Risk factors for Alzheimer's disease: a population-based, longitudinal study in Manitoba, Canada

Suzanne L Tyasa, Jure Manfredab, Laurel A Strainc and Patrick R Montgomeryd

a PhD Program in Gerontology, Sanders-Brown Center on Aging and Kentucky School of Public Health, University of Kentucky, USA.
b Departments of Internal Medicine and Community Health Sciences,
c Centre on Aging and Department of Sociology,
d Section of Geriatric Medicine, University of Manitoba, Canada.

Suzanne Tyas, Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40536–0230, USA. E-mail: styas{at}uky.edu

Abstract

Background Current knowledge of risk factors for Alzheimer's disease (AD) is limited. Data from a longitudinal, population-based study of dementia in Manitoba, Canada were used to investigate risk factors for AD.

Methods Cognitively intact subjects completed a risk factor questionnaire assessing sociodemographic, genetic, environmental, medical and lifestyle exposures. Five years later, 36 subjects had developed AD and 658 remained cognitively intact.

Results Older subjects or those who had fewer years of education were at greater risk of AD. After adjusting for age, education and sex, occupational exposure to fumigants/ defoliants was a significant risk factor for AD (relative risk [RR] = 4.35; 95% CI : 1.05–17.90). A history of migraines increased the risk of AD (RR = 3.49; 95% CI : 1.39–8.77); an even stronger effect was noted among women. Self-reported memory loss at baseline was associated with subsequent development of AD (RR = 5.15; 95% CI : 2.36–11.27). Vaccinations and occupational exposure to excessive noise reduced the risk of AD.

Conclusions Some well-known risk factors for AD were confirmed in this study and potential new risk factors were identified. The association of AD with a history of migraines and occupational exposure to defoliants/fumigants is of particular interest because these are biologically plausible risk factors.

KEY MESSAGES

Keywords Alzheimer's disease, risk factors, epidemiology, longitudinal studies

Accepted 1 November 2000

As populations age, diseases related to ageing affect more people and represent a source of growing concern. The prevalence of Alzheimer's disease (AD), a major cause of dementia, rises exponentially with increasing age.1,2 Aside from personal costs, AD represents a major economic burden on health care and social services.3,4 The cause of AD is unknown and there is neither a cure nor a universally effective treatment. Identification of factors that influence the risk of developing AD, however, may provide insights into its cause and suggest potential strategies for prevention or treatment.

Because relatively few risk factors have been established, a broad-brush approach to their identification is often taken. Many potential risk factors have been investigated because of their connection with proposed causes of AD, such as genetic, environmental or infectious mechanisms.58 Older age is a well-known risk factor; many studies have also shown that fewer years of education are associated with a greater risk of AD.9 One of the most strongly supported risk factors is a family history of AD and other dementias, which has been associated with AD in most1019 but not all studies,2023 including a pooled analysis of prospective studies.23 Substantial evidence also suggests that a history of head injury increases the risk of AD,17,2427 although other studies, including two reports using longitudinal data,11,23 have not found a significant association.1115,20,21,23,28,29

The association of AD with other plausible genetic, environmental, medical and lifestyle factors is less established. Briefly, family history of disease and parental age have been studied because they reflect exposures to genetic factors. A family history of diseases other than dementia, such as Down syndrome12,17,19,30 and Parkinson's disease,13,30 has been associated with AD in some studies but not others.15 The evidence does not generally support an association of AD with parental age at the birth of the individual with AD,1316,20,21,31,32 but a meta-analysis of four case-control studies33 did find results suggesting that late maternal age at index birth may increase the risk of AD.

Recreational or occupational exposures to vibratory tools and a wide variety of chemical compounds have been investigated because of their hazardous properties.34 Many of these exposures were found to be unrelated to AD11,13,24,3437 but one study15 that used ‘manual work’ as a proxy for exposure to occupational toxins did find a significant association.

