Neuropsychol Rev (2007) 17:259273

DOI 10.1007/s11065-007-9035-9

The Effects of Tobacco Smoke and Nicotine on Cognition

and the Brain
Gary E. Swan & Christina N. Lessov-Schlaggar

Received: 18 June 2007 / Accepted: 26 June 2007 / Published online: 10 August 2007
# Springer Science + Business Media, LLC 2007

Abstract Tobacco smoke consists of thousands of compounds including nicotine. Many constituents have known
toxicity to the brain, cardiovascular, and pulmonary
systems. Nicotine, on the other hand, by virtue of its
short-term actions on the cholinergic system, has positive
effects on certain cognitive domains including working
memory and executive function and may be, under certain
conditions, neuroprotective. In this paper, we review recent
literature, laboratory and epidemiologic, that describes the
components of mainstream and sidestream tobacco smoke,
including heavy metals and their toxicity, the effect of
medicinal nicotine on the brain, and studies of the
relationship between smoking and (1) preclinical brain
changes including silent brain infarcts; white matter hyperintensities, and atrophy; (2) single measures of cognition;
(3) cognitive decline over repeated measures; and (4)
dementia. In most studies, exposure to smoke is associated
with increased risk for negative preclinical and cognitive
outcomes in younger people as well as in older adults.
Potential mechanisms for smokes harmful effects include
oxidative stress, inflammation, and atherosclerotic processes. Recent evidence implicates medicinal nicotine as
potentially harmful to both neurodevelopment in children
and to catalyzing processes underlying neuropathology in
Alzheimers Disease. The reviewed evidence suggests
caution with the use of medicinal nicotine in pregnant
mothers and older adults at risk for certain neurological
disease. Directions for future research in this area include
the assessment of comorbidities (alcohol consumption,
G. E. Swan (*) : C. N. Lessov-Schlaggar
Center for Health Sciences, SRI International,
333 Ravenswood Avenue,
Menlo Park, CA 94025, USA
e-mail: gary.swan@sri.com

depression) that could confound the association between

smoking and neurocognitive outcomes, the use of more
specific measures of smoking behavior and cognition, the
use of biomarkers to index exposure to smoke, and the
assessment of cognition-related genotypes to better understand the role of interactions between smoking/nicotine and
variation in genotype in determining susceptibility to the
neurotoxic effects of smoking and the putative beneficial
effects of medicinal nicotine.
Keywords Tobacco smoke . Nicotine . Brain . Cognition .
Dementia

Overview
Tobacco smoke is probably the single most significant
source of toxic chemical exposure to humans. The World
Health Organization forecasts cigarettes will kill nearly 9
million people per year globally by the year 2030 (Mathers
and Loncar 2006). Smoking is associated with an increased
incidence of cardiovascular disease including coronary
heart disease (e.g., angina, myocardial infarction, suddendeath, and congestive heart failure), cerebrovascular disease
(e.g., transient ischemic attacks, stroke), and vascular
diseases (e.g., claudication, aortic aneurysm and atherosclerosis) and is the primary cause of chronic obstructive
airways disease (e.g., mucous hypersecretion, interference
with ciliary function, and alveolar destruction) (U.S.
Department of Health and Human Services 1989).
Despite the large amount of premature cardiovascular
morbidity and mortality attributable to tobacco use, early
reports suggested that smoking could actually be protective
against certain CNS disorders such as Parkinsons and
Alzheimers Disease (AD) and dementia (Checkoway et al.

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Neuropsychol Rev (2007) 17:259273

nicotines short-term salutary effects exist in the literature,

there are far fewer long-term, prospective investigations of
nicotines effects on the prevention, reduction, or reversal
of neurological disease. In fact, there is emerging evidence
that nicotine may not be uniformly neuroprotective and that
nicotine is highly toxic to the developing brain if exposed
through maternal smoking, environmental sidestream
smoke, or use of nicotine replacement therapy. Another
conclusion of this review is that while nicotines short-term
positive cognitive effects appear to be undeniable, it is still
too early to view nicotine as a viable candidate for longterm use in the management of neurological disease.
Nicotine, through direct impact on blood pressure, heart
rate, and subsequent hemodynamic shear forces or indirect
pathways such as a promoter of oxidative stress and/or tau
phosphorylation could, ultimately, have negative impacts
on the very conditions it is being used to treat. As an aid to
the reader, a summary of the organization of this review is
provided as Fig. 1.

2002; Lee 1994; van Duijn et al. 1994). This work, relying
primarily on case-control designs of older adults with or
without disease, was most certainly biased by a healthy
survivor effect. One of the purposes of the present paper is
to review current evidence involving prospective studies of
the relationship between smoking and neurobehavioral
outcomes including single assessments of cognitive status,
serial measures of cognitive performance, preclinical
morphological outcomes such as brain atrophy, white
matter hyperintensities (WMHIs), and silent infarcts, in
addition to disease outcomes such as vascular dementia
(VaD) and AD. A conclusion of this review is that while
there is substantial evidence that smoking is harmful to the
brain at both the functional and morphological levels, much
more work is needed as to the further specification of high
risk smoking behavior (e.g., smoking topography), functional outcomes (e.g., specific neuropsychological measures
and the rate of decline in performance on them), morphological outcomes (e.g., impact on specific regions and
features of the brain), and the probable synergies that exist
between smoking and other cerebrovascular risk factors
including genetic variation to heighten risk for negative
outcomes.
Nicotine, the primary constituent of tobacco smoke
leading to addiction and chronic, long-term use, acts on
the cholinergic system through its effects on nicotinic
acetylcholine receptors. Short-term administration of nicotine enhances several cognitive functions such as attention,
working memory, and executive function. This observation
led to the investigation of medicinal nicotine as a possible
therapeutic for CNS disorders. While numerous studies of
Fig. 1 Summary of pathways
(direct and mediating) by which
tobacco smoke and medicinal
nicotine influence biobehavioral
and ultimate brain outcomes

