According to selection criteria, 22 original articles11,12,13,14,15,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40
(19 case–control studies and three cohort studies) were included. One of the articles, as mentioned above, is a reanalysis of three independent series of case–control studies on AD and EMF.15
Therefore, the questionnaires were finally applied to 24 original studies.
Table 3 presents a summary of the main methodological aspects of the studies analysed, including population studied, data collection period, assessment of exposure and control of confounding bias.
Table 3Summary of main methodological aspects of the epidemiological studies on the relationship between Alzheimer's disease and selected occupational exposures
In Table 4 the results of the expert evaluation of the studies are presented. For the 24 studies, the median for the GQI was 36.6%. The article with the highest score reached a GQI of 62.9%. There was great variability in the quality of the different studies, with a range of 43.4% between the papers with the highest and lowest score. All the case–control studies but one27
showed a GQI below 50%. Five case–control studies scored below 25%, and the lowest score in the total sample was for a case–control study (GQI
19.4%). Quality in the three cohort studies was greater and more homogeneous than that seen in the case–control studies. The lowest value in the cohort studies corresponded to a prospective cohort study (GQI
Table 4Relative risks, quality (Global Quality Index, see explanation in the text) and likelihood for the presence of biases in epidemiological studies on the relationship between Alzheimer's disease and selected occupational exposures
The most common potential bias is that of misclassification in the exposure, present in 18 of the 24 studies analysed (75.0%). The second in order of frequency is the potential bias arising from the use of surrogate informants, present in 12 of the 17 studies (70.6%). The third potential bias is that of misclassification of the disease, which appeared in 11 of the 24 studies (45.8%), followed by bias of selection present in 10 studies (41.7%). Confounding was considered the less frequent potential type of bias (fig 1).
Figure 1Number of biased studies (estimated as probably or highly probably biased) and direction of bias (decreasing or increasing association, or when no conclusion was reached about direction) in selected studies on the relationship between (more ...)
In only one case, in bias arising from the use of surrogate informants, was it judged that the effect of bias might at least probably increase the association between AD and the assessed exposure, in this case to EMF. For the remaining studies the experts either judged that the observed association was probably underestimated or they failed to reach a conclusion about the effect of the potential biases under consideration. In 16 of the 18 studies affected by potential misclassification in the exposure (88.9%), it was judged that this effect could give rise to a non‐differential misclassification which would bias the associations towards the null (fig 1 and table 4).
In the reviewed papers, for the specific occupational exposures considered, 11 studies explored the relationship of AD with solvents, seven with electromagnetic fields (EMF), six with pesticides, six with lead and three with aluminium. Solvents and pesticides are the exposures with the highest number of high quality studies (five and four studies, respectively, with a score above the median GQI), followed by EMF (three studies) and lead and aluminium (two studies for each exposure) (table 4).
For pesticides, research of greater quality and prospective design found increased and statistically significant associations with AD. Tyas et al38
reported adjusted relative risk (aRR) of 4.35 (95% CI 1.05 to 17.90) for exposure to defoliants and fumigants (a smaller and non‐significant association was found for exposure to the wider category of “pesticides, fertilisers”: aRR
1.45, 95% CI 0.57–3.68) and Baldi et al40
found aRR for occupational exposure to pesticides in men of 2.39 (95% CI 1.02 to 5.63). The two case–control studies assessing risk associated with pesticide exposure and with GQI above the median26,37
found evidence of smaller and non‐significant associations, supporting the hypothesis that potential biases might have affected these results, decreasing the associations towards the null (table 4). Finally, one of the remaining two case–control studies assessing exposure to pesticides30
found an unadjusted RR of 2.54 (95% CI 0.41 to 27.06) for organophosphates.
For the remaining occupational agents considered in this review the evidence of an association is less consistent. For solvents, only two out of the 11 studies analysing this exposure found a significant association with AD. The two studies focused on the same population base. The first27
is a high quality case–control study (the case–control study with the highest score for GQI), an example of proper selection and diagnostic bias control, where only the aRR in exposed men was significantly increased (aRR
6.3, 95% CI 2.2 to 18.1). The second paper32
included only cases with a spouse who was willing to collaborate in the interview, which might increase the likelihood of selection bias. With this restriction the aRR for solvent exposure during more than 18 years reached statistical significance (aRR
2.62, 95% CI 1.07 to 7.43), although it fell to 1.77 (95% CI 0.81 to 3.90) when exposure was classified as ever/never. However, a prospective cohort study,38
also assessing exposure to solvents and with a high quality ranking (GQI) in our evaluation, did not find association with this exposure focused in degreasers (aRR
0.88, 95% CI 0.31 to 2.50), and neither did the other two case–control studies with above the median GQI scores.24,26
- Epidemiological literature on Alzheimer's disease and occupational exposures is, in general, scarce.
- Some agents have received most of the attention (pesticides, solvents, electromagnetic fields, lead and aluminium), mostly in case–control studies.
- In general, results are consistent with an increased risk of Alzheimer's disease in relation to occupational exposure to pesticides.
There are three studies assessing risk for occupational exposure to EMF with high quality, well above that of the other studies,33,35,36
including the study with the highest GQI score in our ranking. However, the highest odds ratio (OR) values for this exposure correspond to the lower quality studies. Our analysis suggests that these studies are likely to be biased and that selection bias might explain these results.
For lead exposure there are no data supporting any association. All the studies are case–control studies, with a relatively low level of quality according to our classification. For aluminium, one of the three studies about this exposure is the second in the quality ranking of the case–control studies.28
Results from this study show no association (aRR
0.95, 95% CI 0.5 to 1.9). In the other two studies associations are also non‐significant (table 4).
- Protection and surveillance of workers exposed to pesticides should consider the potential risk of Alzheimer's disease.
- Further research, and mostly follow‐up studies, can provide more conclusive evidence about this association and other risks from occupational exposures.