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The influence of smoking on the risk of Alzheimer's disease C. Merchant, MD, MPH; M.-X. Tang, PhD; S.. Albert, PhD, MSc; J. Manly, PhD; Y. Stern, PhD; and R. Mayeux, MD, MSc Article abstract--0bjectioe: To investigate the.relationship between cigarette smoking and Alzheimer s disease (AD) in a prospective community-based study in northern Manhattan. Background: Results from previous case-control studies suggest that there is a protective effect of smoking on AD. However, the recent prospective Rotterdam Study found that there was an increased risk of AD for smokers, particularly those without an apolipoprotein-E (APOE)rt4 allele. Methods: The authors examined data from a community-based longitudinal study of local elders residing in northern Manhattan to determine whether tobacco use increases or decreases the risk of AD. Information regarding the frequency of tobacco use was obtained in structured interviews at the baseline assessment. Standardized clinical assessments were subsequently completed on each subject at annual visits during which incident.cases of AD-were identified. Results: Thee relative risk (RR) of AD among former smokers was 0.7 (95% CI, 0:5 to.1.1)..The;RR-among current smokers was 1.9-(95% Ci,.1:2 to 3.0). Smokers without anAPOE-e4 allele had the highest risk ofADt(RR =2:1;'95% CI, 2.1 to 3[7)~compared with those with an APOE-E4 allele (RR = 1:4; 95% CI, 0:6 to 3:3). Conclusions: Ourresults~ are consistent with;the observationn that . . . ... . . . .. . . . smoking increases the risk of AD. However, we found that among previous smokers who quit smoking, there may be a slight reduction in the risk of AD. - . NEUROIAGY 1999;52:1408-1412 It has been proposed that smoking augments.cliolin- ergic metabolism by upregulation of.cholinergic nico- tinic . receptors in the brain.' Many of the man- ifestations:ofAlzheimer's disease (AD) are attributed to alterations in acetylcholine metabolism24 and as a result, smoking was thought to decrease the risk or at least retard the onset of symptoms associated taith AD thiough this mechanism. Methodological limitations of previous case-control studiess-7 have;generated interest in conducting pro- spective studiesto examine the relationship`between smoking: and AD. A recent study from The Nether- lands examined the association of cigarette smoking with dementia and AD.e Their results show that in comparison with those who.never smoked, smokers had a twofold increase risk of dementia and AD. . In:our prospective commi}nity-based study, weex- amined data colleeted prospectively from elders re= siding in northern Manhattan. We postulated that the risk of AD would be elevated among current smokers compared with past smokers or those' who do not have a smoking history. Recognizing the link between apolipoprotein E(APOE)-e4. alnd AD,'-rr we posited that the e4 allele might effect the association between smoking and AD risk. Methods. Setting and participants. Data were ana- lyzed from a sample of Medicare recipients in threee contig- uous zip codes within the community of Washington Heights in northern Manhattan, New York City. A total of 2,128 persons participated.in the initiall phase of the study. A. 90-minute; in-person interview of general health and function was completed. This structuredinter- view aIso1ncluded questions about years of formal educa- tion. The interview was followed by a standardized clinical assessment including a~inedical history, physical and neu- rologic,eu+nunation, and~ a brief (approti-mititely ] hour) neuropsyc:hologicalbattery developedpreviously#or use in thiscommunity."•"These same clinicalassessments were used in the annual follow-up of all participants. 'I`heinter- viewswere conducted in either English or Spanish. The Columbia University Institutional Review Board reviewed and approved-this project. All participants provided writr ten informed:consent. .For-•this -studg- data-were--exciuded~=fi-oin--290- people (13.6%n)..who were found demented-at the:initial.interview __ .., _,...._ (using the metho.ds described), 349 (16:4%) who refused subsequent'#ollow-up, 155(735) who dieil~after theinitial examinatiou,: 129 (6.1%) missing smoking information, 25 (1.2%) individuals with PD, 117(5:5'%) with stroke, and 1 individual' with both PD and stroke.All-data from the remaini~a-1,062 elderly (730 women and 352 men) without dementia wen>.o c:onsidered appropriate'for the investiga- tion. Annual follow-up exaniinations were conducted over an average of2:04 years. AD diagnosis. All participants were examined by a neurologist or an appropriately trained.internist or psychi- From the Gertrude H. Sergievsk,y Center (Drs. Meraltant, Tang, Albert, Manly, Stern, and Mayeua), the Taub Center for.Alzheimer's Disease Research in the City of New York (Drs. Merchant, Tang, Albert, Manly, Stern, and Mayeux), and the Departments of Neurology (Drs. Merchant, Stezn, and Mayeux) and Psychiatry (Drs. Manly, Stern, and Mayeuzl, College of Physicians and Surgeons, Columbia University, New York, NY. Supported by federal grants AG07232 and AG08702, the Charles S. Robertson Memorial Gift for AlzheimeYs Disease 5om the Banbury Fund, and the Blanchette Hooke Rockefeller Fund. . Received October 20, 1998- Accepted in final form January 9, 1999. Address rorrespondence and raprint requests to Dr. Richard Mayeuz, G.H. Setgievsky Center, 630 West 168th Street, Columbia University, New York. NY 10032. 1408 Copyright ® 1999 by the American Academy of Neurology ~ `yyySV6OO5 .

