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To study the interaction among genetic and environmental risk factors, a reanalysis of case-control studies of Alzheimer's disease (AD) was conducted based on the original data of all studies carried out to January 1, 1990. Seven studies were included in the present analysis, comprising a total of 814 AD patients and 894 control subjects. When comparing those with a positive and negative family history of dementia, similar odds ratio were found for late maternal age [1.7; 95% confidence interval (0.6–4.8) vs. 2.0 (1.1–3.5)], head trauma [1.7 (0.7–4.2) vs. 1.9 (1.1–3.2)], and history of depression [2.0 (0.2–19.8) vs. 2.1 (0.8–1.7)]. This suggests a model in which these risk factors increase the risk for AD independent of family history of dementia. Among those with a positive family history of dementia, the odds ratios for family history of Down's syndrome [4.2 (0.9–20.0))] and of Parkinson's disease [3.3 (0.4–28.2)] tended to be higher than among those with a negative family history of dementia [2.6 (0.8–8.5) and 2.4 (0.8–7.0), respectively]. However, for both disorders the difference in odds ratio was not statistically significant. For history of cigarette smoking, there was no association to AD for those with no first degree relatives with dementia and an inverse relation with AD for those with a positive family history. Although in all analyses, family history of dementia remained significantly associated with AD in the absence of other factors, the odds ratio associated with family history of dementia tended to be lower for those with a positive smoking history, particularly for those with two or more affected relatives. These findings suggest that smoking may interact specifically with a genetically determined process.

To study the interaction among genetic and environmental risk factors, a reanalysis of case-control studies of Alzheimer's disease (AD) was conducted based on the original data of all studies carried out to January 1, 1990. Seven studies were included in the present analysis, comprising a total of 814 AD patients and 894 control subjects. When comparing those with a positive and negative family history of dementia, similar odds ratio were found for late maternal age [1.7; 95% confidence interval (0.6-4.8) vs. 2.0 (1.1-3.5)], head trauma [1.7 (0.7-4.2) vs. 1.9 (1.1-3.2)], and history of depression [2.0 (0.2-19.8) vs. 2.1 (0.8-1.7)]. This suggests a model in which these risk factors increase the risk for AD independent of family history of dementia. Among those with a positive family history of dementia, the odds ratios for family history of Down's syndrome [4.2 (0.9-20.0)] and of Parkinson's disease [3.3 (0.4-28.2)] tended to be higher than among those with a negative family history of dementia [2.6 (0.8-8.5) and 2.4 (0.8-7.0), respectively]. However, for both disorders the difference in odds ratio was not statistically significant. For history of cigarette smoking, there was no association to AD for those with no first degree relatives with dementia and an inverse relation with AD for those with a positive family history. Although in all analyses, family history of dementia remained significantly associated with AD in the absence of other factors, the odds ratio associated with family history of dementia tended to be lower for those with a positive smoking history, particularly for those with two or more affected relatives. These findings suggest that smoking may interact specifically with a genetically determined process.

To investigate the possible association between Alzheimer's disease and late maternal age at index birth, we conducted a collaborative re-analysis of existing case-control data sets. Of the 11 studies participating in the EURODEM project, four were included in the analyses regarding maternal age. In all four studies, cases were matched to controls by age and gender, and only population controls were considered. Analyses were conducted on the individual data sets, on the pooled sample, and on subgroups defined by gender, age at onset, and familial aggregation of dementia. Maternal age of 40 years and over was found to be suggestively associated with a higher risk of Alzheimer's disease (overall relative risk = 1.7; 95% confidence intervals: 1.0-2.9). In subgroup analyses, the association was statistically significant for women and for sporadic cases. Adjustments for education or analyses restricted to case-control pairs matched by type of respondent did not modify these results noticeably. The association was confirmed by a test of consistency with the Down's syndrome risk model; results of this test were again more definite for sporadic Alzheimer's disease. In addition, three of the four studies also suggested an increased risk for maternal age at index birth between 15 and 19 years (overall relative risk = 1.5; 95% confidence intervals: 0.8-3.0). Although consistency across studies was not always complete, only some of the increased relative risks reached statistical significance, and information regarding maternal age obtained through a next-of-kin interview may have limitations, our study suggests that both early and late maternal age should be further investigated as possible risk factors for Alzheimer's disease.

