Smoking Debate Still Smolders

Everyone knows that smoking is bad for you. But there is some evidence, both epidemiological and molecular, that smokers are at reduced risk for neurodegenerative diseases such as Alzheimer's (AD) and Parkinson's (PD). Epidemiological evidence has come mainly from cohort studies, which many researchers claim are subject to bias, while molecular data have implicated the α7 nicotinic acetylcholine receptor as mediating any potential benefit of smoking (see ARF related news story for coverage of both issues). This week, two new papers inject fresh data into both veins of the debate.

First, the epidemiology. In the March 23 Neurology, the EURODEM Incidence Research Group, which includes principal investigators from Denmark, France, The Netherlands, and the UK, reports the results of a longitudinal study designed to assess the impact of smoking on the cognitive abilities of nondemented volunteers. First author A. Ott and colleagues enrolled more than 17,000 people over the age of 65 in the study. After an average of 2.3 years, over 9,000 of them were reevaluated with the Mini-Mental Stage Examination (MMSE), a commonly used cognitive test. Adjusting for a variety of parameters, including age, sex, and education, Ott found that those who never smoked fared much better in the test than did current or former smokers.

MMSE test scores in volunteers who had never smoked declined by an average of 0.03 points per year. The rate of decline was slightly higher in former smokers (0.06 points per year), but substantially higher in smokers (0.16 per year). In the last group, the number of cigarettes smoked positively correlated with the extent of the decline. The results suggest that far from being protective, smoking probably increases one's risk of suffering some sort of cognitive loss. This may not necessarily be due to a higher risk for AD, however, because as the authors point out, smoking may cause cerebral infarcts that could manifest as a loss in cognitive function.

In the Journal of Neurochemistry, Jun Tan and colleagues at the University of South Florida, report that the α7 nicotinic acetylcholine receptor (α7nAChR) may modulate the activation of microglia. Though the precise role played by these immune cells in neurodegenerative diseases is unclear, some researchers believe that they may exacerbate pathology under certain conditions (see ARF related news story). First author Douglas Shytle and colleagues tested cultured microglial cells for the receptor and found that both the messenger RNA and protein are expressed.

To test the physiological significance of this expression, Shytle determined if the receptor plays any role in the immune reactivity of the microglia. These cells are known to respond to immune challenge, such as lipopolysaccharide (LPS) stimulation, by the phosphorylation of proteins p44/42 and p38 MAP kinase, and by the release of the cytokine tumor necrosis factor α (TNFα). Shytle found that if the cells were first treated with nicotine or acetylcholine, then LPS-induced phosphorylation and release of TNFα were attenuated.

These results, the authors suggest, reveal a mechanism whereby nicotine may be neuroprotective, but they caution that this hypothesis needs to be tested in vivo before any conclusions can be made.—Tom Fagan

Comments

    • User Profile Image Thomas Beach
      Banner Sun Health Research Institute
    • Posted:

    The epidemiological evidence should now be regarded as strongly against a protective role for smoking in Alzheimer's disease. Although several early prevalence studies showed that AD was less prevalent in elderly smokers, at least one large incidence study (Rotterdam study; Ott et al., 1998) and one large follow-up study (Honolulu-Asia Aging Study; Tyas et al., 2003) have both reported that smokers have greater than twofold increases in AD risk. Another large prospective study (British doctor study; Doll et al., 2000) found a slight increase in AD risk. As argued by several authors (Riggs, 1992; Kukull, 2001; Almeida, 2002; Hill, 2003), it is likely that the prevalence studies are confounded by differential survival of smokers. The prevalence rate of a condition is dependent on both the actual occurrence of the condition and on the length of time a subject has the condition. At least one report documents that elderly smokers do have decreased survival over a five-year period (Wang et al., 1999). Smoking may affect AD risk through vascular risk factors that outweigh the benefits of nicotine.

    References:

    Ott A, Slooter AJ, Hofman A, van Harskamp F, Witteman JC, Van Broeckhoven C, van Duijn CM, Breteler MM. Smoking and risk of dementia and Alzheimer's disease in a population-based cohort study: the Rotterdam Study. Lancet. 1998 Jun 20;351(9119):1840-3. PubMed.

    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. PubMed.

    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. PubMed.

    Riggs JE. Cigarette smoking and Parkinson disease: the illusion of a neuroprotective effect. Clin Neuropharmacol. 1992 Apr;15(2):88-99. PubMed.

    Kukull WA. The association between smoking and Alzheimer's disease: effects of study design and bias. Biol Psychiatry. 2001 Feb 1;49(3):194-9. PubMed.

