Dickerson TJ, Janda KD.
Glycation of the amyloid beta-protein by a nicotine metabolite: a fortuitous chemical dynamic between smoking and Alzheimer's disease.
Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8182-7.
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Comment on Janda et al.
There is a great deal of interest in the role that nicotine and its metabolites might play in potential therapies for Alzheimer's disease. This study from Tobin Dickerson and Kim Janda of the Skaggs Institute of Chemical Biology looks in detail at glycation of the amyloid b protein by a nicotine metabolite. The justification for this analysis was given as the existing evidence that nicotine exposure leads to delayed onset of Alzheimer's disease, citing one paper.
This assertion needs addressing. The literature suggesting that there is a protective effect from smoking was based on animal studies and early epidemiological studies, mostly of case-control design. Case-control studies are subject to bias. Longitudinal studies are generally felt to provide a less biased result. The longitudinal studies of smoking and Alzheimer's disease have either produced no association (e.g., Doll et al., 2000), or overall increased risk (e.g., Tyas et al., 2003). The literature has been reviewed systematically by Almeida and colleagues, 2002, and a review of the impact of study design has been published relatively recently (Kukull, 2001).
While laboratory results are of interest as they investigate possible molecular mechanisms, which may or may not bring therapeutic benefit, it is important that the full range of epidemiological evidence is provided for readers, rather than the single paper, which justifies the particular molecular approach.
Doll R, Peto R, Boreham J, Sutherland I.
Smoking and dementia in male British doctors: prospective study.
BMJ. 2000 Apr 22;320(7242):1097-102.
Tyas SL, White LR, Petrovitch H, Webster Ross G, Foley DJ, Heimovitz HK, Launer LJ.
Mid-life smoking and late-life dementia: the Honolulu-Asia Aging Study.
Neurobiol Aging. 2003 Jul-Aug;24(4):589-96.
Almeida OP, Hulse GK, Lawrence D, Flicker L.
Smoking as a risk factor for Alzheimer's disease: contrasting evidence from a systematic review of case-control and cohort studies.
Addiction. 2002 Jan;97(1):15-28.
The association between smoking and Alzheimer's disease: effects of study design and bias.
Biol Psychiatry. 2001 Feb 1;49(3):194-9.
I find these results interesting. Since I'm not an expert in Ab aggregation, I cannot comment on the experimental results, other than to say that they are very preliminary. Unfortunately, the epidemiology on smoking and AD is not uniformly in favor of it being protective, and there are many dissenting studies. In several studies, smoking increases the risk of AD (or of vascular dementia, or both).
The AD field is collecting a mounting number of negative clinical trials which were designed to test risk factors (or protective factors) noted in observational studies. NSAIDs and estrogen are two key examples. Before attempting to try nornicotine in human studies, it would be interesting to see whether the antiaggregation effect in vitro corresponds to lowering of amyloid levels and burden in transgenic mice when the compound is given chronically.