Mechanisms of action of non-steroidal anti-inflammatory drugs for the prevention of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is accompanied by an activation of the innate immune system, and many epidemiological studies have shown reduced risk for dementia or AD associated with chronic consumption of non-steroidal anti-inflammatory drugs (NSAIDs). These observations led to animal model studies to test the hypothesis that NSAIDs can be disease-modifying for some aspects of AD pathogenesis. NSAIDs cannot only suppress inflammatory targets, which could contribute to neuroprotection, they also slow amyloid deposition by mechanisms that remain unclear. Several large clinical trials with NSAID therapies with AD subjects have failed, and cyclooxygenase-2 does not appear to be a useful target for disease modifying therapy. However, there may be apolipoprotein E E4 pharmacogenomic effects and a real but delayed positive signal in a large primary prevention trial with naproxen. This encourages researchers to re-address possible mechanisms for a stage-dependent NSAID efficacy, the subject of this review.

Fig. (1). NSAIDs act in the pro-dromal period

AD pathogenesis begins with genetic or environmental risk factors that accelerate through a prolonged period of at least several decades of Aβ (plaque) and phospho-tau (ptau) (tangle) pathogenesis and later plateau based on studies in Down’s syndrome [51, 52] and cross-sectional studies of cognitively intact individuals dying with AD pathology prior to cognitive deficits [50, 53]. Imaging and cerebrospinal fluid biomarker studies both confirm that amyloid accumulation and tau pathology clearly precede cognitive decline defined as mild cognitive impairment (MCI) by at least several years [–56]. The transition from cognitively normal to MCI is accompanied by increased ultrastructural and gene expression evidence for increased synapse loss in AD vulnerable regions [57, 58]. This synaptic marker loss includes an early loss of N-methyl-D-aspartic acid receptor subunits [59] and drebrin [60, 61], a marker for excitatory synapses [62].