ORIGINAL CONTRIBUTION

Pooled Analysis of Tobacco Use

and Risk of Parkinson Disease
Beate Ritz, MD, PhD; Alberto Ascherio, MD, DrPH; Harvey Checkoway, PhD;
Karen S. Marder, MD, MPH; Lorene M. Nelson, PhD; Walter A. Rocca, MD, MPH;
G. Webster Ross, MD; Daniel Strickland, PhD; Stephen K. Van Den Eeden, PhD; Jay Gorell, MD†

Context: Epidemiologic studies have reported that ciga-
rette smoking is inversely associated with Parkinson dis-
ease (PD). However, questions remain regarding the effect
of age at smoking onset, time since quitting, and race/
ethnicity that have not been addressed due to sample size
constraints. This comprehensive assessment of the ap-
parent reduced risk of PD associated with smoking may
provide important leads for treatment and prevention.
Objective: To determine whether race/ethnicity, sex,
education, age at diagnosis, and type of tobacco modify
the observed effects of smoking on PD.
Design, Setting, and Participants: We conducted
the first ever pooled analysis of PD combining individual-
level data from 8 US case-control and 3 cohort studies
(Nurses’ Health Study, Health Professionals Follow-Up
Study, and Honolulu-Asia Aging Study) conducted be-
tween 1960 and 2004. Case-control studies provided data
for 2328 PD cases and 4113 controls matched by age, sex,
and ethnicity; cohort studies contributed 488 cases and 4880
controls selected from age- and sex-matched risk sets.
Main Outcome Measure: Incident PD.
Results: We confirmed inverse associations between PD
and smoking and found these to be generally stronger
in current compared with former smokers; the associa-
tions were stronger in cohort than in case-control stud-
ies. We observed inverse trends with pack-years smoked
at every age at onset except the very elderly (⬎75 years
of age), and the reduction of risk lessened with years since
quitting smoking. The risk reductions we observed for
white and Asian patients were not seen in Hispanic and
African American patients. We also found an inverse as-
sociation both for smoking cigars and/or pipes and for
chewing tobacco in male subjects.
Conclusions: Our data support a dose-dependent re-
duction of PD risk associated with cigarette smoking and
potentially with other types of tobacco use. Impor-
tantly, effects seemed not to be influenced by sex or edu-
cation. Differences observed by race and age at diagno-
sis warrant further study.
Arch Neurol. 2007;64(7):990-997

Author Affiliations are listed at
the end of this article.
†Deceased.
E
ARLY CASE-CONTROL STUD-
ies suggesting that patients
with Parkinson disease (PD)
are less likely to be smok-
ers were criticized as bi-
ased. The observation is counterintui-
tive; cigarette smoke has long been
recognized as a cause of adverse health ef-
fects. Thus, selective survival of PD cases
and reporting bias were suggested as pos-
sible explanations. In the 1990s, reports
from prospective cohort studies lent more
credibility to the assertion that smoking
may play a protective role in PD.1-3 Re-
cent studies also suggested that PD risk is
particularly low in active smokers with a
long history of intense smoking; some even
suggested dose-related risk reductions with
increasing pack-years of smoking.3-7 This
prompted speculation as to whether and
how these observations might inform PD
treatment and prevention.8
The small size of most PD studies and
the aggregate nature of meta-analytic
data, including the most recent meta-
analysis,9 limit our ability to answer im-
portant questions about the role smok-
ing plays in PD. These questions include
the importance of smoking intensity vs du-
ration, the influence of age of starting or
quitting, the time interval after smoking
cessation and before disease onset, and the
type of tobacco product (cigarettes, ci-
gars, pipes, or chewing tobacco). Further-
more, no single PD study to date has had
adequate sample size or diversity to ad-
dress the influence of race/ethnicity, sex,
education, or age at diagnosis on the ob-
served smoking effects. Here, we address
these issues in the first ever pooled analy-
sis of PD where we combine individual-
level data from 8 US case-control and 3 co-
hort studies.