atrist, and all underwent neuropsychological testing. The data from the initial and follow-up examinations and inter- views, and any existing medical records and imaging stud- ies were reviewed collectively at a consensusconference of physicians and neuropsychologists to establish diagnoses. Clinicians were unaware of the APOE genotype during the diagnostic process. The diagnosis of dementia or the spe- cific clinical diagnosis of AD-was based on specified re- search criteria"15 and required evidence of cognitive deficit on clinical evaluation.in addition to objective neuro- psychological firndings, as well as-evidenceof impairment in social or occupational function. Patients meeting crite- ria14 forprobable-or possible ADwith a Clinical Dementia Rating's score of 1.0 or higher were considered to have the clinical diagnosis of AD. To exclude the diagnosis of mixed dementia (i.e., AD and va_scular.dementia), cerebrovascu- lar disease was identified by a clinical history of stroke or TIA, or by evidence of cerebrovascular, lesions on brain imaging. All those with any history of cerebrovascular dis- ease or mixed dementia were.excluded-from the study. Ethnic.group. ~For ethnicgrdupclassification weused the format suggested by the 1990 United States Census Bureau." In the first question, participants were asked to which ethnic group they belonged. The possible responses included white, black (African American or Caribbean American), American Indian, Asian, or other. Regardless of the response, a second question-asked whether or not the person being interviewed considered him or herself Hispanie:-Several choices were then provided.to indicate specific,:Hrspanic origin (e.g.;-:Puerto-~Rico;-Dominican Re- public,Cuba), Each.individual was also asked to identify the'country-of their birthplace. For this-study, we.used the categoriesof.black. (non-Hispanic),.wMte (non-Hispanic), and Hispanic consistent with the census.data.-- IRisk {actw intenviem. A-structured risk factor ques- tionnau'e w as developed for~-the z~~.us,mentof exposures to putative risk-factors related to-dement.ia.'a The interviews weregiven in English andSpanish-.accordingto the prefer- -enceofthepatient.--- . T-For.smoking there were three sets`af questions. A trig- ger question asked whether ornot the individual ever smoked at least one cigarette per day fora period of 1 year -or more: If the answer was -no, no further questions were -asked;If the subject answered yes, -the individuall was askedatwhat agetheybegan smoking;!whether they were still.smoking,'at.what age they-had stoppedif no longer smoking; and how many cigaiettesron-average they had smoked or still.smoked-per day. -~°- - The two other'sets of smoking.questions asked about cigar and pipe=use. Both began-with. attrigger question asking'whether the individuals;had ever smokeda`cigaror pipe. If thesubject answered no,'nofurther'questions were asked. If the subject answered yes, follow-up questions similar to those for cigaretteswere asked' but referred to the number of cigars or pipe-fulls smoked daily. A composite vascular "heart" disease variable was for- mulated to assess whether cardiac disease may act.as a possible confounder of AD. The-vascular disease variable included anyone reporting a history of myocardial infarc- tion, congestive heart failure, angina, and anyone taking cardiac medication. APOE genotyping. The APOE genotype ~ for each par- ticipant was determined after isolating DNA from white Table I Demographic profile ofpoputatiombnsed study Characteristics - Alzheimer's disease Total at risk n 142 920 Women, n (%) 99 (69.7) 631(68.6) Age, y (SD) 77.2 (5.7)* 75.1 (6.2) Education, y (SD) - 7.1 (3.8)* 9.0 (4.5) Ethnic group, n (%) - African American 57 (40.1) 291(31_6) White 21(14.8) . 