    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. PubMed.

    Hill RD, Nilsson LG, Nyberg L, Bäckman L. Cigarette smoking and cognitive performance in healthy Swedish adults. Age Ageing. 2003 Sep;32(5):548-50. PubMed.

    Wang HX, Fratiglioni L, Frisoni GB, Viitanen M, Winblad B. Smoking and the occurrence of Alzheimer's disease: cross-sectional and longitudinal data in a population-based study. Am J Epidemiol. 1999 Apr 1;149(7):640-4. PubMed.

    View all comments by Thomas Beach

  2. Nicotine as a pure drug has been demonstrated to be neuroprotective in numerous in-vivo and in-vitro models. In-vitro studies indicate that the α7 subtype of nAChR mediates some types of nicotine-induced neuroprotection in cortical and hippocampal neuron cultures(1,2). α7 nAChR is a ligand-gated ion channel; receptor activation leads to net inward current and membrane depolarization. The current carried by α7 nAChRs comprises a significant fraction of calcium. Thus, α7 nAChR activation potentially influences neurotransmitter release, second messenger activity, and gene transcription. α7 nAChRs are also highly desensitizing in that prolonged exposure (seconds) to agonist causes significant receptor inactivation(3). While initially leading to transient nAChR activation, chronic exposure to nicotine will result in downregulation of receptor function.

    The studies presented by the EURODERM Incidence Research Group and Jun Tan and colleagues further the notion that, while smoking is bad, nicotine is potentially good by activating neuroprotective second messenger cascades in neurons, or, based on Tan’s findings, negatively modulating the inflammatory response of microglia.

    The EURODERM group convincingly demonstrates that elderly smokers and former smokers lose cognitive function more rapidly than their non-smoking counterparts. Amongst the smokers, this decline correlates with the number of cigarettes smoked per day. While we cannot parse out from this study which component(s) of a cigarette are responsible or the mechanism by which smokers’ cognitive function declines, it will be of import to determine the relative contribution of chronic nicotine exposure via effects on neuron, microglia, and astrocyte function (where several nicotinic receptor subunits are expressed) versus the contribution of inhaled tar and carbon monoxide via effects on cardiovascular function and risk of stroke.

    Jun Tan and coworkers report that microglial release of TNF-α in response to LPS and other infectious challenges is attenuated by α7 nAChR stimulation. In conjunction with additional observations regarding α7 receptor distribution and function in brain, this new data sets the stage for complex cholinergic interactions between neuronal and immune cell populations mediated by the α7 nAChR. For instance, astrocytes synthesize and release acetylcholine in addition to kynurinic acid, which is a potent α7 antagonist(4). Several studies have demonstrated that astrocytes express α7 receptors as do inhibitory and excitatory neurons(5,6). In addition, the cholinergic neurons that exhibit vulnerability in several neurodegenerative diseases express this and other nicotinic receptors(7).

    Based on Shytle and colleagues' findings, the cholinergic tone and inflammatory status within a particular brain region might determine whether a compensatory response is launched by the neuron, microglia, and astrocyte network, or a positive feed-back loop is set up that leads to chronic inflammation and neurodegeneration. Considering these two papers together, chronic nicotine exposure, such as that experienced by smokers’ brains, may contribute to cognitive decline by raising the net inflammatory status of the brain by desensitizing α7 nAChRs on microglia and tipping the balance between compensation and neurodegeneration.

    References:

    Shaw S, Bencherif M, Marrero MB. Janus kinase 2, an early target of alpha 7 nicotinic acetylcholine receptor-mediated neuroprotection against Abeta-(1-42) amyloid. J Biol Chem. 2002 Nov 22;277(47):44920-4. PubMed.

    Dajas-Bailador FA, Lima PA, Wonnacott S. The alpha7 nicotinic acetylcholine receptor subtype mediates nicotine protection against NMDA excitotoxicity in primary hippocampal cultures through a Ca(2+) dependent mechanism. Neuropharmacology. 2000 Oct;39(13):2799-807. PubMed.

    Dani JA, Radcliffe KA, Pidoplichko VI. Variations in desensitization of nicotinic acetylcholine receptors from hippocampus and midbrain dopamine areas. Eur J Pharmacol. 2000 Mar 30;393(1-3):31-8. PubMed.