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 Table 1. Characteristics of Study Subjects

Cohort Studies
Case-Control Studies US Health
Professionals3
New Northern Northern
Washington York California Central Olmsted California Health Nurses’
Study State7 Detroit 5
City15 210 California12 County6 Nebraska 13
114 Honolulu2 Professionals Health
Cases, No. 364 108 205 496 179 149 253 491 139 191 158
Controls, No. 488 464 306 541 228 129 712 1245 1390 1910 1580
Mean age, y a 68.1 71.1 72.7 70.9 66.9 71.5 72.1 58 74.1 69 65.6
Male, % a 61 63 43 61 54 60 53 57 100 100 0
White,% 93 84 48 83 81 100 97 88 0 91 98
African American,% 2 13 14 5 2 0 1 7 0 1 1
Asian,% 2 1 0 4 3 0 ⬍1 4 100 2 1
Hispanic,% 1 1 36 7 9 0 ⬍1 0 0 0 0
Ever smoked cigarettes, 449 (53) 33 (59) 218 (43) 554 (54) 217 (53) 116 (43) 493 (51) 761 (51) 999 (65) 1082 (54) 978 (57)
No. (%) b
Cigarettes smoked, 26.0 44.3 38.5 38.2 19.8 43.7 44.0 16.3 d 45.6 28.7 21.0
mean, pack-years c
Age started smoking, 18.4 18.8 20.3 19.2 17.9 19.6 19.4 NA 20.8 20.4 20.1
mean, y
Age stopped smoking, 39.6 48.5 51.1 45.8 42.8 48.5 48.2 NA 51.1 54 42.4
mean, y
Ever/regularly smoked 177 (21) 164 (29) 60 (12) 169 (16) 86 (21) 63 (23) 153 (16) 203 (13) 200 (13) 196 (9) NA
cigars and/or pipe,
No. (%)

Abbreviation: NA, not available.

a Controls were matched to cases by age and sex in all studies.
b Out of all subjects for whom cigarette smoking information was available.
c In ever smokers.
d Smoking information was obtained in baseline survey only (1964 through 1972) and not updated at time of case diagnosis (1965 through 1992).

METHODS tive American, other), education (⬍12 years, 12 years, 13-15

STUDY DESIGN
Detailed smoking data were obtained from lead investigators
of 8 population-based or nested case-control studies5-7,10-14 and
3 cohort studies.2,3 The pooled data set included a total of 2328
PD cases and 4113 controls from case-control studies and 488
cases and 4880 controls selected in a nested case-control man-
ner from cohort studies. For our pooling effort, we asked that
each cohort identify 10 controls per case from age- and sex-
matched risk sets of all unaffected subjects at the time of case
diagnosis. Methods of identifying subjects and diagnosing cases
have been described previously.2,3,5-7,10-14 We included in our
analyses only those cases considered newly diagnosed such that
data were collected via interview within 3 years of diagnosis in
case-control studies. Age at diagnosis, but not age at first on-
set of motor symptoms, was available for all studies.
Requested covariate data included year of diagnosis or ref-
erence date (diagnosis or interview date), respondent type (self
or proxy), sex, date of birth, ethnicity, education, and tobacco
consumption. Specific information on tobacco included smok-
ing status, age started/stopped smoking, years and quantity
smoked, regular cigars or pipe smoking, and chewing tobacco
or snuff use. When requested data were not available, the study
was excluded from the specific analysis.
DATA ANALYSIS
Relative risks (odds ratios [ORs]) with 95% confidence inter-
vals (CIs) and dose-response trends, where applicable, were es-
timated for pack-years of cigarette smoking, smoking status (cur-
rent, former, never), and cigar-pipe smoking (ever regularly vs
never). The logistic regression models were adjusted for sex,
ethnicity/race (white, African American, Hispanic, Asian, Na-
years, ⱖ16 years), and an indicator variable for each study. For
unaffected subjects, we used time/age at which the matched case
had been diagnosed as the reference date for assessing smok-
ing. Subgroup analyses were conducted after stratification by
sex, age at diagnosis, race/ethnicity, and education. Stratum se-
lection for subgroup analyses was guided, and often limited,
by the level of detail in each of the studies contributing data
and the number of subjects per stratum.
For primary analyses involving smoking status and pack-
years, we excluded 1 study at a time from the pooled data set
to examine the influence of each study group and the consis-
tency of patterns of estimated effects. Trend tests for categori-
cal variables were conducted using the mean (for continuous)
or midpoint of each category. Finally, we examined the influ-
ence of the time interval after smoking cessation in categories
(never smoker; current smoker or quit smoking within past year;
quit smoking ⬎1 to 5, ⬎5 to 15, ⬎15 to 25, or ⬎25 years prior
to reference date). Through pooling we assembled enough data
to assess effect measure modification of pack-years smoked by
major racial/ethnic categories (African American, Asian, His-
panic, and white), age at diagnosis (⬍75 years, ⱖ75 years), and
time elapsed since quitting (0-4, 5-24, ⱖ25 years).
RESULTS
Major demographic and smoking-related characteris-
tics for each study in this pooled analysis are presented
in Table 1. Most case-control studies enrolled slightly
more male than female patients while each of the cohort
studies recruited exclusively subjects of 1 sex. On aver-
age, study subjects were in their mid 60s to early 70s when
diagnosed with PD or recruited as controls. Participants
were overwhelmingly white (81%-100%), except for the