Constituents of Tobacco Smoke

Mainstream Smoke
To understand the toxic effects of tobacco smoke on the
cardio- and cerebrovascular systems, it is important to
characterize its complex nature. Cigarette smoke consists of
two phases: a particulate (tar) phase and a gas phase. The
particulate phase contains more than 1017 free radicals per
gram while the gas phase contains more than 1015 free

Constituents of tobacco smoke

Chemicals
Heavy metals
Free radicals
Nicotine

Mode of
exposure
Mainstream
Sidestream
Medicinal
nicotine

Duration of
exposure
Acute
Occasional
Chronic

Dose
Quantity

Biobehavioral effects
Cholinergic system activation
Enhanced performance
Oxidative stress
Inflammation
Atherosclerosis

Negative outcomes
Preclinical brain changes
Cerebrovascular disease
Cardiovascular & pulmonary disease
Developmental neurotoxicity

Medicinal
nicotine

Dose
Concentration

Host characteristics
Age
Gender
Comorbidity
Genetics
Environmental factors

Duration of
exposure
Acute
Occasional
Chronic

Mode of
exposure
Patch
Gum
Spray
Lozenge

Biobehavioral effects
Cholinergic system activation
Enhanced performance
Neuronal protection
Oxidative stress

Negative outcomes
Hyperphosphorylaiton of tau
Developmental neurotoxicity
Dependence liability

Neuropsychol Rev (2007) 17:259273

radicals per puff. Whereas the radicals associated with the

gas phase have a shorter lifespan (seconds), those associated
with the particulate phase are longer-lived (hours to months)
(Ambrose and Barua 2004).
Among the 4,700 compounds found in tobacco smoke,
many are associated with brain toxicity including vinyl
chloride, a risk factor for brain cancer, hydrogen cyanide,
and arsenic. Other components that could negatively impact
the pulmonary system with secondary effects on the CNS
include acrolein, acetaldehyde, formaldehyde, and cadmium
(tobacco smoke is the main source of cadmium in humans;
Bernhard et al. 2005; Fowles and Dybing 2003). Still other
components with potential cardiovascular or CNS effects
include ammonia, cresol, catechol, carbon monoxide, hydroquinone, lead, methyl ethyl ketone, nitric oxide, phenol,
styrene, toluene, and butane (Fowles and Dybing 2003).
From the standpoint of brain toxicity, the presence of
heavy metals in tobacco smoke is particularly troubling
given recent epidemiologic evidence that metal exposure is a
risk factor for AD pathology primarily through an increase in
oxidative stress (Liu et al. 2006). Lifetime exposure to lead
as marked by levels in bone in older adults is associated
cross-sectionally with lower levels of functioning in the
domains of language, processing speed, eye hand coordination, executive functioning, verbal memory and learning,
visual memory, and visual construction (Shih et al. 2006),
with steeper declines in global cognitive function (Weisskopf
et al. 2004), and with increases in white matter lesion
burden, decreases in total brain volume, frontal and total
gray matter volume, and parietal lobe white matter volume
(Stewart et al. 2006; Rowland and McKinstry 2006).
While many of the toxic constituents of tobacco arise from
the plant itself, others derive from the manufacturing process
and still others are purposely added to enhance the flavor,
aroma, and/or addictiveness of nicotine. For example,
ammonium compounds enhance the reinforcing aspects of
cigarettes by (1) enrichment of the mainstream smoke with
nicotine; (2) more complete and faster absorption of nicotine;
(3) enhanced impact of nicotine at both peripheral and central
nicotinic receptors, and (4) improvement of the sensory
characteristics of the substance (Willems et al. 2006).
Although the toxic effects of ammonium compounds (along
with many others for that matter) appear to be directed
largely at the pulmonary system, we would still expect
tobacco smoke to have an indirect deleterious effect on the
CNS, because pulmonary health is intimately connected to
the functioning of the brain (Richards et al. 2005).
Sidestream Smoke
Given the toxicity of mainstream tobacco smoke as
described above, it is perhaps not surprising that sidestream
smoke (the smoke from the burning end of a cigarette

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combined with the exhaled smoke from the smoker),

contains the same CNS toxic components and, for some
constituents, at higher levels. For example, compared to
mainstream smoke, exposure to sidestream smoke results in
higher concentrations of carboxyhemoglobin, nicotine, and
cotinine in blood of research animals than exposure to
equal quantities of mainstream smoke. Sidestream condensate is 26 times more tumorigenic per gram than
mainstream condensate (Schick and Glantz 2005; Whincup
et al. 2006). Sidestream smoke is also associated with
cardiovascular disease with relative risks of 1.21.3, with
the effects being, on average, 80 to 90% as large as those
from active smoking (Barnoya and Glantz 2005).
There is evidence that exposure to sidestream smoke has
an adverse effect on cognition and behavior in children
(Yolton et al. 2005). In this study, 5,683 children between
the ages of 6 and 16 years from the third National Health
and Nutrition Examination Survey (NHANES III) were
examined for cotinine (a biomarker for exposure to sidestream smoke in nonsmokers) in serum and for performance
on a number of cognitive and intellectual tests. The authors
observed a doseresponse relationship in which higher
cotinine levels were associated with greater deficits in
reading, math, and visuospatial reasoning, but not shortterm memory. Prospective studies reveal that maternal
smoking during pregnancy results in children with deficits
in general intellectual function and auditory processing
(Fried et al. 1997, 2003, McCartney et al. 1994). Jacobsen
et al. (2007) recently reported that prenatal exposure to
maternal smoke was associated with deficits in both
auditory and visual domains in adolescent females whereas
in male adolescents, maternal smoking during pregnancy
was associated with deficits only in conditions requiring
auditory attention. Prenatal exposure to active maternal
smoking is also associated with alteration in temporal lobe
function and deficits in visuospatial memory (Jacobsen
et al. 2006) along with reduced performance on tests of
verbal and working memory in adolescents who have
recently stopped smoking (Jacobsen et al. 2005).
Infants of mothers who smoke have a dramatically lower
birth weight; on average 200 g less than gestation matched
controls. Reductions in birth weight have serious consequences since they are strongly associated with infant
morbidity and mortality. Nicotine and cotinine have direct
toxic effects since these compounds readily cross the
human placenta. Smoking decreases the flow of uterine
blood to the placenta through mechanisms that include
vasoconstriction. Furthermore, smoking induces changes in
the endothelial nitric oxide synthase (eNOS) levels in the
placenta with the effects depending on eNOS genotype.
Maternal smoking alters other important aspects of placental
function such as progesterone production, estrogen metabolism, amino acid transport, as well as activity of drug

