By Themis Halka
Alzheimer’s disease is a preoccupying neurodegenerative disease, and the leading cause of dementia. Treatment of Alzheimer’s disease can only relieve symptoms and slow down neuronal death – there is no cure available to restore the loss of neural tissue. Therefore, acting on the risk factors and finding new neuroprotective agents that could help reduce the burden of Alzheimer’s disease by slowing down neuronal death is crucial.
Over the last few decades, various studies have revealed the possible neuroprotective properties of nicotine, a stimulant psychoactive agent contained in tobacco. Hence, there are suggestions of a possible protective effect of smoking on certain central nervous systems disorders like dementia, Alzheimer’s disease or Parkinson disease.1 Despite being the active compound present in tobacco smoke, nicotine is not the only component present in tobacco and cigarettes in general but is inhaled alongside various other agents whose roles may not be neuroprotective. So, does smoking really provide neuroprotective benefit for Alzheimer’s disease?
Nicotine is a stimulant psychoactive drug, able to increase the activity of nerves in the central nervous system via its action on the nicotinic cholinergic receptors. Extensive research has been conducted on the acute effects of nicotine on cognition. Several short-term positive cognitive effects of nicotine were identified, especially on the enhancement of selective attention, recognition memory and working memory, even though these results remain disputed by some.1 Clinical studies also showed the benefits of nicotine patches in the short-term improvement of cognitive performance in a variety of groups, including Alzheimer’s disease patients and schizophrenics, particularly on attention performance.2 A study from Smith et al. originally found that active nicotine nasal sprays could improve performance on spatial organisation tasks, verbal memory and reaction time in schizophrenic patients, in a double-blind placebo-controlled design3. However, the same investigators were unable to repeat the finding of improved verbal memory upon repetition of the study, highlighting the still limited clinical relevance of nicotine in managing schizophrenia.4
Even though results are inconsistent, it is generally suggested that nicotine may have therapeutic effects on some neuropathological processes in ageing adults. However, the clinical relevance of these observations is still questioned. Short-term use of nicotine has been shown to improve cognitive function, but effects of more prolonged use is less certain. Furthermore, whilst possibly neuroprotective in adults, nicotine is thought to be very harmful to developing foetuses and younger children, via the generation of free radicals that can deplete the antioxidant defence mechanisms and increase oxidative stress in neural cells.5
Importantly, the difference between nicotine absorption and smoking needs to be considered. Whilst the clinical relevance of nicotine’s neuroprotective effect is still under investigation, tobacco smoke has been proven to be harmful for the brain. Tobacco smoke comprises 4700 compounds, including many neurotoxic constituents like vinyl chloride, hydrogen cyanide or arsenic.1 The presence of heavy metals in tobacco smoke is particularly concerning in relation to brain toxicity, as recent epidemiological evidence pointed out metal exposure as a risk factor for Alzheimer’s disease pathology, through an increase in oxidative stress.6 These toxic constituents can arise from the tobacco plant itself, be derived from the manufacturing process, or either be purposefully added to enhance the aroma, flavour or addictiveness to nicotine.1 It is also important to note that side stream smoke contains the same toxic component as mainstream smoke, with even higher levels of some constituents like carboxyhaemoglobin present, and was shown to have adverse effects on cognition and behaviour in children.1
Due to the nature of cognitive decline, studies investigating its interaction with smoking are designed over long periods of time. The normal cognitive decline due to the ageing process needs to be taken into account, for example by using prediction models.1 Investigating the impact smoking alone has on brain function is a challenge. However, some observational studies have found an association between smoking and dementia (as well as Alzheimer’s disease), that involved both duration and heaviness of smoking.1 Furthermore, a study by Tyas et al. highlighted the correlation between smoking and the presence of neocortical and hippocampal neuropathology, as well as the increase of neuritic plaques – all pathological features of Alzheimer’s.7