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 60
A % Controls who start smoking
% PD cases who start smoking
50 % Controls who stop smoking
% PD cases who stop smoking
40 % Smokers among controls
% Smokers among PD cases

30

Smokers, %
20

10

–10

–20
0 10 20 30 40 50 60 70 80 90 101
Age, y

60
B

50

40

30
Smokers, %

20

10

–10

–20
0 10 20 30 40 50 60 70 80 90 101
Age, y

Figure. Percentage of smokers among female patients and controls from case-control studies by age (A) and among male patients and controls from case-control
studies by age (B). PD indicates Parkinson disease.

New York City study11 and the cohort study of Asian
males.2 In case-control studies, about half the subjects
reported ever having smoked cigarettes regularly and men
reported smoking more often than women (Figure). Most
participants initiated smoking in their late teens (mean
age, 18 years in men, 21 years in women), and most smok-
ers who had quit did so between the ages of 40 and 50
years. For both sexes, the percentage of subjects who
smoked peaked at age 30 years and declined steadily there-
after. Smoking initiation and quitting followed the same
general age pattern for cases and controls, but a smaller
percentage of patients with PD reported having ever
smoked regularly and those who stopped did so on av-
erage 2 to 5 years earlier than control subjects (men, 43
vs 45 years; women, 44 vs 49 years). Our cohort data gen-
erally confirmed these patterns (results not shown). The
average pack-years of cigarettes consumed by smokers
varied considerably between studies (16-46 pack-
years), reflecting both differences in the average amount
of cigarettes smoked per day (0.6-1.3 packs per day) and
the average duration of smoking (25-35 years).
While almost one-fifth of study participants reported
regular cigar and/or pipe smoking (Table 1), this to-
bacco use was almost exclusively reported by men (30%
vs 0.7%) and was more prevalent among cigarette smok-
ers: only 19% of regular cigar/pipe smokers did not re-
port regular cigarette smoking. In the 5 case-control stud-
ies that ascertained use of chewing tobacco, the reported
lifetime prevalence was generally low (4%-5% of all sub-
jects; 7% of all men, but only 1% of nonsmoking men).
Our pooled-risk estimates for current and former vs
never smoking suggest a similar sized risk reduction for
PD among men and women but a stronger reduction in
current than former smokers and in cohort studies com-

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 Table 2. Pooled Adjusted Odds Ratios (and 95% CIs) for Parkinson Disease for Current/Former/Ever Smokers
Compared With Never Smokers