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metabolizing enzymes. The genetic variations in some drug

metabolizing enzymes greatly exacerbate the negative effects
of maternal smoking on birthweight (Zdravkovic et al. 2005).
Nicotine
A number of studies have demonstrated that chronic
nicotine exposure induces increased numbers of CNS
nicotinic acetylcholine receptors (nAChRs) in animals and
human smokers in vivo (Sabbagh et al. 2002). Nicotinic
acetylcholine receptors are ligand-gated ion channels consisting of and subunits. At least 12 nAChRs have been
identified with the heteromeric 42 being the most
common subtype in the brain and the homomeric 7 being
the next most common. Postmortem and laboratory studies
demonstrate that smokers have widespread up-regulation of
nAChRs, likely related to desensitization of these receptors
from nicotine exposure. Nicotinic acetylcholine receptors
are widespread throughout the brain, with the rank order
(high to low) distribution of density being: thalamus, basal
ganglia, cerebral cortex, hippocampus, and cerebellum
(Brody et al. 2004).
Cerebral responses to acute administration of nicotine or
smoking include a reduction in global brain activity,
activation of the prefrontal cortex, thalamus, and visual
systems, activation of the thalamus and visual cortex during
visual cognitive tasks, and increased dopamine concentration in the ventral striatum/nucleus accumbens. Responses
to chronic nicotine/cigarette exposure include decreased
monoamine oxidase (MAO) A and B activity in the basal
ganglia and a reduction in 42 nicotinic acetylcholine
receptor availability in the thalamus and putamen. These
findings indicate that the acute effect of smoking is the
enhancement of neurotransmission through cortico-basal
ganglia-thalamic circuits, either by direct stimulation of
nAChRs, direct stimulation via dopamine release or MAO
inhibition, or a combination of these factors. Enhanced
neurotransmission may account for the most commonlyreported cognitive effects of cigarette smoking including
improved attentional performance and related effects such
as improvements in reaction times, arousal, motivation, and
sustained attention (Brody 2006).

Epidemiological Evidence of the Relationship

Between Tobacco Smoke and Brain Outcomes
Silent Brain Infarcts, WMHI, Leukoariosis, Other
Volumetric Measures
Given that smoking is a risk factor for stroke, it is
reasonable to suspect that it is also associated with
preclinical brain changes that may precede the onset of

Neuropsychol Rev (2007) 17:259273

symptomatic stroke or other forms of clinical disease. Early,

smaller studies found inconclusive evidence of an association, with one study reporting an association between
smoking and higher levels of brain atrophy on CT scan in
adults aged 4069 years (Kubota et al. 1987) while another
reported no association with silent lacunar infarcts in 270
subjects free of neurological deficits over the age of
40 years (Shintani et al. 1998).
More recently however, larger, cross-sectional and prospective investigations support the conclusion that smoking
history is a reliable risk factor for preclinical brain changes.
Howard et al. (1998), in an analysis of 1,737 participants aged
55 to 70 from the Atherosclerosis Risk in Communities
Study, found that the prevalence of silent cerebral infarction
was 1.8 times greater in current smokers as compared to
nonsmokers. A larger number of packyears of smoking was
associated with higher prevalence, suggesting a dose
response relationship. While a later study of 1,077 participants of age 6090 years in the Rotterdam Scan Study did
not find an association between smoking status and the
prevalence of silent brain infarct, it did observe an association
with the prevalence of symptomatic infarcts (Vermeer et al.
2002). A subsequent study in the same group of people
found that smoking was associated with an accelerated risk
(1.4) for incident silent brain infarct (e.g., new infarcts
following initial evaluation; Vermeer et al. 2003).
White matter hyperintensities and subcortical atrophy are
associated with lower performance on measures of executive function (e.g., word fluency and performance on the
Stroop ColorWord Test; Soderlund et al. 2006) and greater
decline in digit symbol substitution and global cognitive
function as assessed by the Mini Mental State Exam
(MMSE) (Longstreth et al. 2005). Smoking was an
independent risk factor for worsening of white-matter grade
in a subset of participants 65 years and older from the
Cardiovascular Health Study (CHS; n=1919) who were
examined twice by MRI over an interval of 5 years. A
second study of non-demented community dwelling older
adults, while not finding a direct association between
smoking and WMHI, did find an association between lower
levels of peak expiratory flow rate, an indicator of certain
forms of lung disease for which smoking is a risk factor, and
WMHI (Murray et al. 2005). Smoking history is associated
with WMHI in most, but not all studies (Brody et al. 2004).
Studies of the association of smoking with volumetric
measures of atrophy suggest a negative relationship (e.g.,
more exposure is associated with smaller volumes). For
example, Swan et al. (2000) found that the number of years
smoked remained an independent predictor of an atrophic
subgroup of older men characterized by smaller brain
volumes and greater levels of WMHI. Longstreth et al.
(2001) also found that smoking history (packyears) was
significantly associated with MR measures indicative of