Medical factors have also been examined because of plausible links to causes of AD. Studies have generally found that immunological history (e.g. allergic conditions, thyroid disease, viral infection) is not associated with AD.1012,14,16,20,21,24,38 The effect of AD on specific medical conditions and medications has also been explored. For example, a history of arthritis or use of anti-inflammatory drugs significantly reduced the risk of AD.13,37,39,40 Longitudinal data41 have implicated vascular factors such as hypertension and atherosclerosis as risk factors for AD although some associations11 are with overall dementia and not AD specifically. Toxicity from general anaesthetics has not been found to increase the risk of AD in case-control13,42 or longitudinal studies.11 Finally, although it has been researched for many years and has received much public attention, a causal role of aluminium in AD remains to be conclusively established.43 Exposure to aluminium through antacid use was not linked to AD.12

Other exposures that have been studied include lifestyle factors such as smoking, drinking, diet, and exercise. Smoking has been widely studied; although several early case-control studies found a protective effect of smoking on AD,44 more recent longitudinal studies have found smoking had no significant effect11,45,46 or increased the risk of AD.23,47,48 A cluster of health habits (smoking, drinking, and exercise) were found not to predict AD in a longitudinal study.49 Because other neurological disorders (e.g. Creutzfeldt–Jakob disease) are caused by slow viruses, possible exposures to infectious agents have been examined (e.g. consumption of raw meat). No evidence of a connection with AD, however, has been observed in case-control studies.16,17,20,24,37

Most of the evidence on risk factors for AD has been based on case-control studies; more recent longitudinal studies have provided contradictory results for some exposures. Longitudinal studies, which identify incident cases of AD, are the preferred design for such risk factor analyses because risk factors for the development of AD rather than for the survival of affected individuals can be investigated. In addition, these designs avoid problems specific to case-control studies of AD, such as the need to obtain exposure data from proxy respondents because individuals with AD are unable to provide the information themselves. Data from the Manitoba Study of Health and Aging (MSHA), a longitudinal, population-based study, were used to investigate risk factors for AD in the province of Manitoba, Canada.

Methods

Study population
Subjects were randomly sampled from a list provided by the provincial health insurance plan, which provides virtually universal coverage. The list excluded members of the military or of the Royal Canadian Mounted Police and residents of a remote, sparsely populated region of the province. The sampling frame was stratified by health region and age group (65–74, 75–84, >=85 years), with subjects in the two older age strata deliberately over-sampled.

The MSHA is a parallel study to the Canadian Study of Health and Aging and used similar instruments for data collection and diagnosis.1 Approximately one-quarter of the subjects in the MSHA also participated in the Canadian Study of Health and Aging. The MSHA sample was drawn from across the province of Manitoba and included rural farming locations, villages, towns and small cities unlike the Canadian Study of Health and Aging sample, which was restricted in Manitoba to two urban centres and their immediate surroundings.

The MSHA researchers interviewed 1763 subjects in 1991/92 and recontacted them in 1996/97 for a follow-up interview. On both occasions, cognitive impairment was assessed using the Modified Mini-Mental State Exam (3MS).50 Individuals scoring less than 78 out of a possible 100 were considered to be potentially cognitively impaired and were invited to participate in a clinical assessment which included neuropsychological testing as appropriate. The diagnostic categories of possible or probable AD were assigned based on this clinical assessment according to National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer's Disease and Related Disorders Association (NINCDS–ADRDA) criteria,51 the standard clinical research protocol for diagnosis of AD.

The 1355 subjects who screened as cognitively intact (3MS score >=78) at the interview in 1991/92 were considered free of cognitive impairment at baseline and constituted the incidence cohort. Because of the length of the interview and of the risk factor questionnaire, subjects received the questionnaire to complete and return by mail. Questionnaires were returned by 1039 (76.7%) of the cohort. Respondents did not differ in age, sex, or depression level (as determined by the Center for Epidemiologic Studies Depression [CES-D] scale52) from those who did not complete the questionnaire. Respondents, however, had significantly (P < 0.05) more years of formal education (mean years = 10.2 versus 9.1) and had, on average, a higher 3MS score at the time of the screening interview (mean score = 90.4 versus 86.7).

This analysis is based on 694 subjects who screened as cognitively intact and completed a risk factor questionnaire in 1991/92, and for whom cognitive status in 1996/97 was known. Excluded were 74 subjects who were ineligible based on their 1996/97 assessment (i.e. subjects had cognitive impairment, but not AD) and 271 subjects for whom information on whether they had developed AD by 1996/97 was not available (191 [70.5%] had died, 64 [23.6%] refused, 14 [5.2%] had moved from Manitoba, and 2 [0.7%] could not be located).