Women Men Total

Cases, Controls, Odds Ratio Cases, Controls, Odds Ratio Cases, Controls, Odds Ratio
Study No. No. (95% CI) a No. No. (95% CI) a No. No. (95% CI) b
Case-control
Current smoker 737 1240 0.48 (0.36-0.64) 668 1112 0.55 (0.43-0.70) 1405 2352 0.53 (0.44-0.63)
Former smoker 880 1442 0.67 (0.55-0.82) 1129 1816 0.79 (0.68-0.93) 2009 3258 0.76 (0.68-0.86)
Ever smoking 955 1694 0.61 (0.51-0.72) 1257 2168 0.74 (0.64-0.86) 2212 3862 0.70 (0.63-0.78)
Cohort
Current smoker 95 904 0.28 (0.14-0.56) 195 1735 0.21 (0.12-0.37) 290 2639 0.23 (0.15-0.36)
Former smoker 148 1319 0.71 (0.50-1.00) 312 2769 0.61 (0.48-0.77) 460 4088 0.64 (0.52-0.77)
Ever smoking 157 1565 0.59 (0.43-0.83) 326 3219 0.52 (0.41-0.65) 483 4784 0.54 (0.45-0.65)

Abbreviation: CI, confidence interval.

a Adjusted for race, education, and original study.
b Adjusted for sex, race, education, and original study.

Table 3. Pooled Adjusted Odds Ratios (and 95% CIs) for Parkinson Disease and Pack-Years of Cigarette Smoking
in Case-Control Studies

Women Men

Cases, Controls, Odds Ratio Cases, Controls, Odds Ratio

Time Smoking No. No. (95% CI) a No. No. (95% CI) a
Nonsmoker b 512 715 1.00 [Reference] 438 559 1.00 [Reference]
Continuous (per 10 pack-years) 727 1218 0.93 (0.88-1.00) 970 1578 0.96 (0.92-0.99)
0 to ⬍9 pack-years 92 153 0.82 (0.61-1.11) 151 213 0.90 (0.70-1.16)
9 to ⬍29 pack-years 51 110 0.73 (0.47-1.13) 128 251 0.68 (0.52-0.88)
29 to ⱕ59 pack-years 37 118 0.53 (0.33-0.85) 137 265 0.80 (0.60-1.05)
ⱖ60 pack-years 35 122 0.52 (0.31-0.89) 116 290 0.64 (0.46-0.89)
Trend P value .01 .02

Abbreviation: CI, confidence interval.

a Adjusted for race, education, original study, and time since quitting.
b Reference group.

pared with case-control studies (Table 2). When com-
bining information on quantity and duration of ciga-
rette smoking, we observed inverse trends for PD with
increasing pack-years of cigarettes smoked: ie, an aver-
age 5% to 8% reduction in relative risk per 10 pack-
years (Table 3). Dose-response patterns were similar
in both sexes and not affected by restriction of compari-
sons with smokers (results not shown). Excluding 1 study
at a time from the pooled data set did not change the re-
sults. For smokers, we also observed inverse trends for
quantity of cigarettes and duration of cigarette smoking
separately.
For both sexes, a strong inverse dose-response trend
was observed for the number of years from cessation of
smoking to PD diagnosis (Table 4). This did not change
when we excluded never smokers from the comparison
group such that the reference group consisted only of
former smokers who had quit 25 years ago or more (re-
sults not shown). In analysis of pack-years stratified by
age at PD diagnosis, we observed a possible trend with
age, especially in men (Table 5). When stratifying by
age at PD diagnosis and time since quitting, the nega-
tive trend with pack-years was still observed in younger
age groups but not among persons aged 75 years and older
(age ⬍75 years per 10 pack-years, OR = 0.92 [95% CI,
0.88-0.96]; age ⱖ75 years, OR = 1.00 [95% CI, 0.96-
1.06]).
The negative associations with pack-years of ciga-
rette smoking were not influenced by educational sta-
tus; ie, effect estimates were similar in different educa-
tional strata (results not shown). However, we noticed
some race/ethnicity-specific effect measure modifica-
tion: the inverse association of pack-years on PD risk was
observed in white patients and possibly in Asian pa-
tients but was not seen in African American (99 cases,
226 controls) and Hispanic patients (130 cases, 160 con-
trols) (OR per 10 pack-years: African American, 1.01 [95%
CI, 0.93-1.11]; Hispanic, 1.02 [95% CI, 0.92-1.12]; Asian,
0.92 [95% CI, 0.70-1.20]; white, 0.94 [95% CI, 0.91-
0.97]; P value for interaction, .01 comparing white pa-
tients with African American and Hispanic patients).
A strong inverse association was suggested for regu-
lar smoking of cigars and/or pipes in our pooled male co-
horts (OR=0.46 [95% CI, 0.28-0.76]); cigar/pipe smok-
ing data was not available for the female cohort. In our
case-control studies, an inverse association with regular
lifetime cigar/pipe smoking was seen only among per-
sons who did not smoke cigarettes (cigarette nonsmok-

