Diclofenac reduces the risk of Alzheimer’s disease: a pilot analysis of NSAIDs in two US veteran populations

But better than coffee? WHOM do we got to to get that simple question answered?

Maybe you want to read these two negative articles on diclofenac:

Major Study Points to Cardiac and Stroke Risks of One of World’s Biggest Drugs

EU regulator advises caution on painkiller diclofenac

 

Your chances of getting dementia.

1. A documented 33% dementia chance post-stroke from an Australian study?   May 2012.

2. Then this study came out and seems to have a range from 17-66%. December 2013.

3. A 20% chance in this research.   July 2013.

4. Dementia Risk Doubled in Patients Following Stroke September 2018 

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Coffee May Lower Your Risk of Dementia Feb. 2013 

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The latest here:

Diclofenac reduces the risk of Alzheimer’s disease: a pilot analysis of NSAIDs in two US veteran populations 

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Olaf Stuve, Rick A. Weideman, Danni M. McMahan, ...

First Published June 25, 2020 Research Article

https://doi.org/10.1177/1756286420935676

Article information

Abstract

Background:

Our aim was to determine whether specific nonsteroidal anti-inflammatory (NSAID) agents are associated with a decreased frequency of Alzheimer’s disease (AD).

Materials and methods:

Days of drug exposure were determined for diclofenac, etodolac, and naproxen using US Department of Veterans Affairs (VA) pharmacy transaction records, combined from two separate VA sites. AD diagnosis was established by the International Classification of Diseases, ninth revision (ICD-9)/ICD-10 diagnostic codes and the use of AD medications. Cox regression survival analysis was used to evaluate the association between AD frequency and NSAID exposure over time. Age at the end of the study and the medication-based disease burden index (a comorbidity index) were used as covariates.

Results:

Frequency of AD was significantly lower in the diclofenac group (4/1431, 0.28%) compared with etodolac (328/14,646, 2.24%), and naproxen (202/12,203, 1.66%). For regression analyses, naproxen was chosen as the comparator drug, since it has been shown to have no effect on the development of AD. Compared with naproxen, etodolac had no effect on the development of AD, hazard ratio (HR) 1.00 [95% confidence interval (CI): 0.84–1.20, p = 0.95]. In contrast, diclofenac had a significantly lower HR of AD compared with naproxen, HR 0.25 (95% CI: 0.09–0.68, p <0.01). After site effects were controlled for, age at end of the study (HR = 1.08, 95% CI: 1.07–1.09, p <0.001) was also found to influence the development of AD, and the medication-based disease burden index was a strong predictor for AD, HR 5.17 (95% CI: 4.60–5.81) indicating that as comorbidities increase, the risk for AD increases very significantly.

Conclusion:

Diclofenac, which has been shown to have active transport into the central nervous system, and which has been shown to lower amyloid beta and interleukin 1 beta, is associated with a significantly lower frequency of AD compared with etodolac and naproxen. These results are compelling, and parallel animal studies of the closely related fenamate NSAID drug class.

