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AlzRisk Risk Factor Literature Search Strategy and Results

Risk Factor: Non-Steroidal Anti-Inflammatory Drugs
  (anti-inflammatory medication, NSAIDs)
Risk Factor Type: Medications
Current Understanding:
The tables below summarize results from a modest number of reports that collectively show no association between use of non-steroidal anti-inflammatory drugs (NSAIDs) and the risk of Alzheimer disease dementia (AD) and total dementia. The results from observational studies are consistent with null findings from a randomized, double-blinded, placebo-controlled trial involving naproxen and celecoxib, which was halted early for safety concerns. While non-aspirin NSAID use (current, ever) assessed at the time of AD evaluation showed a protective association against AD risk, non-aspirin NSAID use assessed in years prior to AD evaluation showed no such association. Because by definition AD does not have an acute onset, but rather progresses over a number of years, the discrepancy in findings indicates that the time-updated analyses may not accurately reflect the association between NSAID use and AD risk. Studies that report time-updated results are particularly susceptible to bias from reverse causation, as individuals with cognitive decline may be less likely to be taking NSAIDs. Observational studies involving aspirin use show a marginally protective effect, although these results may be undermined by confounding by indication, healthy user bias, or selection bias. Because there are known risks to NSAID use, including cardiovascular events and gastrointestinal bleeding and ulceration, future studies examining the effect of NSAIDs by dose, duration, and timing on AD risk will likely be limited to observational studies. Because of these significant safety concerns and lack of evidence of any benefit, NSAID use is definitely not recommended to prevent AD. For a more in depth commentary, please see the Discussion.
Last Search Completed: 04 April 2015

Risk Factor Overview


We searched MEDLINE and EMBASE for peer-reviewed articles reporting on the association between non-steroidal anti-inflammatory drugs (NSAIDS) and Alzheimer’s disease (AD) incidence in cohort or nested case-control studies. The search returned 808 unique citations that, after title and abstract review against our inclusion criteria [Make hyperlink], were narrowed down to 51 citations for full-text review. Of these, 19 fully met criteria for inclusion in our summary tables. Among the included were four articles from the ADAPT trial, and another two from the Rotterdam study. We review such potentially duplicate articles on a case-by-case basis, and select the most informative article(s) based on sample size, follow-up time, exposure assessment or modeling, and appropriateness of analytic methods. Please see our methods section for more detail on our general systematic review methods.

We ran an update of the search in Pubmed and Embase on April 1, 2015, which covered articles published between April 12, 2014 and April 1, 2015. The new search returned 19 new citations on Pubmed. We excluded 18 citations that did not meet our inclusion criteria (e.g., topic not appropriate, mouse studies). One study was excluded after full text review because it did not meet inclusion criteria. The same excluded study was among the 11 new citations on Embase that returned on the updated search. We excluded the 10 remaining citations that did not meet our inclusion criteria. No articles were added to our Alzrisk tables from this updated search.

Search & Review Flowchart
Search Strategy
Selection of Papers Reporting on Data from the Same Cohort

Search Strategy Flowchart

Search Strategy

Using our systematic review methods, we developed a search strategy (table below) for Pubmed and Embase.

Search Strategy Table

Selection of Papers Reporting on Data from the Same Cohort

Some cohort studies produced multiple articles reporting on the association between alcohol use and risk for Alzheimer’s disease. To avoid presenting duplicate results, we reviewed such articles on a case-by-case basis and selected the most informative article(s) based on sample size, follow-up time, exposure assessment or modeling, and appropriateness of analytic methods.

Alzheimer's Disease Anti-Inflammatory Prevention Trial (ADAPT)

The ADAPT trial was a placebo randomized trial of naproxen and celecoxib among persons age 70 and above with a family history of dementia. The ADAPT Research Group published preliminary findings in 2007, and the first set of results in 2009 after the trial was halted early amid rising concerns about the safety of Cox-2 inhibitors. Afterwards, some studies followed patients who were enrolled in the trial and reported their outcomes, including Breitner 2011 and Dyre 2012. The latest and most comprehensive follow-up study was reported by the ADAPT Research Group in 2013, and is the ADAPT publication we selected to represent this study.

Rotterdam Study

Two papers were published using data from the Rotterdam Study. In’t Veld 1998 used a nested case-control analysis to study duration of NSAID use for up to 3 years, with varying length between the time of use and time of diagnosis (0.5 to 10 years). Later, In’t Veld 2001 reported results from a cohort analysis for up to 8 years use of aspirin or non-aspirin NSAIDs with four times as many AD cases. We included both studies because they provided unique information on NSAID effects for various durations of use and time since use.


ADAPT. Results of a follow-up study to the randomized Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT). Alzheimers Dement, 2013. 9(6): p. 714-23.
Breitner, J.C., et al. Risk of dementia and AD with prior exposure to NSAIDs in an elderly community-based cohort. Neurology, 2009. 72(22): p. 1899-905.
Drye, L.T. and P.P. Zandi. Role of APOE and Age at Enrollment in the Alzheimer's Disease Anti-Inflammatory Prevention Trial (ADAPT). Dement Geriatr Cogn Dis Extra, 5012. 2(1): p. 304-11.
Group, A.R., et al. Naproxen and celecoxib do not prevent AD in early results from a randomized controlled trial. Neurology, 2007. 68(21): p. 1800-8.
Szekely, C. A., R. C. Green, et al. (2008). "No advantage of A beta 42-lowering NSAIDs for prevention of Alzheimer dementia in six pooled cohort studies." Neurology 70(24): 2291-2298.