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 Table 4. Estimated Effects (Odds Ratios and 95% CIs) for Number of Years Since Subjects Quit Cigarette Smoking
in Case-Control Studies a

Women Men

Cases, Controls, Odds Ratio Cases, Controls, Odds Ratio

Cigarette Smoking No. No. (95% CI) b No. No. (95% CI) b
Nonsmoker/stopped ⬎25 years ago c 591 855 1.00 [Reference] 707 994 1.00 [Reference]
Stopped ⬎15 to 25 years ago 38 87 0.66 (0.44-0.99) 109 185 0.87 (0.66-1.13)
Stopped ⬎5 to 15 years ago 44 100 0.62 (0.42-0.91) 93 181 0.76 (0.58-1.01)
Stopped ⬎1 to 5 years ago 10 62 0.23 (0.12-0.46) 19 57 0.57 (0.33-0.98)
Current smoker or stopped ⱕ1 year ago 45 127 0.55 (0.38-0.80) 59 174 0.48 (0.34-0.66)
Trend P value ⬍.001 ⬍.001

Abbreviation: CI, confidence interval.

a Case-control studies excluding the “Northern California 1” study for which no time of quitting was available.
b Adjusted for race, education, and original study.
c Reference group.

Table 5. Estimated Effects (Odds Ratios and 95% CIs) for Pack-Years of Smoking by Age and Sex

Women Men

Cases, Controls, Odds Ratio Cases, Controls, Odds Ratio

Age Group No. No. (95% CI) a No. No. (95% CI) a
Case-control studies
All ages 719 1218 0.94 (0.88-1.00) 964 1564 0.95 (0.92-0.99)
⬍60 y 105 165 0.83 (0.65-1.07) 161 174 0.90 (0.75-1.08)
60-74 y 346 567 0.91 (0.83-0.99) 496 826 0.94 (0.89-0.99)
ⱖ75 y 268 486 0.96 (0.87-1.07) 307 564 1.01 (0.95-1.07)
P for interaction b 0.07 0.01
Cohort studies
All ages 150 1479 0.90 (0.76-1.07) 316 3114 0.92 (0.84-0.99)
⬍60 y 25 233 0.71 (0.39-1.29) 37 367 0.75 (0.45-1.14)
60-74 y 119 1190 0.96 (0.80-1.15) 161 1563 0.87 (0.77-0.98)
ⱖ75 y 6 56 NC 118 1184 0.97 (0.88-1.06)
P for interaction b NC 0.07

Abbreviations: CI, confidence interval; NC, not calculated.

a Adjusted for race, education, original study, and time since quitting; 10-year increments of pack-years.
b Interaction of age at diagnosis and pack-years.

