Nonsteroidal Anti-Inflammatory Drugs for the Prevention of Alzheimer’s Disease: A Systematic Review

Abstract

Objective: Alzheimer’s disease, the most prevalent dementia, is a prominent source of chronic illness in the elderly. Laboratory evidence suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) might prevent the onset of Alzheimer’s disease. Since the early 1990s, numerous observational epidemiological studies have also investigated this possibility. The purpose of this meta-analysis is to summarize and evaluate available evidence regarding exposure to nonaspirin NSAIDs and risk of Alzheimer’s disease using meta-analyses of published studies. Methods: A systematic search was conducted using Medline, Biological Abstracts, and the Cochrane Library for publications from 1960 onwards. All cross-sectional, retrospective, or prospective observational studies of Alzheimer’s disease in relation to NSAID exposure were included in the analysis. At least 2 of 4 independent reviewers characterized each study by source of data and design, including method of classifying exposure and outcome, and evaluated the studies for eligibility. Discrepancies were resolved by consensus of all 4 reviewers. Results: Of 38 publications, 11 met the qualitative criteria for inclusion in the meta-analysis. For the 3 case-control and 4 cross-sectional studies, the combined risk estimate for development of Alzheimer’s disease was 0.51 (95% CI = 0.40–0.66) for NSAID exposure. In the prospective studies, the estimate was 0.74 (95% CI = 0.62–0.89) for the 4 studies reporting lifetime NSAID exposure and it was 0.42 (95% CI = 0.26–0.66) for the 3 studies reporting a duration of use of 2 or more years. Conclusions: Based on analysis of prospective and nonprospective studies, NSAID exposure was associated with decreased risk of Alzheimer’s disease. An issue that requires further exploration in future trials or observational studies is the temporal relationship between NSAID exposure and protection against Alzheimer’s disease.

Steroid and nonsteroidal anti-inflammatory drugs, cognitive decline, and dementia

“…In observational studies, exposure to NSAID were possibly associated with decreased risk for cognitive decline and AD, depending on class and dose, longer duration or younger age at intake, and APO4 vulnerability (Szekely et al, 2004;Szekely et al, 2008;Vlad et al, 2008;de Craen et al, 2005;Gorelick, 2010;Szekely and Zandi, 2010). Conversely, the three randomized controlled trials performed using rofecoxib, celecoxib and naproxen, suggested an increased risk in AD and no consistent association or worsening of cognitive function with naproxen (in global summary scores and verbal fluency) (Thal et al, 2005;Lyketsos et al, 2007;Martin et al, 2008).…”

Estrogen anti-inflammatory activity in brain: A therapeutic opportunity for menopause and neurodegenerative diseases

“…In addition, a number of proinflammatory mediators, such as cytokines, and inflammatory-associated factors such as cyclooxygenase-2 (COX-2) and inducible-nitric oxide synthase (iNOS) are elevated in the CNS or cerebrospinal fluid of neurodegenerative disease patients. Furthermore, recent epidemiological studies indicate that the chronic use of nonsteroidal anti-inflammatory agents (NSAIDs) reduces the risk of PD and AD ( [39,152,154,225]) and inheritance of polymorphisms resulting in enhanced expression of various inflammatory mediators was reported to increase the risk of these two pathologies ( [32,246]). Importantly, activated microglia were found at the histopathological sites of several brain disorders, including neurodegenerative diseases such as AD, MS, PD, ALS (amyotrophic lateral sclerosis) and AIDS-associated dementia ( [56,93,116,153] and [192]).…”

“…Recent evidence suggests that inflammatory processes play an active role in AD; epidemiological studies reported that the use of nonsteroidal anti-inflammatory drugs is associated with marked reduction in the risk of AD ( [106,154,156,219,225]). Following this initial observation, additional reports were published that witnessed the involvement of neuroinflammation in AD pathogenesis and progression.…”

Elevated microsomal prostaglandin‐E synthase‐1 in Alzheimer's disease

“…Interestingly, nonsteroidal anti-inflammatory drugs (NSAIDs) are able to reduce PGE 2 production and have been shown to reduce the risk of AD [2][3][4]. Nevertheless, in clinical studies, cyclooxygenase (COX)-2 inhibitors and NSAIDs have not been effective in slowing or reversing AD progression or cognitive decline [2,[4][5][6][7]. NSAIDs might prevent or reduce the amyloid burden and oxidative damage caused by proamyloidogenic EP2 stimulation via PGE 2 [8] and enhancement of microglial amyloid-β (Aβ) phagocytosis [9].…”