Neuropsychol Rev (2007) 17:259273

atrophy, WMHI, and/or infarct in 3,230 older adult

members of the CHS. Brody et al. (2004) reported that
smokers had smaller relative cortical gray matter volumes
and densities in the prefrontal cortex, smaller left dorsal
anterior cingulate cortex volumes and lower cerebellar gray
matter densities than nonsmokers. More packyears of
exposure were associated with lower prefrontal cortical gray
matter. The studies reviewed above suggest the possibility
that differences in brain characteristics could predate the
onset of smoking thereby potentially confounding these
associations.
Cognition
Effects of Nicotine
Much of the early work showing that nicotine leads to an
enhancement of cognitive performance was confounded by
the study of smokers who had been deprived overnight, and
thus, were experiencing deficits induced by withdrawal
(Heishman and Henningfield 2000). The acute effects of
nicotine on cognition have been extensively studied and are
characterized by enhanced selective attention, recognition
memory, and working memory in nonsmokers and nondeprived smokers in some (Ernst et al. 2001; Foulds et al.
1996; Perkins et al. 1994; Kumari et al. 2003; Le Houezec
et al. 1994; Phillips and Fox 1998; Pritchard et al. 1992) but
not all studies (Landers et al. 1992; Petrie and Dreary 1989;
Heishman et al. 1993; Spilich et al. 1992; Hasenfrantz et al.
1989; Keenan et al. 1989; Hindmarch et al. 1990; Jacobsen
et al. 2006; Sakuri and Kanazawa 2002). The most
commonly replicated cognitive effect of nicotine administration is improved performance and reaction times on tasks
that require vigilant attention in nicotine dependent smokers
(Brody 2006; Ilan and Polich 2001; Rezvani and Levin
2001). Perkins et al. (1994) reported dose-dependent
improvements in cognitive task performance on a recognition memory task, and Foulds et al. (1996) reported
improvement in performance on a task of sustained
attention. Rusted and Trawley (2006) recently reported
acute improvements in prospective memory following
nicotine administration. Moreover, even after brief abstinence, smokers exhibit reduced functional efficiency (as
indexed by the BOLD measure of region-specific blood
oxygen) in the right frontal eye field in a test of selective
attention that was reversed with the resumption of smoking
(Xu et al. 2007). Consistent with the human studies, French
et al. (2006) recently reported that nicotine improves the
ability of aged female rats to handle increasing levels of
demand on working memory.
Clinical studies using nicotine skin patches have
demonstrated that short-term nicotine treatment can improve cognitive performance in a variety of groups: normal

263

non-smoking adults, AD patients, schizophrenics, and

adults with Attention-Deficit Hyperactivity Disorder. The
improvement is seen principally in terms of improved
attentional performance. The nicotine-induced memory
improvement does not diminish with chronic administration and has been seen to persist even after withdrawal.
In experimental studies using animal models, working
memory improvements have been demonstrated with
acute and chronic nicotine treatment (Rezvani and Levin
2001).
In a paper that will surely be regarded in the future as
seminal to understanding cross-study differences in the
impact of nicotine on cognition, Jacobsen et al. (2006)
found that nicotine administration worsened accuracy of
verbal working memory in dopamine receptor D2 (DRD2)
957T allele carriers while having no effect in 957C
homozygotes regardless of current smoking status. Prior
evidence suggested that carriers of the 957T allele have
increased DRD2 binding availability in humans (Hirvonen
et al. 2004). It is possible that nicotine causes an overshoot
of dopaminergic stimulation in 957T carriers, leading to
reduced efficiency and performance. The importance of this
study is that it suggests the possibility that nicotine will be
effective in the enhancement of cognition of some but not
all people and that variation in cognition-related genotypes
could explain inconsistencies previously noted in the literature.
Because the prevalence of tobacco use among individuals with schizophrenia may be as high as 80% (Leonard
and Adams 2006; Williams and Foulds 2007; Hughes et al.
1986; de Leon and Diaz 2005), interest continues to focus
on the use of medicinal nicotine to enhance reduced
cognition associated with schizophrenia. Smith and colleagues (Smith et al. 2002; Smith et al. 2006) used a doubleblind, placebo-controlled design to examine the effects of
nicotine nasal spray on cognition in schizophrenics. They
found that active nicotine nasal spray improved performance
on a spatial organization task, and some measures of verbal
memory and reaction time (Smith et al. 2002). In a
subsequent study, these investigators were unable to replicate
the initial finding for verbal memory and concluded that the
clinical relevance of nicotine to the management of
schizophrenia remains limited (Smith et al. 2006).
While nicotine may have therapeutic effects on neuropathologic processes in aging adults, the opposite effect
may be the case in developing fetuses and younger
children. Nicotine induces free radicals, depletes antioxidant defense mechanisms, and increases markers of
oxidative stress in neural cells (Qiao et al. 2005). Moreover,
a recent preclinical study using a rat model found that
prenatal nicotine exposure induced permanent changes in
indices of cholinergic and serotonergic synaptic function
that was similar in adolescent animals after exposure to
nicotine at levels equivalent to those found in smokers, the

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effect being greater in males than in females (Slotkin et al.

2007). This result, along with others, led to a recent caution
about the potential harmful effects of nicotine replacement
therapy in pregnant mothers on the neurological development of their fetuses (Ginzel et al. 2007).
Effects of Smoking
In the first prospective study of the relationship between
smoking in middle age and later life cognitive performance
(over a 20-year interval), Galanis et al. (1997) reported that
continuous smoking over that interval was associated with
an increased risk of cognitive impairment (odds ratio=1.4)
on the Cognitive Ability Screening Instrument (CASI; Teng
et al. 1994) in 3,429 Japanese-American men. Characteristic of more recent investigations of the relationship between
smoking and one-time measures of cognition are the studies
of Aleman et al. (2005) and Muller et al. (2007). These
studies employed more specific measures of processing
speed, memory, and executive function. Aleman et al.
examined the relationship between vascular risk factors,
including smoking, and performance in several cognitive
domains in 400 independently living men 40 to 80 years of
age and concluded that smoking was one of the strongest
predictors of decreased processing capacity and speed along
with a reduced MMSE score. A subsequent study of this
cohort determined that cardiovascular disease, one of the
results of smoking, was associated with lower memory
performance (Muller et al.). Thus, these studies demonstrate
that smoking can have both direct and indirect negative
effects on cognition.
Cognitive Decline
In this section, we consider the evidence for an association
between smoking and subsequent change in cognitive
performance as assessed at two or more time points. An
early study administered cognitive assessments to 10,963
individuals on two occasions separated by 6 years. At first
exam, subjects ranged in age from 47 to 70 years.
Cognitive assessments included the delayed word recall
test, a 10-word delayed free recall task in which the
learning phase included sentence generation with the study
words, the digit-symbol substitution test, and the first letter
word fluency test using letters F, A, and S. The presence of
hypertension and diabetes at baseline was associated with
greater decline in cognitive tests, but smoking status was
not associated with change in cognitive scores on these
tests (Knopman et al. 2001).
A number of subsequent papers, however, provide more
evidence for the assertion that smoking is associated with
greater decline in a variety of cognitive domains including:
verbal memory (assessed by a 15 item word-learning task in