ers, OR = 0.78 [95% CI, 0.58-1.05]; cigarette smokers,
OR=1.13 [95% CI, 0.93-1.37]). Chewing tobacco was rare
especially among nonsmokers, and we did not see any
association with PD in analyses that included women.
However, after adjustment for all other types of smok-
ing, an inverse association for use of chewing tobacco was
suggested for men (OR = 0.66 [95% CI, 0.43-1.02]).
COMMENT
The large data set of this pooled analysis enabled us to
investigate aspects of cigarette smoking and subgroup-
specific associations that could not be addressed ad-
equately in previous studies. Our analyses confirmed prior
reports of an inverse association between cigarette smok-
ing and PD similar in size to those reported in a recent
meta-analysis.9 We also showed that associations did not
differ by sex or educational status. Although we found
that current smokers and those who had continued to
smoke to within 5 years of PD diagnosis exhibited the
lowest risk, a decrease in risk (13%-32%) was also ob-
served in those who had quit smoking up to 25 years prior
to PD diagnosis. This later observation suggests that the
risk reduction is unlikely to be attributable to recent
changes in smoking habits resulting from behavior modi-
fications related to incipient disease onset.
Inverse associations with smoking were stronger in
our pooled analyses of cohort data. In cohort studies,
smoking is assessed repeatedly and prior to disease on-
set. Thus, smoking information in these studies is likely
more accurate and not influenced by recall bias. Better
exposure assessment reduces misclassification bias; thus,
smoking might be more strongly negatively related to PD
than estimates from case-control studies suggest.
Women are generally less likely to be affected by
PD.10,13,15 We found that both elderly female patients and
controls reported a lower lifetime prevalence of ever hav-
ing smoked (20% vs 32% smoked at the peak age of 30
years) compared with their male counterparts (44% vs
54% smoked at age 30 years). Female smokers generally
smoked less than male smokers (female patients and con-
trols on average smoked 56 and 64 pack-years; men, 64

