall, it seems to be in line with other evidence suggesting inflammation as having a key role in neurodegeneration (…) It further contributes to the understanding of chronic inflammation as a target for additional study and intervention.”
Study limitations
The study had several limitations: it included only individuals from The Netherlands, most of them white, so the results cannot be generalised to all people.
There was also some missing data for participants, and some information, like alcohol use, was self-reported. The study also cannot establish cause.
Additionally, the study was also able to only look at prescription use of NSAIDs, even though they’re also available over the counter. It’s possible some participants, whom researchers noted not to be taking NSAIDs, were actually doing so.
Regarding the diagnosis of Alzheimer’s, researchers could not include biomarkers, so misclassification is possible – and the possibility that participants who used NSAIDs long-term were healthier than those who only used NSAIDs in the short term.
Researchers account for the use of aspirin in one of the models, and did not categorise it as an NSAID. When analysing aspirin separately, they did not find an association between long-term use and reduced dementia risk.
The authors note that with the slight increase in risk for all-cause dementia from short-term and intermediate-term use, the “effect estimates were too small to obtain clinical relevance”.
Furthermore, they acknowledge that looking at all-cause dementia includes dementia subtypes where NSAIDs may have no impact. Thus, if these subtypes are included in the analysis, it is possible to have weakened effect estimates.
Finally, it is also possible that researchers did not account for certain relevant factors or that participants were not taking prescribed medication.
Study author Mohammad Arfan Ikram, MD, PhD, professor of epidemiology at the Erasmus University Medical Centre in The Netherlands, further noted several limitations:
“The main one is that it is an observational study, so people were not randomised. In other words, there is a reason why these individuals did versus did not take NSAIDs. Reasons may include arthritis, pain, or other inflammatory conditions. It is impossible in such studies to fully adjust for the effect of these other conditions. If these other conditions are in any way linked to dementia, it may distort our findings.”
Meaning for clinical practice
Overall, the research highlights a potential benefit of NSAID use in the long term, and could also help with creating therapeutics that protect against dementia.
Williams noted that it “suggests exposure to anti-inflammatories over time may be of potential benefit”.
“However,” he cautioned, “there are potential side effects and risks associated with currently available NSAIDs. The findings that the association was stronger for non-amyloid lowering NSAIDs than those with known amyloid lowering properties is interesting, implying that the mechanism of action may not be entirely related to amyloid reduction. So other anti-inflammatory pathways and/or genetic risk factor effects may be contributing to the benefits.”
More research is needed before making major changes to clinical recommendations, and the study itself also notes that it may be inappropriate for older adults to use NSAIDs, he added.
No silver bullet
Why are researchers still struggling to cure Alzeheimer’s, arguably one of the most important diseases confronting humankind disease? asks Canadian scientist Donald Weaver in The Conversation.
Despite decades of research, there is still no curative treatment, no “magic bullet” that stops this degenerative brain disease in its tracks, he writes.
Finding the magic bullet has proving to be an immense challenge. A magic bullet is a drug that completely cures a disease, doing so with few if any side-effects.
Penicillin is a great example. It kills bacteria, leading to cures for infectious diseases like strep throat, while causing minimal side-effects.
Aspirin, on the other hand, is definitely not a magic bullet. It is a symptomatic agent reducing fever and pain in diseases like strep throat, but fails to actually cure the underlying disease.
Alzheimer’s needs a magic bullet, not an aspirin-like agent.
In the 1980s, it was thought to be caused by a deficiency of a brain chemical messenger called acetylcholine. This theory, called the “cholinergic hypothesis”, inspired extensive research resulting in several drugs being introduced in the late 1990s, namely donepezil, rivastigmine and galantamine.
Regrettably, these three agents offer only limited symptomatic effects, temporarily improving memory and cognition but doing nothing to address the underlying disease processes. They are “aspirins”.
Theories of Alzheimer’s disease
Over the past 25 years, the search for the magic bullet for Alzheimer’s has intensified.
Disappointingly, since 2010, more than 200 magic bullet discovery programmes have failed. Although these unsuccessful drugs targeted a variety of different approaches to Alzheimer’s, many were designed to prevent the folding and aggregation of beta-amyloid protein.
This is the so-called “amyloid hypothesis”, which conjectures that Alzheimer’s is caused by the aberrant production of a protein called beta-amyloid that twists itself into an abnormal shape to form disease causing brain toxic clumps.
Though most amyloid-targeting drugs based have failed, two recent therapeutics, lecanemab and donanemab, have shown limited success, but demonstrate significant side-effects and definitely are not cures. The search continues.
Why are we struggling?
The brain is the most complex structure in the human body and Alzheimer’s is arguably one of the most complex diseases of the brain. Finding a drug to fix such a complicated network is daunting.
For years, scientists have been so focused on devising treatments to block brain-damaging amyloid clumps that we have fallen into an intellectual rut, sometimes neglecting other worthwhile explanations. And there is a wealth of viable alternatives.
For example, a growing number of scientists think Alzheimer’s is caused by inflammation, like arthritis of the brain.