    Hilmas C, Pereira EF, Alkondon M, Rassoulpour A, Schwarcz R, Albuquerque EX. The brain metabolite kynurenic acid inhibits alpha7 nicotinic receptor activity and increases non-alpha7 nicotinic receptor expression: physiopathological implications. J Neurosci. 2001 Oct 1;21(19):7463-73. PubMed.

    Alkondon M, Pereira EF, Albuquerque EX. alpha-bungarotoxin- and methyllycaconitine-sensitive nicotinic receptors mediate fast synaptic transmission in interneurons of rat hippocampal slices. Brain Res. 1998 Nov 9;810(1-2):257-63. PubMed.

    Gray R, Rajan AS, Radcliffe KA, Yakehiro M, Dani JA. Hippocampal synaptic transmission enhanced by low concentrations of nicotine. Nature. 1996 Oct 24;383(6602):713-6. PubMed.

    O'Neill MJ, Murray TK, Lakics V, Visanji NP, Duty S. The role of neuronal nicotinic acetylcholine receptors in acute and chronic neurodegeneration. Curr Drug Targets CNS Neurol Disord. 2002 Aug;1(4):399-411. PubMed.

    View all comments by Kelly Dineley

  3. The problem with testing smokers and ex-smokers to determine if nicotine has neuroprotective properties is obvious. This is an unhealthy route of entry for nicotine, as opposed to transdermal, gum, lozenge, etc., where the cerebral vascular, oncologic, and other risks from smoking shouldn’t apply and confound the data. I first encountered this "smoldering debate," about three years ago when I was asked to review for the American Journal of Psychiatry (2001;158:1540-1541) a small but extremely informative and thought-provoking book entitled Nicotine in Psychiatry (Piasecki and Newhouse eds). Shortly thereafter, I attended the Alzheimer's conference in Stockholm, Sweden, where I learned from colleagues, mostly from outside the US, that there was considerable interest in testing smokeless nicotine for various syndromes including Alzheimer's and Parkinson’s. One attendee had even taken the step of using the patch even though she had never been a smoker. I gave this some thought after I returned home, did some research on the risks of long-term use of exogenous smokeless nicotine (about which there was nearly no information), and made the decision to make myself a study of one subject. My decision was partly influenced by the fact that my mother had recently passed away at age 85 after two years with what appeared to be Alzheimer's. After two years on the gum (the patch was problematic because of skin irritation), I can report no ill effects, and possible some benefits in terms of weight control and giving me an edge in activities requiring total focus and quick reflexes (Ping Pong).

    I propose that a group of interested professionals, such as ourselves, ideally in middle age, with a family history of Alzheimer's and no previous smoking history, begin using smokeless nicotine on a regular basis so that 20 years from now we will have some pooled data and hopefully an answer (i.e., if the expectation is a five or 10 percent Alzheimer's prevalence, reducing this to much less than what might be statistically significant if the number of volunteer subjects was high enough).

    I’d be interested in your opinion of this approach, and if there is interest in participating.

    References:

    Hartman N: Book review, M Piasecki, PA Newhouse (eds): Nicotine in Psychiatry: Psychopathology and Emerging Therapeutics. Am J Psychiatry  2001; 158:1540–1541.

     

    View all comments by Neil Hartman

  4. Most interesting study. Wine was recently added to the good things you must take to live... after years of bad news.

    It will be interesting to hear about salt too. There was one study done in Florida on a dozen old men who improved mentally with excessive table salt added to their diets.I remember reading about it about 25 years ago. Fifty years ago I tried on myself consuming larger amouts of salt and noticed some increase in awareness ability.
    At that time my stepfather had an angina attack so we all gave up excessive salt.

    References:
    Personal experience 1927-- Yale --- living---2004 HBW

    View all comments by Herbert Walker

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References

News Citations

  1. Nicotine and β Amyloid—Smoking Guns?
  2. New Orleans: New Approaches to Lift Microglia Mysteries

Further Reading

No Available Further Reading

Primary Papers

  1. Shytle RD, Mori T, Townsend K, Vendrame M, Sun N, Zeng J, Ehrhart J, Silver AA, Sanberg PR, Tan J. Cholinergic modulation of microglial activation by alpha 7 nicotinic receptors. J Neurochem. 2004 Apr;89(2):337-43. PubMed.
  2. Ott A, Andersen K, Dewey ME, Letenneur L, Brayne C, Copeland JR, Dartigues JF, Kragh-Sorensen P, Lobo A, Martinez-Lage JM, Stijnen T, Hofman A, Launer LJ, . Effect of smoking on global cognitive function in nondemented elderly. Neurology. 2004 Mar 23;62(6):920-4. PubMed.

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