Oxidative stress seems key in the onset and progression of Alzheimer’s disease, as it leads to inflammation (and ultimately to cell death) as well as promoting amyloid-beta deposition, one hallmark of Alzheimer’s.8 Oxidative stress has been found to result in the generation of reactive oxygen species which leads to oxidative toxicity in neurons. The performance of antioxidant mechanisms thus seems crucial to reduce the harmful impact of amyloid-beta deposition. If nicotine could act as an antioxidant at low acute doses9, other components of tobacco smoke could participate to deplete the pool of antioxidants, increasing neuronal sensitivity to oxidative stress.8 Smoking might also induce the release of pro-inflammatory mediators, which could be further damaging for the brain by enhancing neuronal dysfunction and death.9 The diverse effects of smoking tobacco, including those on pulmonary and cardiovascular function, might also have an indirect impact on brain function.9
Assessing the impact of smoking on neurological functions is challenging, as investigating the effects of smoking in isolation to various other factors like alcohol consumption is not always possible. Importantly, the effects of smoking might not be homogeneous in the population: it has been suggested, for example, that the effects of smoking might be more pronounced for certain polymorphisms, like the ApoE4 allele, which has been previously implicated in the development of Alzheimer’s.10 Identifying risk factors and devising guidance on smoking behaviour in relation to central nervous system disorders, in particular Alzheimer’s disease, is challenging. Nicotine’s neuroprotective role is receiving much research attention, but its potential clinical relevance remains uncertain. This is further complicated by the general toxic effects of smoking on health – which tend to discourage its use. To this day, clinical guidelines for Alzheimer’s disease declare smoking to be harmful and promote its avoidance.11
- Swan, Gary E, and Christina N Lessov-Schlaggar. “The Effects of Tobacco Smoke and Nicotine on Cognition and the Brain.” Neuropsychology review 17.3; 2007: 259–273.
- Rezvani, A. H., & Levin, E. D. Cognitive effects of nicotine. Biological Psychiatry; 2001: 49, 258–267.
- Smith, R. C., Singh, A., Infante, M., Khandat, A., & Kloos, A. Effects of cigarette smoking and nicotine nasal spray on psychiatric symptoms and cognition in schizophrenia. Neuropsychopharmacology; 2002: 27, 479–497.
- Smith, R. C., Warner-Cohen, J., Matute, M., Butler, E., Kelly, E., Vaidhyanathaswamy, S., et al. Effects of nicotine nasal spray on cognitive function in schizophrenia. Neuropsychopharmacology; 2006: 31, 637–643.
- Qiao, D., Seidler, F. J., & Slotkin, T. A. Oxidative mechanisms contributing to the developmental neurotoxicity of nicotine and chlorpyrifos. Toxicology and Applied Pharmacology; 2005: 206, 17–26
- Liu, G., Huang, W., Moir, R. D., Vanderburg, C. R., Lai, B., Peng, Z., et al. Metal exposure and Alzheimer’s pathogenesis. Journal of Structural Biology; 2006: 155, 45–51.
- Tyas, S. L., White, L. R., Petrovitch, H., Ross, G. W., Foley, D. J., Heimovitz, H. K., et al. Midlife smoking and late life dementia: The Honolulu Asia Aging Study. Neurobiology of Aging; 2003: 24, 589–596.
- Casserly, Ivan, and Eric J Topol. “Convergence of Atherosclerosis and Alzheimer’s Disease: Inflammation, Cholesterol, and Misfolded Proteins.” The Lancet (British edition) 363.9415 (2004): 1139–1146.
- Zhang, X. Y., Tan, Y. L., Zhou, D. F., Haile, C. N., Wu, G. Y., Cao, L. Y., et al. Nicotine dependence, symptoms and oxidative stress in male patients with schizophrenia. Neuropsychopharmacology; 2007: 1–5.
- Durazzo TC, Mattsson N, Weiner MW; Alzheimer’s Disease Neuroimaging Initiative. Interaction of Cigarette Smoking History With APOE Genotype and Age on Amyloid Level, Glucose Metabolism, and Neurocognition in Cognitively Normal Elders. Nicotine Tob Res. 2016; 18(2): 204-211. doi:10.1093/ntr/ntv075
- Alzheimer’s Society. Smoking and dementia. Available at: https://www.alzheimers.org.uk/about-dementia/risk-factors-and-prevention/smoking-and-dementia [last viewed on 12th of June 2022]