Neuropsychol Rev (2007) 17:259273

which participants were shown each word for 2 s, then

asked to write down all they could remember; total correct
over three trials was recorded) and visual search speeds in
3,035 participants over a 10-year interval beginning when
the participants were an average of 43 years of age
(Richards et al. 2003); MMSE scores in 17,006 persons
aged 65 and older over an average interval of 2.3 years (Ott
et al. 2004); memory (a composite factor score comprising
the seven subscales from the Selective Reminding Test,
Buschke and Fuld 1974) in older adults (more than 75 years
of age) and those without an APOE 4 allele over a 5-year
interval Reitz et al. 2005); and auditory verbal learning
(Rey 1964) and executive function in 298 individuals of
mean age 66 years over a 2-year interval (Starr et al. 2007).
In an attempt to separate the effects of aging from the
effects of smoking, the studies cited above either adjusted
for age in the prediction models or conducted analyses on
the sample after stratification by age group.
Overall, smoking appears to be associated with greater
rates of decline in verbal memory and processing speed.
This association may be age-dependent and mediated by
genotype status of APOE. The decline in these domains is
also paralleled by smokings association with greater rates
of functional decline in the physical domain (Wang et al.
2002; Atkinson et al. 2005). The available published data,
however, are not sufficiently detailed to permit further
conclusions about smokings effects on decline in specific
components of verbal memory (e.g., short or long delayed
recall, free or cued recall, and recognition memory).
Dementia
A number of studies have reported an association between
smoking and an accelerated risk for dementia (Meyer et al.
1999; Meyer et al. 2000), AD (Tyas et al. 2003; Juan et al.
2004; Luchsinger et al. 2005; Hulse et al. 2005; Aggarwal
et al. 2006), and VaD (Tyas et al. 2003; Roman 2005; Stella
et al. 2007). Only a few studies have failed to find an
association between smoking and dementia (Kalmijn et al.
2000) or AD (Bowirrat et al. 2002; Bhargava et al. 2006).
In a study of conversion of mild cognitive impairment
(MCI) to dementia in 165 elderly outpatients followed for
an average of 3 years, risk factors associated with the
probability of conversion included atrial fibrillation and low
serum folate levels, but not smoking (Ravaglia et al. 2006).
In viewing these results it is important to point out that
varying approaches to case definition exist across studies.
These include the use of: (1) clinical and DSM-III-R or
DSM-IV criteria for dementia (Loeb and Meyer 1996; Gold
et al. 1997; Meyer et al. 1999; Meyer et al. 2000), AD
(Juan et al. 2004; Bowirrat et al. 2002), and VaD (Stella et
al. 2007), or (2) the use of consensus guidelines for AD
(McKhann et al. 1984; Tyas et al. 2003; Luchsinger et al.

Neuropsychol Rev (2007) 17:259273

2005; Kalmijn et al. 2000; Bhargava et al. 2006) and VaD

(Roman et al. 1993; Roman 2005). The use of different
diagnostic approaches in case definition introduces additional complexity in characterizing the literature on smokings role in the different forms of dementia.
Of special note is the study by Tyas et al. (2003), which
related midlife risk factors in 3,734 men seen between the
years of 1965 and 1971 and then followed for assessment
for dementia from 1991 to 1996 (mean age=78 years). The
risk of AD in smokers increased with packyears of smoking
at medium and heavy smoking levels. In an autopsied
subsample, the number of neuritic plaques increased with
amount smoked. When very heavy smokers were excluded,
there was a strong doseresponse relationship among
smokers between amount smoked and risk of AD, AD plus
cerebrovascular disease, and all dementias combined.
Compared with light smokers, the adjusted risk of AD
was significantly increased among smokers, with an even
higher risk of AD in the heavy smoking group. Compared
with never smokers, former smokers had significantly more
neuropathology in the neocortex and slightly more in the
hippocampus. Medium and heavy smokers had significantly more neocortical neuropathology than light smokers.
A recent focus of study in the etiology of AD has been
on the role played by atherosclerotic vascular risk factors in
increasing the risk of cognitive impairment, AD, and
vascular cognitive impairment (Gorelick 2004). Casserly
and Topol (2004), in their review of the evidence,
concluded that vascular risk factors converge to increase
the presence of mis-folded amyloid after a substantial
incubation period, thereby contributing to the risk of AD.
This hypothesized convergence received empirical support
in a study by Newman et al. (2005) in which the incidence
of dementia and of AD was higher in the presence of
cardiovascular disease other than stroke in elderly participants of the CHS. Rates of AD were the highest in those
with peripheral arterial disease, with an adjusted hazard
ratio of 2.4. Again, the evidence suggests that smoking can
have both direct and indirect negative effects on risk for
neurodegeneration.

