Environmental risk factors for dementia: a systematic review

Background Dementia risk reduction is a major and growing public health priority. While certain modifiable risk factors for dementia have been identified, there remains a substantial proportion of unexplained risk. There is evidence that environmental risk factors may explain some of this risk. Thus, we present the first comprehensive systematic review of environmental risk factors for dementia. Methods We searched the PubMed and Web of Science databases from their inception to January 2016, bibliographies of review articles, and articles related to publically available environmental data. Articles were included if they examined the association between an environmental risk factor and dementia. Studies with another outcome (for example, cognition), a physiological measure of the exposure, case studies, animal studies, and studies of nutrition were excluded. Data were extracted from individual studies which were, in turn, appraised for methodological quality. The strength and consistency of the overall evidence for each risk factor identified was assessed. Results We screened 4784 studies and included 60 in the review. Risk factors were considered in six categories: air quality, toxic heavy metals, other metals, other trace elements, occupational-related exposures, and miscellaneous environmental factors. Few studies took a life course approach. There is at least moderate evidence implicating the following risk factors: air pollution; aluminium; silicon; selenium; pesticides; vitamin D deficiency; and electric and magnetic fields. Conclusions Studies varied widely in size and quality and therefore we must be circumspect in our conclusions. Nevertheless, this extensive review suggests that future research could focus on a short list of environmental risk factors for dementia. Furthermore, further robust, longitudinal studies with repeated measures of environmental exposures are required to confirm these associations.


Background
Dementia is a syndrome of cognitive and functional decline, commonly occurring in later life as a result of neurodegenerative and cerebrovascular processes beginning earlier in the life course [1,2]. It is a major and growing public health concern with substantial increases projected in the future, particularly in low-to-middle income countries [3][4][5]. Furthermore, there is now a consensus that a substantial proportion of cases are potentially preventable [6][7][8][9]. Preventing or, perhaps more realistically, delaying the clinical onset of dementia would have a substantial effect on disease numbers [10][11][12]. It has been suggested that approximately a third of Alzheimer's dementia cases could be attributed to seven potentially modifiable risk factors: diabetes, midlife hypertension and obesity, smoking, depression, cognitive inactivity, and low educational attainment [13,14]. Adding to this amount of risk explained estimates of population attributable fractions derived from genetic factors [15], it is likely that a large proportion of variance in dementia risk remains unexplained. Therefore, there is an urgent need to identify further potentially modifiable risk factors for dementia.
There is evidence from studying geographical variation in dementia rates that environmental risk factors may also be important in the pathogenesis of dementia [16][17][18][19].
Two previous reviews have reported on environmental risk factors for Alzheimer's disease: both concluded that aluminium in drinking water and electromagnetic fields were important and one also highlighted occupational exposure to solvents and pesticides [20,21]. However, both these reviews focused on Alzheimer's disease rather than all-cause dementia and neither of them used robust, systematic review methodology and so may not have covered all potentially important risk factors. Thus, we present the first comprehensive systematic review on environmental risk factors for dementia.

Information sources
We identified studies using three approaches. First, we conducted an electronic search of the PubMed and Web of Science databases from their start to January 2016 (Appendix 1). This search returned relevant primary studies and review articles. Second, we scrutinised bibliographies of included studies and review articles for additional studies which had not been identified by the search. Third, we reviewed a small number of hand-picked studies, based on our knowledge of the literature from scrutiny of articles related to publically available environmental data.

Search strategy
A shortlist of environmental factors was created based on previous work investigating environmental risk factors on health in general [22]. We also included factors not included in the general list which we knew had been linked to dementia risk, such as trace elements (for example, selenium [23]). Thus, the list of environmental factors which we searched for were air pollution, climate, ultraviolet radiation, green space, industrial pollution, water quality, noise pollution, low-frequency and radiofrequency radiation, radon, nuclear facilities, contamination, and trace elements.

Screening & eligibility
Records returned from the search were screened based on titles and abstracts for suitability. Conference proceedings, books and editorial publications were excluded. Of the remaining studies, articles were then selected if they reported an association (including null associations) between an environmental factor and any dementia.
The main exclusion criteria were: animal studies; single case studies; studies where the exposure was a physiological measure which could not be directly linked with the environment, for example autopsy studies measuring levels of trace elements in the brain or measuring serum levels of a substance; studies with outcomes other than clinical dementia, e.g. cognitive decline; studies of specific symptoms or features (e.g. inflammation, oxidative stress) of dementia rather than the full dementia syndrome; studies where the exposure was solely nutritional; or where insufficient data were reported in the paper. Since we have recently published a systematic review and metaanalysis on the association between rurality and urbanicity on dementia [16], we did not consider this in the present review. Relevant review studies were carefully examined and additional primary articles not identified in the search were included (see below for definition). However, if a review reported multiple new studies, we included the review as a single source of evidence, summarising its findings rather than including every study individually (for example, Loef and Walach, 2012 [24] included 101 individual studies). We refer to the review studies in the main text and, where relevant, performed additional focused searches to identify any more recent articles which would have been included in these reviews. We also reported the most recent report from studies, removing any earlier report(s) (e.g., Rondeau et al., 2000 [25]).

