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ARTICLES: K. M. Hayden, P. P. Zandi, A. S. Khachaturian, C. A. Szekely, M. Fotuhi, M. C. Norton, J. T. Tschanz, C. F. Pieper, C. Corcoran, C. G. Lyketsos, J.C.S. Breitner, K. A. Welsh-Bohmer For the Cache County Investigators Does NSAID use modify cognitive trajectories in the elderly?: The Cache County Study Neurology 2007; 69: 275-282 [Abstract] [Full text] [PDF]

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Does NSAID use modify cognitive trajectories in the elderly?: The Cache County Study

Donald F. Weaver, Michael D. Carter   (21 September 2007)

Does NSAID use modify cognitive trajectories in the elderly?: The Cache County Study 21 September 2007
Donald F. Weaver, Dalhousie University, Canada Depts of Medicine and Chemistry, Chemistry Building, Dalhousie University, Halifax, NS, Canada,, Michael D. Carter Send Correspondence to journal: Re: Does NSAID use modify cognitive trajectories in the elderly?: The Cache County Study donald.weaver{at}dal.ca Donald F. Weaver, et al.	We read the article by Hayden et al with interest. [1] The authors found that NSAID use may help to prevent cognitive decline in older adults. The effect was more pronounced in people having one or more APOE ε 4 alleles, with this group experiencing a difference of 0.40 points per year on the Modified Mini-Mental State Examination (3MS) relative to controls (p = 0.0005). Surprisingly, those individuals without an ε 4 allele who started NSAID use after age 65 showed greater decline than nonusers (-0.16 points per year, p = 0.02). The marked variability among the NSAIDs included in this study, both in chemical structure and known in vivo activities (Table), demonstrates that caution should be exercised in the interpretation of results. While all members of the NSAID class of drugs exhibit anti-inflammatory activity, although to varying extents, they are significantly different in other respects. For instance, both non-specific COX inhibitors and COX-2 selective inhibitors were included in the group. Furthermore, and of great significance to a dementia study, NSAIDs have widely differing abilities to modulate production of the neurotoxic Alzheimer peptide, Aβ 42. [2] The authors attempted to investigate this variable in a sub-analysis, but their ability to do so was limited by low power due to the small number of non-Aβ 42- lowering NSAID users. Similarly, some of the NSAIDs included in the study (e.g. ibuprofen and sulindac sulfide) are known to strongly inhibit Aβ aggregation into toxic aggregates, while others act much more weakly in this capacity (e.g. naproxen and indomethacin). [3] The diversity of chemical structure within the group including molecular dimensions, molecular weight, chirality, charge, and hydrophobicity also varies widely. (See structures of ibuprofen and rofecoxib in Table). This diversity increases the likelihood of disparate binding within the group varying CNS proteins, eliciting varying degrees of unknown biological effects. The wide degree of chemical variability in molecular size and shape within the family of NSAIDs contributes to the diversity of biological effects for the group further confounding interpretation of results. Table References 1. Hayden KM, Zandi PP, Khachaturian AS, et al. Does NSAID use modify cognitive trajectories in the elderly? Neurology 2007;69:275-282. 2. Weggen S, Eriksen JL, Das P, et al. A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature 2001;414:212-216. 3. Hirohata M, Ono K, Naiki H, Yamada M. Non-steroidal anti-inflammatory drugs have anti-amyloidogenic effects for Alzheimer's beta-amyloid fibrils in vitro. Neuropharmacology 2005;49:1088-1099. Disclosure: The authors report no conflicts of interest. The authors of the article were offered the opportunity to respond but declined.