Data analysis
Subjects who screened as cognitively impaired in 1996/97 and whose diagnosis in the clinical assessment was probable (n = 15) or possible AD (n = 21) were considered incident AD cases. Because of the small number of cases, these categories were combined in the analyses. This approach is consistent with recommendations to improve inter-rater reliability by combining the diagnoses of possible and probable AD.53 The remaining 658 subjects who screened as cognitively intact in 1996/97 were designated as controls. Exposure information was collected in 1991/92 for all subjects. (See Table 1Go for a description of the study sample.)


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Table 1 Sociodemographic characteristics of study sample
 
Risk factors were divided into five categories: sociodemographic, genetic, environmental, medical, and lifestyle factors. Multiple logistic regression models were developed to assess the association between AD and each of the risk factors. All models were adjusted for age, sex and education unless otherwise stated to control for their effects and to facilitate comparison with the results of other studies. The number of subjects in some categories, particularly exposed cases, was small for many of the factors and should be considered in interpretation of the results. The software program SPSS for Windows®, version 8,54,55 was used for all of the analyses.

Results

The sociodemographic factors examined were age, sex and education. Age and education were both significantly related to AD in logistic regression models, with each year of age increasing the risk of AD (relative risk [RR] = 1.18; 95% CI : 1.11–1.26, adjusted for sex and education) and each year of education decreasing it (RR = 0.86; 95% CI : 0.76–0.96, adjusted for sex and age). Sex was not significantly associated with AD.

A family history of various diseases was not significantly related to AD for any of the diseases examined, including dementia (Table 2Go). Restricting the definition of a positive family history of dementia to those with affected first-degree relatives did not alter the results. Parental age at subject's birth did not influence the risk of developing AD (Table 2Go).


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Table 2 Association of Alzheimer's disease with genetic factors
 
Of the occupational and recreational exposures examined, only defoliants/fumigants and excessive noise were significantly related to developing AD (Table 3Go). Occupational exposure to defoliants or fumigants was a significant risk factor for AD (RR = 4.35; 95% CI : 1.05–17.90). Such exposure was significantly more common in subjects who had ever been farmers. The possibility of subjects obtaining their occupational exposure to defoliants or fumigants through working as farmers was thus explored. The risk of AD was significantly higher among subjects who reported ever having been a farmer (RR = 2.59; 95% CI : 1.05–6.40), but this association disappeared after controlling for defoliant/fumigant exposure. Results from additional analyses of AD and defoliant/fumigants suggest that interactions with age and education may be important, but such effects could not be fully explored because of the small number of cases. Although alcohol use has been suggested to be an important confounder of some occupational exposures,35 it was not a significant confounding variable for defoliant/fumigant exposure in these data.


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Table 3 Association of Alzheimer's disease with occupational factors
 
The risk of AD was reduced in subjects reporting occupational exposure to excessive noise. Only one of the cases, however, reported such an exposure. Recreational exposures examined included turpentine, paints/stains/lacquers, aerosol or spray paints, paint remover, film developing fluids, dyes, pesticides/ herbicides, plastic cement/glues, plastic resins, epoxy resins, and fuels/gas/petroleum. None of these factors significantly influenced the risk of developing AD.

Of the medical factors, only a history of migraines and a history of memory loss were significantly associated with AD (Table 4Go). Subjects with migraines were more than three times as likely to develop AD (RR = 3.49; 95% CI : 1.39–8.77). A separate model was developed for women because of the higher prevalence in women of both AD1,2 and migraines;56,57 the association between migraines and AD was even stronger in women (RR = 5.78; 95% CI : 2.00–16.74) than in men and women combined. The effect of depression on the association between migraines and AD was explored because depression has been found to be related to both AD58 and migraines.59,60 Depression indicated by CES-D score was a significant confounder for women but migraine remained a significant risk factor for AD in women even after adjustment for depression. We could not replicate these analyses in separate models for men because few men had migraines.


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Table 4 Association of Alzheimer's disease with medical factors
 
A history of memory loss was also associated with a significantly increased risk of AD (RR = 5.15; 95% CI : 2.36–11.27). This memory loss may have been an early sign of dementia in those still considered cognitively intact, a hypothesis supported by the lower mean 3MS score for subjects who reported memory problems compared with those who did not (89.9 versus 91.6; independent samples t-test P = 0.02).

