. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nat Genet. 2009 Oct;41(10):1094-9. PubMed.

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  1. The paper by Lambert and colleagues is important and timely. For those of us in the field of neuroinflammation, their report adds fuel to the hypothesis that immune/inflammatory pathways are not epiphenomena, but are rather pathoetiologic in AD. Specifically, the authors have found that the complement receptor 1 gene, critically important for enabling the innate immune humeral response, is a bona fide genetic risk factor for AD. This represents a greater-than-incremental addition to a growing body of literature, both from the clinic and from transgenic AD mouse models, that strongly suggests these signaling pathways are intimately involved in the manifestation of AD pathology. Importantly, the authors’ GWAS approach in over 7,000 combined cases and controls provides a powerful message to remain focused on immune/inflammatory signaling pathways as possible therapeutic targets for the clinical syndrome.

    That said, I would like to comment on a statement made above by Julie Williams, that “our results suggest the possibility that inflammation may be primary to disease development.” As important as the current work of Lambert and colleagues is, it deserves mentioning that this suggestion actually arose in the 1990s due to epidemiologic studies (currently at least 25) that reported on the risk relationship between non-steroidal anti-inflammatory drugs (NSAIDs) and AD (see Szekely et al., 2007 for a review). Many of these early studies examined inflammatory conditions such as arthritis, for which NSAIDs are commonly indicated, and found an inverse association with AD. Based on these studies, it was suggested that history of arthritis was a surrogate for NSAID exposure, leading later investigations to focus specifically on NSAID use. There have been at least 12 such non-prospective studies to date, 10 of which concluded that AD patients were less likely to have been using these agents than were non-demented controls.

    Christine Szekely and Peter Zandi recently performed a systematic review of these studies (which met stringent inclusion criteria), with a resulting meta-analysis for eight non-prospective studies (1,833 cases and 13,780 controls) that showed a 53 percent AD risk reduction in those study participants who reported using non-aspirin NSAIDs compared with non-users (Szekely et al., 2004). They also performed a meta-analysis for five prospective studies (836 AD cases and 16,294 controls) and found a 29 percent risk reduction.

    Interestingly, AD risk reduction was more pronounced for longer (>2 years) duration of NSAID use, where a risk reduction of 58 percent was evident. Unfortunately, the one randomized controlled clinical trial of NSAIDs in non-demented elderly, ADAPT, was prematurely halted after two years of treatment and two years of follow-up due to possible cardiotoxicity of certain NSAIDs; post-hoc analysis of these data is still underway. [Editor's note: for recent news on ADAPT, see ARF related ICAD story.]

    In conclusion, the international genetics teams should be commended for a well-executed and powerful GWAS-based analysis of AD risk. The data of Lambert et al. stress the importance of keeping the AD therapeutic searchlight aimed at immune/inflammatory signaling pathways and providing an important target molecule: complement receptor 1.

    References:

    . NSAIDs for the chemoprevention of Alzheimer's disease. Subcell Biochem. 2007;42:229-48. PubMed.

    . Nonsteroidal anti-inflammatory drugs for the prevention of Alzheimer's disease: a systematic review. Neuroepidemiology. 2004 Jul-Aug;23(4):159-69. PubMed.