Table 2.

Selected epidemiological studies, meta-analyses, and clinical trials for the use of NSAIDs in AD.

Title	Type of study	Study population	NSAIDs investigated	Main conclusions	Comment
Aspirin, steroidal and non-steroidal anti-inflammatory drugs for the treatment of Alzheimer’s disease5	Cochrane review, included 14 randomized controlled trials	The number of participants was 352, 138, and 1745 for aspirin, steroid, and NSAID groups, respectively.	- Aspirin - Steroids - “traditional” NSAIDs (naproxen, indomethacin, ibuprofen, piroxicam, nimesulide) - selective COX-2 inhibitors	There was no significant improvement of cognitive decline in AD patients for any NSAID.	Review did not include subgroup analysis for single NSAIDs.
NSAID Exposure and Risk of Alzheimer’s Disease: An Updated Meta-Analysis From Cohort Studies6	Meta-analysis included 16 cohort studies	236,022 participants	- Aspirin - Other NSAIDs	Current or former NSAID use was associated with a significant risk reduction of developing AD in comparison with participants who did not take NSAIDs.	- There was no risk reduction for aspirin alone, or for other NSAIDs when analyzed separateley from aspirin. - The study did not include separate subgroup analyses for specific NSAIDs other than aspirin.
Protective effects of NSAIDs on the development of Alzheimer disease90	Retrospective case control study	246,199 veterans	- Ibuprofen - Other NSAIDs	The odds ratio (OR) for AD decreased significantly for patients who received NSAIDs for more than 5 years. Effect was more pronounced for ibuprofen.	The study did not report hazard ratios (HR) to evaluate time-to-event data, and information about the progression of AD was therefore not available.
Clinical trial of indomethacin in Alzheimer’s disease92	Double-blind, placebo-controlled study over 6 months;	AD patients, 160 participants	Indomethacin	Indomethacin slows down progression of cognitive decline in AD patients.	An important caveat of this study is the limited scale/ number of participants and study duration.
A randomized controlled study on effects of ibuprofen on cognitive progression of Alzheimer’s disease93	Randomized, controlled study over 12 months	Patients with mild to moderate AD, 130 participants	Ibuprofen versus placebo	There was no difference of cognitive decline between treatment and placebo group.	Participants who were ApoE ε4 carriers treated with ibuprofen did not have a significant cognitive decline.
Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial94	Randomized, controlled study over 12 months	Mild to moderate AD, 351 participants	Rofecoxib or naproxen versus placebo	There was no benefit of treatment with NSAIDs for cognitive function.	—
Rofecoxib: no effect on Alzheimer’s disease in a 1-year, randomized, blinded, controlled study96	Randomized, controlled trial over 12 months	Mild or moderate AD in 692 patients	Rofecoxib versus placebo	There was no benefit of Rofecoxib on cognitive function.	The results persisted after adjusting for severity of dementia at baseline, presence of ApoE ε4 allele, and donepezil use.
Long-term efficacy and safety of celecoxib in Alzheimer’s disease97	Randomized, controlled trial over the course of 52 weeks	Mild to moderate AD, 308 patients completed treatment	Celecoxib versus placebo	There was no benefit of celecoxib on cognitive function.	—
Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial98	Randomized, controlled study over a duration of 18 months	Mild AD, 1649 patients were included in the study	Tarenflurbil versus placebo	There was no benefit of NSAID on cognitive decline or loss of activities of daily living.	—
Naproxen and celecoxib do not prevent AD in early results from a randomized controlled trial99	ADAPT (Alzheimer’s Disease Anti-inflammatory Prevention Trial), randomized, controlled trial for duration of 6 months	Recruitment of 2528 asymptomatic individuals with at least one first-degree relative with AD-like dementia	Naproxen or celecoxib versus placebo	A trend toward efficacy for both NSAIDs was present, however there was no clear benefit of NSAIDs on cognitive function.	Recruitment started in early 2001. The study was suspended in 2004 due to significantly increased cardiovascular risk of celecoxib.
Non-steroidal anti-inflammatory drug (NSAID) use and Alzheimer disease in community-dwelling elderly patients101	Cross-sectional retrospective study	2708 study individuals	- Aspirin - Non-aspirin (diclofenac, ketorolac, piroxicam)	NSAID users had a 50% lower risk for being affected by AD. In subgroup analyses, the most significant risk reduction was seen for diclofenac.	After correction for confounders, the association between NSAID use and lower risk for AD was significant only for non-aspirin NSAID use.
A double-blind, placebo-controlled trial of diclofenac/misoprostol in Alzheimer’s disease102	Randomized controlled pilot study over 25 weeks	Mild to moderate AD, 41 patients	Diclofenac 50 mg daily vs control group	Trend for improved cognition with diclofenac after 6 months (compared to declined MMSE in the control group)	An important caveat of this study is the very low number of study participants.
Diclofenac reduces the risk of Alzheimer’s disease: a pilot analysis of NSAIDs in two US veteran populations7	Retrospective cohort study	AD patients (1431 receiving diclofenac, versus 14,646 receiving etodolac, and 12,203 receiving naproxen for at least 1 year)	- Diclofenac (average of 131.3 mg daily) versus naproxen or etodolac	The incidence rates for AD in both the naproxen and etodolac group were significantly higher than for diclofenac.	Study had some limitations: –Small sample size for diclofenac –Retrospective design –Inclusion of patients based on chart review only

AD, Alzheimer’s Disease; COX-2, cyclooxygenase 2; MMSE, mini-mental state examination; NSAID, non-steroidal anti-inflammatory drug.