The only other significant medical factor was a history of influenza, tetanus, polio, or diphtheria vaccinations. The RR for each type of vaccination was less than one but not significantly so: subjects who had received any of these vaccinations were at a significantly reduced risk of AD (RR = 0.40; 95% CI : 0.17–0.96).

None of the tobacco use, alcohol use, diet or exercise variables were significantly associated with AD (Table 5Go). Types of tobacco use were not investigated with logistic regression models because only three subjects who were not also cigarette smokers reported the use of pipes or cigars.


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Table 5 Association of Alzheimer's disease with lifestyle factors
 
Discussion

Many risk factors for AD have been studied. Although some factors (e.g. age, education) are consistently associated with AD, little evidence exists for others and results for these factors must be considered exploratory. One major limitation is that research until recently has been based primarily on case-control studies. In this study, longitudinal data were analysed to identify factors associated with the risk of developing AD.

Subjects who had been exposed to defoliants/fumigants were more likely to have developed AD. The risk was significantly higher among subjects who reported ever having been a farmer, but this association disappeared after controlling for defoliant/ fumigant exposure. The risk of AD among farmers thus may be explained by their greater likelihood of such an exposure rather than by farming per se.

Because defoliants and fumigants have neurological effects, they may be causally associated with AD. Other studies have examined occupational exposures and AD but have not focussed on defoliants or fumigants. With farmers constituting one-quarter of the subjects, this study was well positioned to detect an association between AD and occupational exposures associated with farming. More detailed definitions of defoliant/fumigant exposure are needed to clarify whether exposure to only one of these chemicals is associated with AD: defoliant and fumigant exposures were grouped together during data collection and individual effects thus cannot be disentangled. Data on intensity of exposure may also be useful in future studies.

Exposure to excessive noise significantly reduced the risk of AD. This effect, however, may be due to unadjusted confounders. For example, this association may reflect the selection of healthier individuals into physically demanding employment such as construction, which is more likely to be characterized by excessive noise.

Migraines or headaches have been reported to have no significant effect on AD12,13,24,61 or to reduce the risk of AD.38,62 In the EURODEM collaborative case-control re-analysis,38 severe headaches or migraines were marginally significant protective factors for all subjects combined but, when stratified by sex, significantly reduced the risk of AD in women. In this study, the effect was in the opposite direction: a history of migraines significantly increased the risk of AD in women. The inconsistent association between migraines and AD in the literature may reflect the challenges of incorporating new research findings into diagnostic protocols for discriminating AD from other dementias with a vascular component. The measures used to assess exposure (headache/severe headaches/migraines) vary across studies, complicating comparisons. The effects of confounding variables and interactions also need to be explored. An association between migraines and AD may be biologically plausible, however, given the disturbances in cerebral blood flow and neurotransmitter systems noted in both disorders.59, 6365

Subjects reporting memory loss in 1991/92 were more likely to develop AD by 1996/97. Although an association between prior memory loss and subsequent development of AD may be expected, the presence of self-reported memory loss among individuals screened as cognitively intact raises issues to consider in longitudinal studies of AD. In this study, no consistent pattern of under- or over-reporting of exposures was observed in subjects with self-reported memory loss compared with those who did not report memory problems. The quality of the exposure data provided by individuals with memory loss, however, may be compromised. Inclusion of these potentially early cases of AD in the incidence cohort may also result in the identification of risk factors for progression of disease rather than simply for the development of new cases of AD. These concerns are not unique to this study but could be highlighted here because information on memory problems was collected as part of the risk factor questionnaire as well as for the screening and diagnostic protocols.

Subjects who had received any vaccinations were at a significantly reduced risk of AD. This apparent protective effect may simply reflect a reduced risk of AD among people who engage in preventive health behaviours, a population who tend to be at lower risk of many diseases, or may be due to unexplained immunological processes. As vaccinations included childhood immunizations, the significant protective effect may also reflect parental socioeconomic status or health behaviours.

Some previously reported risk factors were not significantly related to AD in this study. For example, head injury was not a significant risk factor. The size of the effect observed (RR = 1.59), however, is similar to that reported in the EURODEM re-analysis25 and the lack of statistical significance may reflect power limitations.

