Article

Nonsteroidal anti-inflammatory drugs are associated with increased neuritic plaques

Department of Pathology, University of Washington, Seattle, WA 98104, USA.
Neurology (Impact Factor: 8.3). 09/2010; 75(13):1203-10. DOI: 10.1212/WNL.0b013e3181f52db1
Source: PubMed

ABSTRACT Observational and experimental studies suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) may protect against Alzheimer disease (AD); however, clinical trials and other observational studies, including the Adult Changes in Thought (ACT) study, show no protection or promotion of AD. The objective of this study is to determine the relationship between common dementia-associated pathologies and mid- to late-life NSAID exposure.
We examined the association of mid- to late-life NSAID use with neuropathologic findings on 257 autopsies from ACT, a population-based study of brain aging and incident dementia. Cumulative standard daily doses (SDD) of nonselective NSAIDs were determined from ≥10 years of computerized pharmacy dispensing data. Analyses were adjusted for selection bias to broaden generalizability of results to 3,026 eligible participants in the ACT cohort. Seven pathologic indices were evaluated: intermediate or frequent score for neuritic plaques, Braak stages V or VI for neurofibrillary tangles, >2 cerebral microinfarcts, the presence of any neocortical Lewy bodies, any macroscopic infarcts, any amyloid angiopathy, and moderate or severe atherosclerosis.
Of the neuropathologic indices evaluated, only neuritic plaque score was significantly increased in participants with greater use of nonselective NSAIDs (p = 0.065), specifically in those with high levels of cumulative use: 1,000-2,000 SDD (adjusted relative risk [RR] 2.16, 95% confidence interval [CI] 1.02-4.25, compared to light/nonuse [<60 SDD]) and >2,000 SDD (adjusted RR 2.37, 95% CI 1.24-4.67).
Increased neuritic plaque accumulation may explain the association between heavy use of nonselective NSAIDs and increased risk of dementia among ACT participants.

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    • "The Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT) testing AD 'prevention' with naproxen and celecoxib was halted due to cardiovascular side-effects induced by naproxen; however, follow-up studies along with some post hoc analysis of this trial suggests that treatment effects could vary depending on underlying, clinically silent AD pathology at the time of trial enrollment [68-72]. Another intriguing observation relating to human NSAID use and AD was a report showing that naproxen use was associated with increased post-mortem brain Aβ pathology [74]. "
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    • "Many studies show an association of nonsteroidal anti-inflammatory drugs (NSAIDS) use with reduction of dementia risk [40]. However, in the Adult Changes in Thought (ACT) study, there was an increased incidence of all-cause dementia and AD dementia in individuals with heavy nonselective NSAID use, and this was associated with an increase in neuritic plaques at autopsy [41]. Our data could provide an explanation for this association. "
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    • "Furthermore, NSAIDs were not associated with reductions in the load of neuritic plaques (NPs) or NFTs in human AD brain. On the contrary, one study showed that heavy NSAID use was associated with a significant increase in NPs [44]. In contrast, it has been shown that the use of corticosteroids significantly decreased the density of NPs and NFTs in the entorhinal cortices, hippocampi and amygdalae of AD patients [45]. "
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