Case-control studies of Alzheimer's disease were re-analysed to examine the association of Alzheimer's disease with family history in first degree relatives of dementia, Down's syndrome and Parkinson's disease. Overall, the relative risk of Alzheimer's disease for those with at least one first degree relative with dementia was 3.5 (95% confidence interval 2.6-4.6). Stratification according to age of onset of Alzheimer's disease showed that the relative risk decreased with increasing onset age. However, among patients with an onset of disease after 80 years, there were still significantly more subjects with one or more first degree relatives with dementia as compared to controls (relative risk 2.6; 95% confidence interval 1.3-5.2). The relative risk of Alzheimer's disease was significantly lower in patients who had one first degree relative with dementia (relative risk 2.6; 95% confidence interval 2.0-3.5) as compared to those who had two or more affected relatives (relative risk 7.5; 95% confidence interval 3.3-16.7). Furthermore, the re-analysis showed a significant association between Alzheimer's disease and family history of Down's syndrome (relative risk 2.7; 95% confidence interval 1.2-5.7), which was strongest in those patients who had a positive family history of dementia. The relative risk of Alzheimer's disease for those with a positive family history of Parkinson's disease was 2.4 (95% confidence interval 1.0-5.8).

Data from case-control studies of Alzheimer's disease (AD) were pooled to examine the possible roles of history of depression, anti-depressant treatment and adverse life events as risk factors. History of depression was found to be associated with AD, although the effect was confined to late onset cases. The association held for episodes of depression more than 10 years before AD onset, as well as for episodes occurring within a decade of onset. No association was found with anti-depressant treatment. However, data were only available from two studies, limiting the power of the analysis. Also, no association was found with the three major life events considered in the pooled analysis: death of spouse, death of a child and divorce.

A re-analysis of the data from 11 case-control studies was performed to investigate the association between head trauma and Alzheimer's disease (AD). To increase comparability of studies, exposures were limited to head trauma with loss of consciousness (hereafter referred to as 'head trauma') and comparisons were restricted to community (versus hospital) controls. Test for heterogeneity across studies was negative; consequently, data were pooled in subsequent analyses. The pooled relative risk for head trauma was 1.82 (95% confidence interval: 1.26-2.67). Stratified analyses showed stronger associations in cases without a positive family history of dementia and in males (versus females). Adjustment of the pooled relative risk for family history of dementia, education and alcohol consumption did not alter significantly the association between head trauma and AD. There was no interaction effect between head trauma and family history of dementia, suggesting that these risk factors operate independently. Mean age of onset was not significantly different in cases with a history of head trauma compared to cases without such a history. The findings of the pooled analysis support an association between reported head trauma and AD.

A meta-analysis, involving the secondary analysis of original data from 11 case-control studies of Alzheimer's disease, is presented for occupational exposures to solvents and lead. Three studies had data on occupational exposure to solvents. Among cases, 21.3% were reported to have been exposed; among controls, this figure was comparable (20.9%). This yielded a pooled matched relative risk of 0.76 (95% CI: 0.47-1.23). Four studies had data on exposure to lead. Exposure frequencies were 6.1% in cases and 8.3% in controls. This resulted in a pooled matched relative risk of 0.71 (95% CI: 0.36-1.41). The meta-analysis was particularly useful in validating negative results from individual studies and in increasing the statistical power for the analysis of lead exposure, where stratum-specific cell sizes were frequently smaller than five in individual studies. However, since exposure in the various studies was ascertained in a rather broad manner, prospective studies are recommended which focus on high-risk occupational populations and which determine the incidence of Alzheimer's disease in these and comparable unexposed populations.

A meta-analysis, involving the secondary analysis of original data from 11 case-control studies of Alzheimer's disease, is presented for alcohol consumption and cigarette smoking. Five studies included in the meta-analysis of alcohol consumption. Alcohol consumption was computed in terms of average weekly intake, measured in ounces of 'pure alcohol'. This variable was categorized into tertiles to represent low, medium and high intake. Analyses showed no excess estimated risk of Alzheimer's disease for any level of alcohol intake. Smoking was analysed in three different manners: (1) lifetime prevalence of smoking (ever/never)--this included eight studies; (2) amount smoked (less than or equal to one pack per day versus more than one pack per day)--this included seven studies; and (3) pack-years--including four studies. A statistically significant inverse association between smoking and Alzheimer's disease was observed at all levels of analysis, with a trend towards decreasing risk with increasing consumption (p(trend) = 0.0003). A propensity towards a stronger inverse relation was observed among patients with a positive family history of dementia, but the difference between this group and the group with no such history was not statistically significant. Although the observed disturbance in nicotinic receptor function in Alzheimer's disease may provide an explanation for these findings, possible biases related to the selection or survival of study subjects cannot be fully ruled out at this time. Prospective, community-based studies of incident cases of Alzheimer's disease are needed to document in detail the smoking history, age of onset of disease and survival of patients and cognitively intact people by smoking status.