Although a family history of dementia is usually a risk factor for AD, it was not significantly associated with AD in this study, consistent with some other studies.e.g.20–23,34 A family history of dementia is only a crude indicator of genetic risk. This measure may have been too imprecise an estimate of genetic risk to be able to detect an association with AD in the MSHA; specific measures of genetic risk, such as apolipoprotein E, were not available in this study. In addition, subjects with a very strong family history of dementia may already have developed AD by 1991/92. If so, they would not be incident cases and thus would be excluded from these analyses. They may also have died before meeting the minimum age criterion (65 years) for entry into the study. Although a genetic component to AD is not disputed, previous reports of an association between family history of dementia and AD in case-control studies may have reflected a reporting bias, with proxy respondents of individuals with AD more likely than unaffected individuals to recall other family members with dementia. The lack of an association in this study and in the pooled EURODEM analyses23 supports this hypothesis.

The accuracy of a diagnosis of AD is a problem inherent to all studies of this disease. Although standard research criteria51 were used, these criteria are not without problems.66 Alzheimer's disease can only be definitively diagnosed after death and some misdiagnoses likely occurred. The presence of AD could also not be assessed for those individuals who were lost to follow-up. The main reason for attrition was death of the subject. This is common in longitudinal studies of aged populations. As dementia is associated with increased mortality, however, this may introduce bias as only risk factors of the surviving cohort can be analysed. Longitudinal studies with repeated ascertainment of dementia are thus a stronger design than a two-wave study design, as interim data would be available on the cognitive status of subjects who died before the end of the study. In addition, data on risk factors were collected by a self-completed questionnaire. Not all subjects returned this questionnaire and those who did differed from those who did not in some characteristics that might be related to their risk of AD. Finally, because a wide range of exposures was investigated, collection of more detailed exposure information for each factor was not feasible.

This study identifies potential risk factors associated with the development of AD. Although the importance of studying incident cases is recognized, analyses are limited by the small numbers of these cases: only 36 subjects were diagnosed with AD between 1991/92 and 1996/97 in the MSHA. Small numbers of cases are not unusual in longitudinal studies. Some factors could not be fully examined, however, because no cases were exposed. On the other hand, the small number of cases means that some factors that might be related to AD may not have reached statistical significance in this study. Thus, factors that might be expected to be related to AD for biological reasons or for which there is previous evidence in the literature of such an association cannot be dismissed as possible risk factors for AD. Factors with elevated relative risks that failed to reach statistical significance in this study also warrant further examination. The purpose of this study was not to eliminate possible risk factors but rather to identify those worthy of further investigation. The observed association of AD with a history of migraines and occupational exposure to defoliants/fumigants is of particular interest because these are biologically plausible risk factors.

Acknowledgments

The Manitoba Study of Health and Aging (MSHA) was funded primarily by Manitoba Health (1990–93) and Manitoba Health's Healthy Communities Development Fund (1995–99). Additional funding was provided through the Canadian Study of Health and Aging by the Seniors Independence Research Program of the National Health Research and Development Program of Health Canada (Project No. 6606–3954-MC(S)). The results and conclusions are those of the authors and no official endorsement by Manitoba Health or Health Canada is intended or should be inferred. The contributions of MSHA-2 Research Group members are gratefully acknowledged. This research was made possible in part by Manitoba Health Research Council and Medical Research Council of Canada postdoctoral fellowships to Suzanne Tyas.

References

1 Canadian Study of Health and Aging Working Group. Canadian Study of Health and Aging: Study methods and prevalence of dementia. Can Med Assoc J 1994;150:899–913.[Abstract]

2 Rocca WA, Hofman A, Brayne C et al. for the EURODEM–Prevalence Research Group. Frequency and distribution of Alzheimer's disease in Europe: A collaborative study of 1980–1990 prevalence findings. Ann Neurol 1991;30:381–90.[ISI][Medline]

3 Ernst RL, Hay JW. The US economic and social costs of Alzheimer's disease revisited. Am J Public Health 1994;84:1261–64.[Abstract]

4 Østbye T, Crosse E. Net economic costs of dementia in Canada. Can Med Assoc J 1994;151:1457–64.[Abstract]

5 Brayne C. Research and Alzheimer's disease: An epidemiological perspective. Psychol Med 1993;23:287–96.[ISI][Medline]

6 Breteler MMB, Claus JJ, van Duijn CM, Launer LJ, Hofman A. Epidemiology of Alzheimer's disease. Epidemiol Rev 1992;14:59–82.[ISI][Medline]

7 Katzman R, Kawas C. The epidemiology of dementia and Alzheimer disease. In: Terry RD, Katzman R, Bick KL (eds). Alzheimer Disease. New York: Raven Press, 1994, pp.105–22.