Similarly, others regard it as an autoimmune disorder of the brain. Some maintain it’s the end-result of a brain infection, with bacteria from the mouth as the potential culprit.
Others believe Alzheimer’s is primarily a disease of miniscule cellular structures called mitochondria – the energy factories that convert glucose from our food and oxygen from the air into the energy required for thinking and remembering.
Still others suggest the disease may arise from the brain’s mishandling of metals, possibly copper or iron.
This diverse range of mechanisms reflects our still evolving but currently inadequate understanding of the complex causes of Alzheimer’s. Making matters worse, these multiple disease processes – amyloid clumping, inflammation, diseased mitochondria – probably begin 20 to 30 years before the afflicted person becomes symptomatic.
The ‘shotgun’ approach
Perhaps it’s naive to think we can ever devise a magic bullet for Alzheimer’s.
Consider another common medical disorder, high blood pressure. There is no single magic bullet for treating hypertension. No such drug exists. Rather, there are many different drugs – working through different mechanisms to reduce blood pressure – which are often used in combination.
If we cannot find a magic bullet for hypertension, which is mechanistically trivial compared with Alzheimer’s, what makes us think we can find one for such a complex brain disease?
But all is not lost. Diseases like hypertension or cancer in which multiple complementary drugs are successfully co-administered may provide a valuable clue. The answer may lie in a magic shotgun blast, as opposed a one bullet. Like a person trying in vain to shoot a tin can off a fence with a single shot, sometimes it’s simpler to use a shotgun blast.
Shotgun shells, after all, usually contain multiple small shot pellets that hit a broader area than a single bullet. In Alzheimer’s, a strong case exists for concurrently using multiple drugs hitting multiple targets – a combination therapy shotgun blast hitting beta-amyloid, inflammation and mitochondria targets (or others) all at once. This would seem to offer a better shot at a cure.
However, this will require new ways of doing clinical trials and significant changes in the established regulatory, statistical and operational procedures of clinical research.
But we must make these changes, whether we like it or not. Passionate scientists with polarised points of view may need to accommodate different perspectives and competitors may need to collaborate.
We may already have curative drugs, we just haven’t used them in the right combination. For the millions of people living with Alzheimer’s, we need to be more innovative and less dogmatic, and discover the path to achieving that goal.
Donald Weaver, Professor of Chemistry and Senior Scientist of the Krembil Research Institute, University Health Network, University of Toronto
Study details
Long-Term Exposure to Non-Steroidal Anti-Inflammatory Medication in Relation to Dementia Risk
Ilse vom Hofe, Bruno Stricker, M. Kamran Ikram, Frank Wolters, M. Arfan Ikram.
Published in Journal of the American Geriatrics Society on 4 March 2025
ABSTRACT
Background
Non-steroidal anti-inflammatory (NSAID) medication could reduce dementia risk due to anti-inflammatory and possibly amyloid-lowering properties. However, the results of observational studies and short-term randomized-controlled trials have been inconsistent, and duration and dose–response relationships are still unclear.
Methods
We included 11,745 dementia-free participants from the prospective population-based Rotterdam Study (59.5% female, mean age 66.2 years). NSAID use from 1991 was derived from pharmacy dispensing records, from which we determined cumulative duration and dose. We defined four mutually exclusive categories of cumulative use: non-use, short-term use (< 1 month), intermediate-term use (between 1 and 24 months), and long-term use (> 24 months). We determined the association with dementia risk until 2020 using Cox regression models, including NSAID use as a time-varying exposure. Models were adjusted for lifestyle factors, comorbidity, and comedication use. We repeated the analyses stratified by previously established amyloid-β lowering properties of different NSAIDs.
Results
During an average follow-up period of 14.5 years, a total of 9520 (81.1%) participants had used NSAIDs at any given time, and 2091 participants developed dementia. Use of NSAIDs was associated with lower dementia risk for long-term users (HR [95% CI]: 0.88 [0.84–0.91]), and a small increased risk with short-term use (HR [95% CI]: 1.04 [1.02–1.07]) or intermediate-term use (HR: 1.04 [1.02–1.06]). The cumulative dose of NSAIDs was not associated with decreased dementia risk (HR for ≤ 25th percentile: 1.06 [1.03–1.09], 26–50th percentile: 1.02 [0.99–1.05], 51–75th percentile: 1.03 [0.99–1.06], > 75th percentile: 0.99 [0.96–1.02]). Associations were somewhat stronger for long-term use of NSAIDs without known effects on amyloid-β than for amyloid-lowering NSAIDs (HR [95% CI]: 0.79 [0.74–0.85] versus 0.89 [0.85;0.93]).
Conclusion
Long-term NSAID use, but not cumulative dose, was associated with decreased dementia risk. This suggests that prolonged rather than intensive exposure to anti-inflammatory medication may hold potential for dementia prevention.
See more from MedicalBrief archives:
Aspirin possibly has ‘modest effect’ in dementia prevention and cognitive impairment
New drugs a boost for Alzheimer’s treatment but finding cause must be a priority
New charting tool to predict risk of Alzheimer’s