Possible Mechanisms
Smoking
Oxidative Stress
Understanding the complex nature of AD has evolved with an
increased appreciation for pathways that involve the generation of reactive oxygen species (ROS) and oxidative stress,
apoptotic injury that leads to nuclear degradation in both
neuronal and vascular cell populations, and the early loss of

265

cellular membrane asymmetry that mitigates inflammation

and vascular occlusion. Oxidative stress is considered to play
a significant role in the onset and progression of AD.
Transient hypoxia in sporadic AD can lead to mitochondrial
dysfunction, impaired membrane integrity, and amyloid
precursor protein cleavage. During the progression of AD,
lipid peroxidation, protein oxidation, and DNA oxidation
occur. There exists a close correlation between oxidative
stress and amyloid deposition. Amyloid has been found to
result in the generation of ROS, such as hydrogen peroxide,
through metal ion reduction and, subsequently, to oxidative
toxicity in neurons. Application of the free radical antioxidant
vitamin E has been demonstrated to prevent neurotoxicity
from amyloid . Cellular oxidative pathways that proceed
through apoptosis appear to be a predominant factor in the cell
loss observed during AD (Chong et al. 2005; Mazza et al.
2007; Mariani et al. 2005; Butterfield et al. 2006).
Compared with non-smokers, on average, active smokers
have more than 25% lower circulating concentrations of antioxidants such as ascorbic acid, carotene, carotene, and
cryptoxanthin. The associations observed with active smoking also appear to hold for passive smoking. Cigarette smoke
is a significant source of oxidative stress. This direct exposure
from cigarette smoke represents only a portion of the total
oxidative stress eventually experienced by the smoker.
Cigarette smoke also contributes to additional endogenous
oxidant formation through effects on the inflammatory
immune response pathway. Cigarette smoke could also result
in increased metabolic turnover with antioxidant micronutrients expended in response to the increased oxidative
stress caused by cigarette smoking or, alternatively, smoking
could decrease micronutrient absorption (Alberg 2002).
Oxidative stress damage is also intimately linked to
glutamate neurotoxicity. An excessive concentration of
extracellular glutamate overactivates ionotropic glutamate
receptors, resulting in intracellular calcium overload and a
cascade of events leading to neuronal cell death (Butterfield
et al. 2006). Exposure of rat brain to cigarette smoke,
results in an increase of ROS and nitric oxide synthase
(NOS) leading to lipid peroxidation, protein oxidation, and
DNA damage. In this model, cigarette smoke also induces
heat shock proteins and apoptosis, a conserved response to
various conditions including oxidative stress (Anbarasi et
al. 2006). Long-term exposure to sidestream smoke has also
been shown to result in the activation of markers indicative
of oxidative stress in mouse brain. Following 6 months of
exposure, an increase of ROS was noted in the cerebellum,
frontal cortex, hippocampus, and striatum along with an
increase in lipid peroxidation. An increase in pro-inflammatory
markers in all areas of the brain was also observed (Manna
et al. 2006).
Cadmium, a component of tobacco smoke, induces
cellular death in cortical neurons in culture, possibly

266

through apoptotic or necrotic mechanisms as a secondary

effect of oxidative stress (Lopez et al. 2006). Nicotine, on
the other hand, in low, acute doses could act as an
antioxidant (Zhang et al. 2007).
Inflammation
Molecular components of the inflammatory response are
found to be in increased concentrations in AD and in lower
amounts in the aging brain without dementia. Inflammatory
markers are also reliably increased in the presence of
atherosclerosis (Whalley et al. 2004). During the acute
phase of inflammatory states, there are quantifiable
increases in C reactive protein, white blood cell count,
and fibrinogen, and decreases in serum albumin (Bakhru
and Erlinger 2005). Interleukin-6 (IL-6) and interleukin8 (IL-8) are important in the recruitment and activation of
inflammatory cells. The induction of these pro-inflammatory
mediators is regulated by the activation of a redox sensitive
transcription factor. This transcription factor has been shown
to be activated by a wide variety of agents including
cigarette smoke (Kode et al. 2006). Moreover, IL-6 levels
have recently been reported to be associated with lower
MMSE scores with smoking as one of the strongest
covariates associated with IL-6 in older adults of mean age
67 years (Wright et al. 2006).
A unique analysis of data from 15,489 individuals who
participated in the NHANES III examined changes in
inflammatory markers and demonstrated a dose-dependent
and temporal relationship with smoking and smoking
cessation. Both inflammatory and traditional risk factors
improved with decreased intensity of smoking. The results
suggest that the inflammatory response to smoking may be
reversible with reduced tobacco exposure and subsequent
smoking cessation (Bakhru and Erlinger 2005).
Atherosclerosis
The damaging effect of smoking on the endothelium seems
to be the final common pathway leading to atherosclerosis
(Roman 2005). Endothelial lesions result not only in stroke,
but also in a number of alterations of the bloodbrain
barrier, cerebral blood flow, and brain metabolism. Tobacco
smoke contains a complex mixture of free radicals that
cause morphological changes of the endothelium, formation
of blebs (bladder-like structures with thin walls that may be
filled with fluid), leakage of macromolecules, and increased
endothelial cell death (Pittilo 2000; Roman 2005). Smoke
reduces prostacyclin release, enhances endothelium-derived
vasodilatation and decreases nitric oxide concentrations in
cyclic guanosine monophosphate (a cyclic nucleotide that
acts as a second messenger by activating intracellular
protein kinases in response to peptide hormones) produc-