8 Mortimer JA. The epidemiology of Alzheimer's disease: Beyond risk factors. In: Iqbal K, Mortimer JA, Winblad B, Wisniewski HM (eds). Research Advances in Alzheimer's Disease and Related Disorders. Chichester: John Wiley & Sons, 1995, pp.3–13.

9 Katzman R. Education and the prevalence of dementia and Alzheimer's disease. Neurology 1993;43:13–20.[ISI][Medline]

10 Amaducci LA, Fratiglioni L, Rocca WA et al. Risk factors for clinically diagnosed Alzheimer's disease: A case-control study of an Italian population. Neurology 1986;36:922–31.[Abstract]

11 Brayne C, Gill C, Huppert FA et al. Vascular risks and incident dementia: Results from a cohort study of the very old. Dement Geriatr Cog Disord 1998;9:175–80.

12 Broe GA, Henderson AS, Creasey H et al. A case-control study of Alzheimer's disease in Australia. Neurology 1990;40:1698–707.[Abstract]

13 The Canadian Study of Health and Aging. The Canadian Study of Health and Aging: Risk factors for Alzheimer's disease in Canada. Neurology 1994;44:2073–80.[Abstract]

14 Ferini-Strambi L, Smirne S, Garancini P, Pinto P, Franceschi, M. Clinical and epidemiological aspects of Alzheimer's disease with presenile onset: A case control study. Neuroepidemiology 1990;9:39–49.[ISI][Medline]

15 Fratiglioni L, Ahlbom A, Viitanen M, Winblad B. Risk factors for late-onset Alzheimer's disease: A population-based, case-control study. Ann Neurol 1993;33:258–66.[ISI][Medline]

16 Graves AB, White E, Koepsell TD et al. A case-control study of Alzheimer's disease. Ann Neurol 1990;28:766–74.[ISI][Medline]

17 Heyman A, Wilkinson WE, Stafford JA, Helms MJ, Sigmon AH, Weinberg T. Alzheimer's disease: A study of epidemiological aspects. Ann Neurol 1984;15:335–41.[ISI][Medline]

18 Prince M, Cullen M, Mann A. Risk factors for Alzheimer's disease and dementia: A case-control study based on the MRC elderly hypertension trial. Neurology 1994;44:97–104.[Abstract]

19 van Duijn CM, Hofman A. Risk factors for Alzheimer's disease: The EURODEM collaborative re-analysis of case-control studies. Neuroepidemiology 1992;11(Suppl.1):106–13.[ISI][Medline]

20 Chandra V, Philipose RN, Bell PA, Lazaroff A, Schoenberg BS. Case-control study of late onset ‘probable Alzheimer's disease’. Neurology 1987;37:1295–300.[Abstract]

21 Katzman R, Aronson M, Fuld P et al. Development of dementing illnesses in an 80-year-old volunteer cohort. Ann Neurol 1989;25:317–24.[ISI][Medline]

22 Wang P-N, Wang S-J, Hong C-J et al. Risk factors for Alzheimer's disease: A case-control study. Neuroepidemiology 1997;16:234–40.[ISI][Medline]

23 Launer LJ, Andersen K, Dewey ME et al. Rates and risk factors for dementia and Alzheimer's disease: Results from EURODEM pooled analyses. Neurology 1999;52:78–84.[Abstract/Free Full Text]

24 French LR, Schuman LM, Mortimer JA, Hutton JT, Boatman RA, Christians B. A case-control study of dementia of the Alzheimer type. Am J Epidemiol 1985;121:414–21.[Abstract]