238 (25.9) Hispanic 62 (43.7) 386 (42.0) Smoking status, n M Never 79 (55.6) 451 (49.0) Past 36(254) 325 (35.3) Current 27 (19.0) 144(15.7) * Indicates significant difference from the total at-risk group based-on chi-square analysis.'- - 0 blood cells and digesting the DNA with Hh¢L" Leukocyte DNA was amplified by PCR using specifically synthesized oligonucleotide primers.and.Taq polymerase modified from those described by . Hixson and- othersRO4' The digested PCR fragments were then separated by electrophoresis. Data ¢nalysis. The:frequencies for each demographic variable (age; gender, education, and ethnicgroup) and for smoking were compared among those at-risk participants and those with AD using chi-square analyses and Fisher's exact tests.'2 -Riskratio estimates weree calculated to-assess the rela- tionship between AD and -smoking, in addition to ~ other demog"raphicvariables: Univariate measures of association were estimated from chi-square analysis. Multivariate risk ratios were estimated from Cox proportional hazard mod- els:for each risk factor.23 As recommended by Korn et al.,'3 thetime-to-event variable was the age at onset of-AD;. therefore, no further age adjustment was required. The first stage of assessment included only smoking history. We then included education, and the final model includedd education=in addition--to ethnicity;-arid APOE: genotype. Tlvs, information was used to identify differences with re- : spect to education and ethnic group identity represented in the community. - Resul.ts. Demographics. Table 1.shows the demo- - graphic characteristics of the study participants by AD and . nondemented control subjects: Obvious group~ differences were.'apparent for age at interview and education. Patients with AD were significantly older than the control subjects (X2 ° 25.0, p< 0.001) and had the least amount of formal- --- education (Xz = 26.4, p< 0.001), whereas patients witl. AD were very similar to control subjects in ethnic group representation and smoking status. - Reliability. The test-retest reliability'8 of the risk fac- tor interview was in the good to excellent range for the questions regarding smoking (K = 0.72). Smoking. The frequency of smoking varied signifi- cantly by age and gender, but not by ethnic group or edu- cation (table 2). Smoking decreased with age,, and varied by sex in that more women reported that they never Apri) (2 of 2) 1999 NEUROId)G]' 52 1409

Table 2 Sraoking history by age; gender, educaCion, and ethnic group ~ . Smokers, n. (%) Characteristics n Current Past . Never Age group, y . 65-74 648 117 (68.4). 239 (66.2) 292 (55.1) 75-84 334 49 (28.7) 99 (27.4) 186 (35.1) 85+ 80 5(2.9)* 23(6,4) . . 52(9.8) Gender Women 730 89 (52.0) 204 (56.5)- 437 (82.5) Men 332 82 (48.0) 157 (43.5) 93 (17.5)* Education, yt 0-7 356 68(40.0) 121(33.8) 167 (31.7) 8-11 287 42 (24.7) 94 (26.3) 151 (28.7) 12+ 412 .60 (35.3) 143(39.9) .. 209 (39.7) V Ethnicityt African American 348 74 (44.3) 117 (32.4) 157 (29.8) White 259 35 (21.0) 92 (25.5) 132 (25.0) Hispanic 448 58 (34.7) 152(42.1) ' 238(45.2) x Denotes a significant difference from the comparison groups in the same category based on chi-square anaiysis.. t Owing to missing data on educational profile, seven partici- ~ . . ' . . pants were omitted. $ There were seven participants who failed to classifythemselves as either white, African American, or Hispanic. smoked. 