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 and 71 pack-years). Yet, we observed very similar in-
verse associations by pack-year in both sexes. Thus, smok-
ing behavior cannot explain the sex difference in PD risk.
Interestingly, while we confirmed the dose-response re-
lationship between pack-years of smoking and PD, the in-
verse association was not seen in subjects older than 75 years
of age at diagnosis, regardless of whether we restricted this
analysis to smokers or included nonsmokers. A lack of pro-
tection due to smoking in older-onset patients with PD had
previously been noted by Mayeux et al16 and in the
EUROPARKINSON study17 while a 2003 meta-analysis cor-
roborated but did not replicate the finding.18 Tzourio et al17
pointed out that many previous studies had been re-
stricted to patients younger than age 75 years. Thus, we
calculated the average age at disease onset for all case-
control studies included in the meta-analysis by Hernan
et al9 and found that in studies reporting strongly protec-
tive ever-smoking odds ratios (OR range, 0.32-0.60) the
average age at PD onset/diagnosis was lower (58 years) com-
pared with studies reporting odds ratios in a less protec-
tive or no association range (ORs between 0.7 and 1.1; av-
erage age at onset, 68 years). However, PD case-control study
results can be affected by selection bias, in part because the
adverse effects of smoking on total mortality are more pro-
nounced among people without PD than among patients
with PD19,20 while cohort study results are sometimes lim-
ited by small numbers of older individuals. Nevertheless,
these findings are consistent with the hypothesis that smok-
ing may delay rather than prevent the onset of PD, and con-
firmation with larger numbers in prospective studies will
be important.
In our analyses of racial/ethnic subgroups, we did not
detect any association of smoking and PD in Hispanic
or African American subjects, although we did observe
an inverse association in white and Asian American sub-
jects; an association in Chinese subjects has been re-
ported previously.21 Therefore, the risk reduction ob-
served in this pooled study seems to be attributable to
white and Asian subjects. Possible explanations include
differential diagnosis and genetic diversity. Genetic poly-
morphisms are known to be differentially distributed
among racial groups22 and diversity of genetic variants
may be responsible for observed racial differences. A num-
ber of genes may modify the effect of smoking on dopa-
minergic neurons, including monoamine oxidases
(MAO A and B), cytochrome P450 enzymes, glutathi-
one S-transferases, N-acetyl transferase, dopamine and
serotonin receptor and transporters, and cannabinoid and
opioid receptors.23 Functional variations in enzymes me-
tabolizing cigarette smoke products may create varia-
tions in the risk profiles for PD in different racial groups
if the underlying genetic variants are differently distrib-
uted among racial groups. Gene-environment interac-
tion studies of MAO B, smoking, and PD have been
equivocal,24-26 but genetic influences on smoking behav-
ior and dopamine metabolism may be too complex to be
addressed in population studies targeting a single gene
or polymorphism. The apparent lack of a smoking-PD
association in African American and Hispanic individu-
als may suggest gene-environment interactions but needs
to be confirmed in future studies that target racially/
ethnically mixed populations.
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Our results for cigar and pipe smoking suggested a 54%
risk reduction for PD in our male cohort studies and a 22%
reduction among non–cigarette smokers assembled in case-
control studies, further corroborating the findings for ciga-
rettes. While our results for the use of chewing tobacco are
based on a very small number of regular users, it too sug-
gests a protective effect, at least in men. Similarly, a recent
study reported that current and former snuff use had a pro-
tective effect in male never-smokers.27
The biochemical basis for possible preventative ef-
fects of smoking, or of a substance delivered through ciga-
rette smoke, is not well understood, but animal stud-
ies28,29 have indicated 2 possible mechanisms: chemical
or biochemical processes may exist by which sub-
stances contained in cigarette smoke such as nicotine or
carbon monoxide exert a protective effect and promote
survival of dopaminergic neurons; or cigarette smoke al-
ters the activity of metabolic enzymes or competes with
other substrates for these enzymes and thereby alters the
production of toxic endogenous (dopamine quinones)
or exogenous (MPP⫹) metabolites.30
Alternatively, behavioral characteristics or personal-
ity traits of patients with PD may be confounding the ob-
served smoking association in that the same genetic or
constitutional traits that increase susceptibility to PD may
also prevent subjects from smoking. Thus, these traits
would be the common cause for both smoking behavior
and PD. Observations that smoking and personality are
associated with dopaminergic functions lend support to
this argument.31,32 Like others, we observed that a larger
percentage of patients with PD never establish a smok-
ing habit (5%-10% fewer cases than controls depending
on sex) and that patients with PD quit smoking, on av-
erage, 2 to 5 years earlier than control smokers. Both ob-
servations fit the personality trait hypothesis. However,
to account for the observed dose-response relationship