25 Mortimer JA, van Duijn CM, Chandra V et al. Head trauma as a risk factor for Alzheimer's disease: A collaborative re-analysis of case-control studies. Int J Epidemiol 1991;20(Suppl.2):S28–35.[Abstract]

26 Schofield PW, Tang M, Marder K et al. Alzheimer's disease after remote head injury: An incidence study. J Neurol Neurosurg Psychiatry 1997;62:119–24.[Abstract]

27 Yamada M, Sasaki H, Mimori Y et al. Prevalence and risks of dementia in the Japanese population: RERF's Adult Health Study Hiroshima subjects. J Am Geriatr Soc 1999;47:189–95.[ISI][Medline]

28 Shalat SL, Seltzer B, Pidcock C, Baker Jr EL. Risk factors for Alzheimer's disease: A case-control study. Neurology 1987;37:1630–33.[Abstract]

29 Soininen H, Heinonen OP. Clinical and etiological aspects of senile dementia. Eur Neurol 1982;21:401–10.[ISI][Medline]

30 van Duijn CM, Clayton D, Chandra V et al. Familial aggregation of Alzheimer's disease and related disorders: A collaborative re-analysis of case-control studies. Int J Epidemiol 1991;20(Suppl.2):S13–20.[Abstract]

31 De Braekeleer M, Cholette A, Mathieu J, Boily C, Robitaille Y, Gauvreau D. Familial factors in Alzheimer's disease (IMAGE Project): A case-control study in the Saguenay-Lac-St-Jean region (Quebec, Canada). Eur Neurology 1989;29(Suppl.3):2–8.

32 Moceri VM, Kukull WA, Emanuel I, van Belle G, Larson EB. Early-life risk factors and the development of Alzheimer's disease. Neurology 2000;54:415–20.[Abstract/Free Full Text]

33 Rocca WA, van Duijn CM, Clayton D et al. Maternal age and Alzheimer's disease: A collaborative re-analysis of case-control studies. Int J Epidemiol 1991;20(Suppl.2):S21–27.[Abstract]

34 Gun RT, Korten AE, Jorm AF et al. Occupational risk factors for Alzheimer disease: A case-control study. Alzheimer Dis Assoc Disord 1997;11:21–27.

35 Graves AB, Rosner D, Echeverria D, Mortimer JA, Larson EB. Occupational exposures to solvents and aluminium and estimated risk of Alzheimer's disease. Occup Environ Med 1998;55:627–33.[Abstract]

36 Graves AB, van Duijn CM, Chandra V et al. for the EURODEM Risk Factors Research Group. Occupational exposures to solvents and lead as risk factors for Alzheimer's disease: A collaborative re-analysis of case-control studies. Int J Epidemiol 1991;20(Suppl.2):S58–61.[Abstract]

37 Li G, Shen YC, Li YT, Chen CH, Zhau YW, Silverman JM. A case-control study of Alzheimer's disease in China. Neurology 1992;42: 1481–88.[Abstract]

38 Breteler MMB, van Duijn CM, Chandra V et al. Medical history and the risk of Alzheimer's disease: A collaborative re-analysis of case-control studies. Int J Epidemiol 1991;20(Suppl.2):S36–42.[Abstract]

39 Breitner JCS, Gau BA, Welsh KA et al. Inverse association of anti-inflammatory treatments and Alzheimer's disease: Initial results of a co-twin control study. Neurology 1994;44:227–32.[Abstract]

40 McGeer PL, Schulzer M, McGeer EG. Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer's disease: A review of 17 epidemiologic studies. Neurology 1996;47:425–32.[Abstract]

41 Hofman A, Ott A, Breteler MMB et al. Atherosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer's disease in the Rotterdam Study. Lancet 1997;349:151–54.[ISI][Medline]

42 Bohnen NILJ, Warner MA, Kokmen E, Beard CM, Kurland LT. Alzheimer's disease and cumulative exposure to anesthesia: A case-control study. J Am Geriatr Soc 1994;42:198–201.[ISI][Medline]

43 Doll R. Alzheimer's disease and environmental aluminium. Age Ageing 1993;22:138–53.[ISI][Medline]

44 Tyas SL. Are tobacco and alcohol use related to Alzheimer's disease? A critical assessment of the evidence and its implications. Addict Biol 1996;1:237–54.[ISI][Medline]