Keywords Alzheimer’s disease, diclofenac, naproxen, etodolac

Introduction

Alzheimer’s disease (AD) is a chronic, progressive, and irreversible age-related neurodegenerative disorder characterized by cognitive and memory impairment. It is the most common cause of dementia in older adults. It was estimated in 2015 that 44 million people were living with AD worldwide, and this number is expected to double by 2050.¹ More than 95% of people with AD have sporadic or late-onset AD, a multi-factorial disorder with environmental factors and genetic predisposition contributing to the pathology.¹
The pathophysiology of AD is characterized by abnormal extracellular accumulation of amyloid-β peptide (Aβ) in amyloid plaques, and abnormal intracellular accumulation of tau protein in neurofibrillary tangles (NFTs).¹ Several theories are published regarding the AD pathogenesis. The amyloid cascade theory proposes that the accumulation of Aβ plaques in the brain is the primary pathogenic event.^2–4 The tau hypothesis proposes that tau hyperphosphorylation is the underlying etiology.^5–9 The cholinergic theory suggests AD is associated with a reduction in the choline acetyltransferase activity and acetylcholine levels in specific areas of the brain such as the cerebral cortex.^10,11 These proposed disease mechanisms result in a loss of synaptic function, mitochondrial damage, activation of microglia, and neuronal death.¹² Neuroinflammation is mediated primarily by microglia cells, and neuroinflammation contributes to AD pathogenesis.^13–15 Microglia activation has a dual effect on AD progression: it leads to (a) a reduction of Aβ accumulation by increasing phagocytosis, clearance, and degradation, and (b) the release of pro-inflammatory cytokines, and triggers the inflammatory cascade that contributes to neuronal damage and death.¹²
Interleukin-1β (IL-1β) is an important pro-inflammatory cytokine in the brain.^16,17 It is generated by the cytosolic nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasomes, where nucleotide-binding oligomerization-domain-like receptors (NLRs) are engaged, resulting in increased IL-1β release.¹⁸ Evidence is growing that IL-1β plays a central role in AD progression.^19,20 The NLRP3-IL-1β is synthesized and released from activated microglia and astrocytes. One study has documented that IL-1β interferes with glutamate reuptake in astrocytes, potentially leading to glutamate toxicity.²¹ Another study showed that soluble oligomeric Aβ increases the formation of mature IL-1β in microglia.¹² Over-expression of IL-1β release from microglia and astrocytes surrounding Aβ plaques occurs in the AD brain.^22,23 Several studies have demonstrated that the over-expression of IL-1β exacerbates tau phosphorylation and NFT development.^24–26 Subsequently, synaptic plasticity leads to disruption of the brain’s learning and memory processes.¹² Finally, the blockade or neutralization of IL-1β in an AD mouse model was protective against cognitive defects, decreased tau pathology and the synthesis of Aβ.¹²
Early studies of AD included the use of non-steroidal anti-inflammatory drugs (NSAIDs).²⁷ In a Cochrane NSAID and Alzheimer’s review, these prior studies in AD patients compared aspirin and NSAID exposures to patients who had not received them and the results from these studies were equivocal.²⁷ Vlad and colleagues, however, concluded that over time, ibuprofen and NSAIDs as a group have a protective effect but that other individual NSAIDs did not consistently exhibit this effect, perhaps due to ‘small numbers of users.’²⁸ In addition, many studies do not specify which NSAIDs were used, although the effects of indomethacin,^29,30 celecoxib,³¹ naproxen^32–35 ibuprofen,³⁶ and naproxen have been studied. Of these, only indomethacin²⁹ and ibuprofen²⁸ were associated with less cognitive decline in AD. A recent meta-analysis of 16 NSAID cohort studies³⁷ reported a decreased likelihood of AD with the pooled data of 236,022 patients; however, individual NSAIDs had no effect when stratified by NSAID type.
It is important to note that there are eight different chemical classes of NSAIDs³⁸ and this may have a significant effect on their ability to interrupt the AD process. In 2006, Joo and colleagues³⁹ found a neuroprotective effect of mefenamic acid administration in in vitro and in vivo models. In 2016, Daniels and colleagues⁴⁰ also detected a protective effect of the fenamate class of NSAIDs against AD and they hypothesized that it was due to inhibition of IL-1β release from the NLRP3 inflammasome in immortalized mouse bone-marrow-derived macrophages. In the initial in vitro phase of their study, the fenamates (flufenamic acid, mefenamic acid and meclofenamic acid) were more effective at inhibiting IL-1β release than celecoxib or ibuprofen, which had no effect on IL-1β release.⁴⁰ In contrast, diclofenac was associated with a modest but significant reduction in IL-1β release. In the second phase of their study, Daniels and colleagues showed that the fenamate drug class also prevented Aβ-induced memory deficits in rats,⁴⁰ and it decreased AD-related neuroinflammation in three AD-transgenic (TG) mice that expressed the presenilin mutation PS1M146V,⁴¹ the mutant amyloid precursor protein APPSwe,⁴² and a transgene of the human mutant P301 tau gene (tauP301L transgene).⁴³ These animals develop a progressive neuropathological phenotype with increasing age that includes Aβ plaques and neurofibrillary tangles.⁴⁴ Fenamate treatment was associated with decreased IL-1β expression and microglial activation in AD mice equivalent to levels in wild-type mice.⁴⁰
Very recently, Rivers-Auty and colleagues, evaluating fenamate NSAIDs, reviewed diclofenac use in a database of patients with Alzheimer’s disease and found that it reduced cognitive deterioration.⁴⁵ At this time, however, this finding has only been presented in abstract form.
The purpose of this retrospective cohort study was to determine whether chronic diclofenac use is associated with a lower frequency of AD in a veteran population compared with chronic use of etodolac or naproxen.