'Pl.ere was no difference in tobacco use across ethnic groups. Themajoritybfsmokers..were cigarette smokers. Only four patients with AD and five nonde- mented subjects restricted their smoking to cigars or a pipe. A few in each group smoked cigars or a pipe as well as cigarettes according to our definition. We did not per- form separate analyses for those who use onlyy cigars or pipes because these were-relatively.infrequent'as expo- sures: However, we did include cigar and pipe smokers in comparing smokers with.nonsm~okers. Among those'who quit smoking, the mean<:time since'-cessation~`was21.4years. Because it was possiblee that smoking might have delayed or hastened the onset of AD, we compared the age at onset of symptoms between smokers and nonsmokers with AD. The mean age at onset of symptomss for smokers with AD was significantly lower than for'nonsmokers (nonsmokers,80.9 zt 5:9versus.;smokers;t;76.5.>` 4.9; p G.0.001). Alzheimer's disease. Although there were no statisti- cally significant differences in the risk of developing AD between current smokers, past smokers, and those who reported never smoking on univariate analysis (X2 = 5.5, p< 0.06), there were slightly more current smokers among the subjects (see table 1). Multivariate.e analysis showed that a past history of smoking was not associated signifi- cantly with AD (relative risk [RR] = 0.7; 95% Cl, 0.5 to 1.1). However, those who were current smokers had an increased risk of developing AD asindicated.by the unad- justed RRs and CIs in table 3(RR = 1.9; 95% CI, 1.2 to 3.0). Adjustment for education and ethnicity did not alter the measure of association between smokingg and AD 1410 NEUROLOGY 52 April (2 of2) 1999 Table 3 ReZati,re risk estimates for smoking in AD Relative risk estimates 195% CI] Tobacco use Total at risk, n AD, n(%) Crude Adjusted* Never 672 79 (11.8) 1.0 reference 1.0 reference Past . 361 36 (9.9) 0.8 [0.5-1.1] 0.7 [0.5-1.11 Current 171 27 (15.8) 1.9 [1.2-3.0] 1.7 [1.1-2.8] ` Multivariate analysis adjusted for education and ethnicity. (RR = 1.7; 95% CI, 1.1 to 2.8)• The association between smoking and AD was slightly lowered in the presence of APOE-e4 (RR = 1.4; 95% CI, 0.6 to 3.3; table 4), but not for current smokers without APOE-e4 (RR = 2.1; 95% CI, 1.2 to 3.7). Table 5 lists the distribution of smoking history by AD status, APOEstatus, and age group. After reviewing these results additional questions arose concerning vascular disease acting as a possible con- founder. Smoking is a risk factor for vascular disease. Car- diacdisease increases the risk of vascular dementia. Therefore, we looked at two additional multivariate models (multiplicative and additive) to determine the likelihood of interaction. The multiplicative proportional hazard model included ethnic group, smoking history, and a composite vascular'heart". disease variable. In the.muitiplicative model theree was no evidence of interaction among those who were both current smokers and had cardiac disease (current smokers: RR = .1.9; . 95% Cl, 1.1 to 3.3; heart disease: RR.=.1.1; 95% CI, 0.72 to 1.78; current smokers x heart disease: RR = 1.1; 95%. CI, 0.4 to 3.2). In the additive model, which included all of the variables just listed, there was the suggestion of interaction among those who were both current smokers and had cardiac disease (current smokers: RR = 1.9; 95%mCI, 1.1 to 3.3; heart disease: RR = 1.1;-959b CI, 0.7 to 1.8; current smokers and heart disease: RR = 2.4; 95% CI, 0.97 to 5.7). However, the number of individuals in this group was small (n = 14), thus limiting the interpretation: Finally, stratification by heart disease did not alter,thee relationship between smoking and AD in those with and without APOE-e4. Table 4 Relative risk estimates forAPOE-c4 status Risk factors Total at risk, n AD, n (%) Relative risk estimates [95% CI] Tobacco use in APOE-e4 carriers Never 118 24 (20.3) 1.0 reference° Past 103 14 (13.6) 0.8 f0.4-1.5] Current 41 7(17.1) 1.4 [0.6-3.3] Tobacco use in 1POE 4 non4 -s carriers Never 336 52 (15.5) 1.0 reference" Past 210 18(8.6) 0.6 [0.3-1.1) Current 100 18 (18.0) 2.1 (1.2-3.71 * Multivariate analysis adjusted for education and ethnicity.