with pack-years in smokers, the trait hypothesis would
have to claim that when the constitutional trait is not
strong enough to prevent smoking completely, it causes
future PD cases to smoke less.
If smoking behavior is influenced by the same under-
lying genetic factors that contribute to PD risk, one would
expect the smoking-PD association to be diminished in
twins discordant for PD. Twin studies, however, re-
ported a 20% to 30% reduction of PD risk for ever or regu-
lar smoking in monozygotic and dizygotic same-sex male
twin pairs discordant for PD.33,34 Both studies also found
dose-response trends with smoking intensity or dura-
tion in male twins discordant for PD, casting doubt on
the possibility that the smoking effect might be solely at-
tributable to genetic confounding, at least in men.
CONCLUSIONS
Our analyses support a protective, dose-dependent role
for cigarette smoking and potentially other types of to-
bacco use on PD risk. Importantly, estimated effects
seemed unaltered by sex or education but were stronger
among those with younger age at onset. Differences ob-
served by race need to be further explored, especially to
assess whether they might be attributable to differential
WWW.ARCHNEUROL.COM
 underdiagnosis or whether they represent genuine dif-
ferences in effect. Ultimately only randomized interven-
tion trials can confirm that some components in to-
bacco are truly neuroprotective, negating the possibility
that a premorbid personality influences smoking behav-
ior among those who later develop PD.
These findings may have implications for the design of
future randomized intervention trials. If the protective effect
of nicotine on PD risk is limited to those with younger age
at onset, trials would best be conducted in younger indi-
viduals. Considering that smokeless tobacco may be pro-
tective, the drug delivery system need not be inhalation,
thus eliminating some of the dangers of smoking. Ciga-
rette smoke is known to have thousands of chemicals; how-
ever, most research in PD treatment has focused on nico-
tine because it protects against nigral neuron damage from
a variety of toxic insults in cell culture and in animal mod-
els of parkinsonism.8,29,30 Yet trials of nicotine delivered by
smoking, transdermal patches, or chewing gum in symp-
tomatic treatment of PD had mixed results.30,35 In the mean-
time, there is more to learn from epidemiologic studies with
enough statistical power to examine PD associations in sub-
groups such as users of chewing tobacco or nicotine gums
and patches, people exposed to secondhand smoke, or
groups that metabolize nicotine or other tobacco constitu-
ents at different rates.
Accepted for Publication: July 23, 2006.
Author Affiliations: Department of Epidemiology and En-
vironmental Health Sciences, University of California, Los
Angeles, School of Public Health, Los Angeles (Dr Ritz);
Department of Neurology, University of California, Los
Angeles, School of Medicine, Los Angeles (Dr Ritz); De-
partments of Nutrition and Epidemiology, Harvard School
of Public Health, Boston, Massachusetts (Dr Ascherio);
Department of Environmental and Occupational Health
Sciences, University of Washington, Seattle (Dr
Checkoway); Gertrude H. Sergievsky Center, Taub In-
stitute, and Departments of Neurology and Psychiatry,
Columbia University College of Physicians and Sur-
geons, New York, New York (Dr Marder); Division of Epi-
demiology, Department of Health Research and Policy,
Stanford University School of Medicine, Palo Alto, Cali-
fornia (Dr Nelson); Division of Epidemiology, Depart-
ment of Health Sciences Research, Mayo Clinic College
of Medicine, Rochester, Minnesota (Dr Rocca); Veter-
ans Affairs Pacific Islands Health Care System, Pacific
Health Research Institute, Honolulu, Hawaii (Dr Ross);
Research and Evaluation, Kaiser Permanente, Southern
California, Pasadena (Dr Strickland); Division of Re-
search, Kaiser Permanente, Oakland, California (Dr Van
Den Eeden); and Department of Neurology, Henry Ford
Hospital, Detroit, Michigan (Dr Gorell).
Correspondence: Beate Ritz, MD, PhD, Department of
Epidemiology and Environmental Health Sciences, UCLA
School of Public Health, 650 Charles Young Smith Dr S,
Los Angeles, CA 90095-1772 (britz@ucla.edu).
Author Contributions: Study concept and design: Ritz,
Ascherio, Checkoway, Marder, Nelson, Rocca, Strickland,
and Van Den Eeden. Acquisition of data: Ascherio,
Checkoway, Marder, Nelson, Rocca, Ross, Strickland,
Van Den Eeden, and Gorell. Analysis and interpretation
(REPRINTED) ARCH NEUROL / VOL 64 (NO. 7), JULY 2007
996
©2007 American Medical Association. All rights reserved.
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of data: Ritz, Ascherio, Checkoway, Nelson, and Rocca.
Drafting of the manuscript: Ritz, Checkoway, and Nelson.
Critical revision of the manuscript for important intellec-
tual content: Ritz, Ascherio, Checkoway, Marder, Nelson,
Rocca, Ross, Strickland, and Van Den Eeden. Statistical
analysis: Ritz, Ascherio, Checkoway, Nelson, Rocca, and
Strickland.
Financial Disclosure: None reported.
Additional Information: The late Dr Gorell was the chair
in Neurology at Henry Ford Hospital in Detroit, Michi-
gan, and a movement disorder specialist and the director
of the William T. Gossett Parkinson’s Disease Center.
Additional Contributions: We thank all coinvestiga-
tors, collaborators, and study subjects who participated
in the original studies.
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