Neuropsychol Rev (2007) 17:259273

tion, thereby increasing aggregation of platelets and

leukocytes. Smoking worsens atheromatous plaque formation in carotid arteries, increases hypertension, and blood
coagulability, serum viscosity and fibrinogen (Roman
2005). Smoking is a major risk factor for peripheral arterial
disease (Willigendael et al. 2004) and carotid atherosclerosis is associated with brain atrophy in older adults (Kin et
al. 2007). Cigarette smoking predisposes individuals to
vasomotor dysfunction, inflammation, and modification of
lipids, important components of the initiation and progression of atherosclerosis (Ambrose and Barua 2004).
In animal models and the human condition, several
studies have demonstrated that both mainstream and sidestream cigarette smoke exposure are associated with a
decrease in vasodilatory function. Nitric oxide, a free radical,
is primarily responsible for the vasodilatory function of the
endothelium. Not only is nitric oxide a vasoregulatory
molecule, it helps regulate inflammation, leukocyte adhesion, platelet activation, and thrombosis. Therefore, an
alteration in nitric oxide biosynthesis could have primary
and secondary effects on the initiation and progression of
atherosclerosis and on thrombotic events (Ambrose and
Barua 2004).
Interaction with Other Risk Factors
Tobacco smoking does not occur in isolation of other risk
factors that contribute to negative cognitive or brain
outcomes. A number of recent analyses provide evidence of
interactions between smoking and other contributors that, for
the most part, remain unexplored. For example, although
alcohol consumption and tobacco use have a high cooccurrence (approximately 80% of alcohol-dependent individuals [Hurt et al. 1994; Pomerleau et al. 1997; Romberger
and Grant 2004; Kessler et al. 1996] and 7090% of those
seeking treatment for alcohol abuse are smokers, Room
2004), the potential importance of their combined effect on
the brain and cognition has only recently been recognized
(Gentry-Nielsen et al. 2004; Gazdzinski et al. 2005).
Meyerhoff and colleagues have published a series of papers
demonstrating that chronic smoking in alcohol-dependent
individuals is associated independently with reduced Nacetylaspartate (NAA) in frontal and midbrain regions
(Durazzo et al. 2004), gray matter deficits in the neocortex
and increased temporal white matter volume (Gazdzinski et
al. 2005; Durazzo et al. 2007), lower cerebral perfusion in
frontal and parietal regions (Gazdzinski et al. 2006), and
greater number of errors on the Wisconsin Card Sorting Task
(Durazzo et al. 2005), a possible result of the neurotoxic
effects of tobacco smoke (Durazzo et al. 2007). These results
suggest the importance of assessing and controlling for the
effects of smoking history in studies of the effects of alcohol
on the brain.

Neuropsychol Rev (2007) 17:259273

Other interactions with potential importance to understanding the relationship between smoking, and cognitive
and brain outcomes involve those with variation in genes
that are implicated by themselves or in combination in the
pathogenesis of cerebrovascular disease. For example,
Pezzini et al. (2004) showed that in relatively young people
(average age of 34.7 years), the APOE 4 allele and
cigarette smoking act synergistically to increase risk for a
cerebral ischemic event. In a subsequent paper, these
authors expanded the scope of their investigation to include
the coagulation factor II (thrombin) (prothrombin), the
coagulation factor V (Factor V), and the 5,10-methylenetetrahydrofolate reductase (NADPH) (MTHFR) genes in
addition to APOE. They found that risk for ischemic stroke
in young people increased with the number of risk alleles
and especially so in current smokers (Pezzini et al. 2005).
While another recent study of the interaction between
APOE and smoking did not find an interaction that affected
cognitive performance in a number of domains in 4,227
participants of age 7080 years from the Nurses Health
Study, the authors stated that this negative result was most
likely due to the low prevalence of smoking in this cohort
(e.g., less than 10%; Kang et al. 2005). Support for the
hypothesis that carriers of APOE 4 have a reduced
antioxidant capacity thereby explaining the adverse synergy
that exists with tobacco smoke in these individuals was
recently reported (Proteggente et al. 2006).
Brain Effects Secondary to Other Conditions
As noted previously, it is possible that smokings apparent
direct effect on the risk for adverse cognitive and brain
outcomes is due to secondary or indirect effects on other
risk-enhancing conditions. For example, although coronary
heart disease (e.g., history of myocardial infarction) was not
associated with increased risk for dementia in one study
(Bursi et al. 2005), in another study, hippocampal volumes
in individuals with coronary artery disease (CAD), compared to those of healthy, matched controls free of
neurological, psychiatric, and cognitive impairment, were
smaller and, because the cases and controls were not
different on conventional risk factors, suggested that CADs
effects on the hippocampus could be due to an unmeasured
third variable common to both such as environmental
stress, a correlate of smoking and also with known negative
impact on this brain structure (Koschack and Irle 2005).
Another potential mediator of the smoking-cognitive/
brain outcomes association is lung function. As mentioned
previously, Richards et al. (2005) found that forced
expiratory volume after 1 s (FEV1) at age 43 years was
associated with lower psychomotor speed at the same age
and with slower decline in psychomotor speed from 43 to
53 years independently of smoking. The authors note that

267

cognitive function may be a marker of the general integrity

of the neurorespiratory regulation system. Smoking could
adversely effect pulmonary status through its impact on
Chronic Obstructive Pulmonary Disease (Rytila et al.
2006), which in turn, could have negative consequences
for cognitive and brain integrity. A cross-sectional analysis
in 469 people aged 6064 years found that indices of lung
function were associated with overall brain atrophy, higher
ventricle to brain ratio, larger WMHI volume, slower
information processing speed, and less fine motor dexterity
independently of smoking (Sachdev et al. 2006).
Depression and smoking are also highly correlated with
each other (Dierker et al. 2002). A follow-up of 6 years of
2,220 participants in the CHS cognition study found that
depressive symptoms were associated with increased risk of
MCI. The authors note that depression may cause damage
in the hippocampus through a glucocorticoid cascade. This
hypothesis is supported by evidence showing that older
adults with higher resting cortisol levels have poorer
memory and greater hippocampal atrophy (Lupien et al.
1998; Barnes et al. 2006). This suggests the need for
studies of the impact of either depression or smoking on the
hippocampus to adjust for the presence of each risk factor.
Neuroprotective Effects of Nicotine and Cotinine
As mentioned previously, there is interest in the possible
neuroprotective effects of nicotine for use in the treatment
of neurodegenerative disorders. The AD brain is characterized by two pathological hallmarks: amyloid plaques,
which are mainly composed of the amyloid peptide,
and neurofibrillary tangles, which consist of hyperphosphorylated tau protein. Chronic nicotine treatment has been
shown to reduce plaque burden in amyloid precursor
protein in transgenic mice (Hellstrm-Lindahl et al. 2004,
Nordberg et al. 2002).
Another recent study revealed that the protective effects
of nicotine on amyloid peptide may be offset by a
promoter effect on the phosphorylation of tau (Oddo et al.
2005). Thus, chronic nicotine intake causes an upregulation
of nicotinic receptors, which is correlated with a marked
increase in the aggregation and phosphorylation state of tau
(Oddo et al. 2005). These results are consistent with a
previously cited epidemiologic study showing a positive
correlation between the amount of smoking and the
neurofibrillary tangle load in brains of 301 patients with a
known history of smoking (Tyas et al. 2003). These studies
highlight the need to test the application of nicotine to
ameliorate AD pathology in a model with both neuropathological lesions because of the differential effects it can
have on each (Oddo et al. 2005).
The effects of nicotine in the aging brain are obviously
complex and may also influence neurotrophic factors.