Table 5 Smoking history by AD status, APOE status, and age group Age group and smoking status 65-74 y Non APOE-e4 carrier, APOE-e4 carrier, n (%) n (%) p.D+ AD- AD+ AD- Current 8 (36-4) 49 (16.8) 1(7.7) 2206.8) Past 5 (22.7) 104 (35.6) 3(231) 58 (44-3) Never 9 (40.9) 139 (47.6) 9(69.2) 51 (38.9) 75-84 y Current 8(20.5) 23 (12.0) 3(15.0) 8(14.0) Past 5(12.8) 68 (35.6) 6(30.0) 19 (33.3) Never 26 (66.7) 100 (52.4) 11(55.0) 30 (52.6) 85+ y Current 0(0) 2(6.1) 1(25.0) 1(8.3) Past 3(27.3) 7(21.2) 1(25.0) 6(50.0) Never 8(72.7) 24 (72.7) 2(50.0) 5(41.7) Discussion. The results of this.prospective study demonstrate that current smokers had a slightly higher risk of AD. The recent Rotterdam Study examined the effect of smoking on dementia and AD.8 Their results show that in comparison with those who never smoked, smokers had an increased risk of dementia (RR = 2.2; 95% CI, 1.3 to 3.6) and AD (RR = 2.3; 95% CI, 1.3 to 4.1). Our results are consistent with the Rotterdam Study findings in this respect. Complementary results were also found with respect to the effect modification role ofAPOE- e4. Results from the Rotterdam Study show that smokers who were not carriers of the APOE-e4 allele had a fourfold increased RR of AD (RR = 4.6; 95% CI, 1.5 to 14.2). Arguments have been posed to explain the rela- tionship between smoking and AD. These discus- sions have focused on previous case-control studies reporting a lower risk for AD associated with smok- ing. Several authors have argued that this protective association may have been related to differential sur- vival based on genetic alterations 8.24-2a A similar ar- gument could be made for our finding among those who quit smoking. There was a suggestion of a pro- tective effect among those who quit smoking. This raises the question of whether those smokers who survived without encountering comorbid conditions (such as cardiovascular disease) commonly associ- ated with tobacco use, who then quit smoking, may have acquired some additional protection, reducing their susceptibility to AD. The capacity of cells to repair DNA declines with age, and is adversely al- tered with smoking.26-28 Therefore, those surviving former smokers may have more effective DNA repair mechanisms. As a consequence, the accumulation of' aging-associated defects in DNA and DNA repair, which are presumed to be associated with AD;-" may be altered among surviving former smokers, reduc- ing their susceptibility to AD. Our study demonstrates that APOE-e4 only slightly modifies the association between smoking and AD (RR overall = 1.9 verses RR without e4 = 2.1). The link between smoking, AD, and APOE ge- notype is controversial. From the Rotterdam Study, Van Duijn et al.'O and Ott et al.a both demonstrated that APOE-e4 had a pronounced effect in patients with AD. Their findings suggest that there is an increased risk of dementia and AD associated with smoking in those without the APOE-e4 allele. How- ever, due to the disproportional mortality rates be- tween smokers and nonsmokers who are APOE-e4 carriers, the question remains whether there are ad- ditional factors in the causal chain possibly related to vascular disease. The results of our study failed to show any significant interaction between smoking, vascular disease, and AD or smoking, vascular dis- ease, AD, and APOE. However, an acute effect of cig- ~ arette smoking is a reduction in cerebral perfusion.30 This poses a crucial threat to elders with existing cere- brovascular compromise. Smoking has also been linked to an increased risk of premature death." Ethnicity and educational attainment are recog- nized correlates of smoking, and both have been linked to AD.3132 After adjusting for these variables in the multivariate analysis, the smoking-associated risk of AD did not change. T,here was no proportional difference in tobacco use across ethnic groups. Both ethnicity and education may be considered proxies for various factors associated with socioeconomic status and health-related behavior. According to a recent review of smoking behavior across ethnicity and socioeconomic status, less educated African Americans were more likely to smoke compared with whites or Hispanics'2 Furthermore, African Americans were less likely to quit smoking than whites or Hispan- ics s2 Based on the findings of our comparative study, -i from a public health standpoint, equal emphasis should be placed on smoking cessation programs across ethnic groups and regardless of socioeconomic status among the elderly. References 1. 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