Interactions of stroke, nonsteroidal anti-inflammatory drugs, and APOE status in dementia risk

Abstract

In this issue of Neurology ®, two independent reports1,2 once again confirm the saliency of the apolipoprotein epsilon 4 (APOE4) allele as a risk factor for Alzheimer disease (AD) or dementia. However, these studies go on to evaluate how APOE4 may be influenced by two other well-known AD/dementia risk factors, one of which, stroke, has been suggested to increase dementia risk,3 and one of which, nonsteroidal anti-inflammatory drug (NSAID) use, has been suggested to decrease AD risk.4 In a relatively large cohort, Szekely et al.1 show that the putative AD protective effects of prior NSAID exposure may owe almost exclusively to decreased risk in APOE4 carriers, with little to no reduction of the ORs for AD among NSAID-using, non-APOE4 subjects. This finding confirms earlier epidemiologic work by Hayden et al.,5 who also observed a significant AD protective effect of NSAIDs that was most notable in APOE4 subjects. Collectively, these studies could go far to explaining several paradoxes surrounding the now voluminous literature on inflammation and AD. The AD cortex (and its embedded vasculature) are clearly subject to chronic, innate inflammatory responses,6 yet AD treatment trials with NSAIDs have been equivocal at best.7 Perhaps beneficial effects in APOE4 subjects have been masked by an absence of benefit in non-APOE4 carriers—a possibility given that only one previous AD/NSAID treatment trial8 included APOE status as a covariate. …