268

Gallinat et al. (2007) reported that NAA concentration was

significantly reduced in smokers as compared to age, sex,
and education-matched nonsmoking adults in the left
hippocampus but not in the anterior cingulate cortex,
thereby suggesting region-specific neuronal damage. On
the other hand, French et al. (2006) recently reported that
along with enhancement of working memory in aging
female rats, nicotine also induced a reduction in the
hippocampal expression of nerve growth factor (NGF)
protein, a positive effect, although this relationship may be
mediated by age and gender.
A recent focus has been on the neuroprotective effects of
cotinine, the major metabolite of nicotine mediated by the
P450 gene, CYP2A6 (Swan et al. 2005). Preliminary data
suggest that cotinine exhibits the properties of a weak 7
subtype nicotinic agonist and that cotinine administration
leads to improvement in performance accuracy on a
delayed matching task in monkeys and can reverse drug
induced deficits in pre-pulse inhibition of acoustic startle in
rats. The drug has also been shown to be as potent as
nicotine in the ability to act as a cytoprotective agent in
cells that express a neuronal cholinergic phenotype (Buccafusco
and Terry 2003; Buccafusco et al. 2007).

Conclusions
Tobacco smoke is a highly complex mixture of compounds,
many of which have known toxic effects on the cardiovascular, cerebrovascular, and pulmonary systems. Because of
the number of compounds present in tobacco smoke, a
complete picture of organ-specific toxicity is not yet
available. However, there is sufficient evidence at the
epidemiologic level to support the conclusion that a history
of smoking is clearly associated with preclinical changes in
the brain (atrophy, silent infarcts, and WMHIs), accelerated
cognitive decline (executive function, verbal memory,
speed of processing), and increased risk for dementia (AD
and VaD). Exposure to sidestream smoke, especially in
fetuses and children, is associated with poorer neurocognitive performance. While the precise mechanisms
underlying these associations is not known definitively, in
part because of the complexity of tobacco smoke, work in
animal models and at the cellular level suggest that tobacco
smoke increases oxidative stress in the brain and other
organs and induces an inflammatory response that may
directly or indirectly promote atherosclerosis and neuropathology associated with AD.
Acute administration of nicotine, as distinguished from
tobacco smoke, appears to enhance measures of vigilance,
selective attention, working and verbal memory, and
executive function in adult nonsmokers and non-deprived
smokers. Most likely this performance enhancement effect

Neuropsychol Rev (2007) 17:259273

is mediated by activation of the cholinergic system and

subsequent downstream effects on neurotransmitter release
including dopamine and serotonin. Although the use of
medicinal nicotine in the management of certain CNS
disorders such as AD and schizophrenia has been proposed,
definitive evidence is lacking. A recent study in animals
showing that nicotine promotes a component of AD
neuropathology suggests that caution is warranted. Because
nicotine is a promoter of oxidation in neural cells, it appears
to be especially toxic to the neurodevelopment of fetuses
and young children.
Almost all of the epidemiological evidence for a
smoking-cerebrovascular disease connection has relied
upon broad, fairly non-specific measures of smoking (e.g.,
classifications such as current, never, former smoking) or
cumulative measures of exposure (e.g., packyears). To
enhance further understanding of this relationship, future
studies should incorporate topographical measures of
smoking (e.g., puff volume, puff rate), biomarkers of
exposure (e.g., cotinine), and biomarkers of oxidative
stress, inflammation, and/or atherosclerosis (Scherer 2005).
Except for investigations reported within the last few
years, much of the epidemiologic evidence for an adverse
impact of smoking on brain function has relied upon global,
non-specific measures such as the MMSE. No doubt this is
a consequence of the difficulty of incorporating more timeintensive measures of specific cognitive functions into large
epidemiologic investigations. Nevertheless, the incorporation of more specific measures such as of working memory
could lead to enhanced understanding of the deleterious
effects of smoking on brain function.
Another area that is likely to lead to increased
understanding of the tobacco smokebrain connection is
the interaction with other risk factors such as alcohol
dependence and depression. The possibility of geneexposure interactions has been raised in the literature and
suggests that some people, by virtue of their genetic
background, may be more susceptible to the harmful effects
of tobacco smoke on the brain. Examination of the synergy
between medicinal nicotine and genetic variation in pathways involved in human cognition will also prove to be
fruitful in understanding adult variability in responses
indicating performance enhancement. Candidate genes of
high interest include: COMT (catechol-O-methyltransferase;
Harris et al. 2005; OHara et al. 2006; de Frias et al. 2005;
Barnett et al. 2007), APOE (apolipoprotein E; Pezzini
et al. 2004), CAMTA1 (calmodulin-binding transcription
activator 1; Huentelman et al. 2007), KIBRA (WW and C2
domain containing 1; Papassotiropoulos et al. 2006),
BDNF (brain derived neurotrophic factor; Egan et al.
2003), SORL1 (sortilin-related receptor, L[DLR class] A
repeats-containing; Rogaeva et al. 2007), PKC (protein
kinase C; de Quervain and Papassotiropoulos 2006), PKA

Neuropsychol Rev (2007) 17:259273

(protein kinase A; de Quervain and Papassotiropoulos

2006), PRNP (prion protein; (Papassotiropoulos et al.
2005)), and HTR2A (5-hydroxytryptamine-2a-receptor; de
Quervain and Papassotiropoulos 2006).

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