45 Wang H-X, Fratiglioni L, Frisoni GB, Viitanen M, Winblad B. Smoking and the occurrence of Alzheimer's disease: Cross-sectional and longitudinal data in a population-based study. Am J Epidemiol 1999;149: 640–44.[Abstract]

46 Doll R, Peto R, Boreham J, Sutherland I. Smoking and dementia in male British doctors: Prospective study. BMJ 2000;320:1097–102.[Abstract/Free Full Text]

47 Ott A, Breteler MMB, van Harskamp F, Stijnen T, Hofman A. Incidence and risk of dementia: The Rotterdam study. Am J Epidemiol 1998;147:574–80.[Abstract]

48 Merchant C, Tang M-X, Albert S, Manly J, Stern Y, Mayeux R. The influence of smoking on the risk of Alzheimer's disease. Neurology 1999;52:1408–12.[Abstract/Free Full Text]

49 Broe GA, Creasey H, Jorm AF et al. Health habits and risk of cognitive impairment and dementia in old age: A prospective study on the effects of exercise, smoking and alcohol consumption. Aust N Z J Public Health 1998;22:621–23.[ISI][Medline]

50 Teng EL, Chui HC. The Modified Mini-Mental State (3MS) Examination. J Clin Psychiatry 1987;48:314–18.[ISI][Medline]

51 McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: Report of the NINCDS– ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's disease. Neurology 1984;34:939–44.[Abstract]

52 Radloff LS. The CES-D scale: A self-report depression scale for research in the general population. Appl Psychol Meas 1977;1:385–401.

53 Baldereschi M, Amato MP, Nencini P et al. for the WHO–PRA Age-associated Dementia working group, WHO-Program for Research on Aging, Health of Elderly Program. Cross-national interrater agreement on the clinical diagnostic criteria for dementia. Neurology 1994;44: 239–42.[Abstract]

54 Norussis MJ, SPSS Inc. SPSS Professional StatisticsTM 7.5. Chicago: SPSS Inc., 1997.

55 SPSS Inc. SPSS® Base 8.0: Applications Guide. Chicago: SPSS Inc., 1998.

56 Linet MS, Stewart WF. Migraine headache: Epidemiologic perspectives. Epidemiol Rev 1984;6:107–39.[ISI][Medline]

57 O'Brien B, Goeree R, Streiner D. Prevalence of migraine headache in Canada: A population-based survey. Int J Epidemiol 1994;23:1020–26.[Abstract]

58 Jorm AF, van Duijn CM, Chandra V et al. Psychiatric history and related exposures as risk factors for Alzheimer's disease: A collaborative re-analysis of case-control studies. Int J Epidemiol 1991;20(Suppl.2): S43–47.[Abstract]

59 Glover V, Jarman J, Sandler M. Migraine and depression: Biological aspects. J Psychiatr Res 1993;27:223–31.[ISI][Medline]

60 Merikangus KR, Stevens DE. Comorbidity of migraine and psychiatric disorders. Neurol Clin 1997;15:115–23.[ISI][Medline]

61 Henderson AS, Jorm AF, Korten AE et al. Environmental risk factors for Alzheimer's disease: Their relationship to age of onset and to familial or sporadic types. Psychol Med 1992;22:429–36.[ISI][Medline]

62 Dewey ME, Davidson IA, Copeland JRM. Risk factors for dementia: Evidence from the Liverpool study of continuing health in the community. Int J Geriatr Psychiatry 1988;3:245–49.[ISI]

63 Crawford JG. Alzheimer's disease risk factors as related to cerebral blood flow: Additional evidence. Med Hypotheses 1998;50:25–36.[ISI][Medline]

64 Francis PT, Cross AJ, Bowen DM. The epidemiology of dementia and Alzheimer disease. In: Terry RD, Katzman R, Bick KL (eds). Alzheimer Disease. New York: Raven Press, 1994, pp.247–61.

65 Welch KMA. Current opinions in headache pathogenesis: Introduction and synthesis. Curr Opin Neurol 1998;11:193–97.[ISI][Medline]

66 Leach J, Levy R. Reflections on the NINCDS/ADRDA criteria for the diagnosis of Alzheimer's disease. Int J Geriatr Psychiatry 1994; 9:173–79.[ISI]