Quality of evidence
Individual studies were appraised for quality. Large, prospective longitudinal studies with a robust measure of the risk factor in question at baseline and a clinical diagnosis of dementia were classified as being of quality level A. High quality cross-sectional studies (i.e., a large sample size with robust exposure and outcome measures) were considered level B quality, and studies which did not reach this level were considered level C quality. The total evidence for an individual risk factor was synthesised to conclude whether there is strong, moderate, or weak evidence for an association (or lack of an association) between the risk factor and dementia or whether there is insufficient evidence to come to a conclusion. The criteria for each level of strength are given in Table 1. The reporting of this systematic review conforms to the PRIMSA guidelines [26].

Results
The PRISMA diagram for the process of screening and selecting records is shown in Fig. 1. From an initial total of 6665 studies returned from the searches, after removing duplicates across the environmental factors, 4784 studies were screened for suitability. Of these, 60 were identified as eligible for inclusion. Table 2 shows the synthesised evidence from all studies with a global judgement about the strength of the evidence for an association from all published studies. The environmental risk factors under consideration fall into the following six groups: air quality, toxic heavy metals, other metals, other trace elements, occupational-related exposures, and miscellaneous environmental factors. Tables 3, 4, 5, 6, 7 and 8 summarise individual studies providing evidence for each risk factor in each category. The tables are organised alphabetically by exposure with higher quality studies being reported first within this grouping and included review studies last of all.

Air quality
Studies of the association between environmental risk factors in air and dementia are summarised in Table 3. Higher levels of nitrogen oxides were observed to be associated with increased dementia risk in two prospective cohort studies: a 15 year prospective cohort study of 1806 healthy men and women in Umeå, Sweden, and a retrospective cohort study of almost thirty thousand individuals identified from the comprehensive Taiwanese health insurance database passively followed up for a decade [27,28]. However, only the prospective study observed a dose-response pattern of association (adjusted HR per 10 μg/m 3 increase in nitrogen oxides, 95 % CI 1.05, 0.98, 1.12) [27]. This study grouped nitrogen oxides into the following cut-offs: 9, 17, and 26 μg/m 3 . The other study only observed an increased risk in the highest quartile and used the following cut-offs for NO 2 concentration: 6652.3, 8349.0, and 9825.5 parts per billion [28]. The discrepancy in the pattern of observation observed in these two studies can be explained by the fact that the former explored higher levels of NO xthe highest cut-off from the latter study (~10 parts per million) approximately corresponds to the lowest cut-off from the former study (~10 mg/L ≡ μg/m 3 ). The latter study also investigated carbon monoxide concentration and found a dose-response association with dementia risk for this exposure (adjusted HR compared to the lowest quartile, 95 % CI: 1.07, 0.92-1.25; 1.37, 1.19-1.58; 1.61, 1.39-1.85) [28]. Similar patterns were seen for men and women separately.
Environmental tobacco smoke was shown to be associated with dementia risk in a cross-sectional study of almost 6000 people in five provinces of China [29]. These investigators asked participants about exposure to environmental tobacco smoke at home, work, and in other locations, duration of exposure as well as estimating cumulative exposure. Rather than a clinical diagnosis, these investigators used the GMS-AGECAT algorithm which has been widely used in epidemiological studies, including the MRC Cognitive Function and Ageing Studies [30,31]. Higher levels of exposure were associated with an increased risk of severe dementia (O3-5) but not moderate dementia (O1-2). The cut off for moderate dementia used in this study showed only a positive predictive value of 68.6 % but the cut off used for severe dementia performed much better (88.1 %) [32]. The cumulative dose analysis showed a dose-response association (adjusted HR compared to a cumulative dose of zero for groups >0-24, 25-49, 50-74, 75-99, ≥100, 95 % CI: 0.99, 0.76- Table 1 Definitions of the strength of the reported association  between individual risk factors and dementia   Strong evidence for environmental risk factor There is a reported association with dementia in the majority of published papers. Moderate or weak evidence for environmental risk factor Although the reported association with dementia is not seen in the majority of published papers, at least one published paper (or only one) supports the association.
Weak evidence may come from a single, poorly designed study.

No evidence for environmental risk factor
No association with dementia has been revealed either due to a lack of relevant research or the observed effect is not seen as significant.  . Also, all effect sizes were larger in never smokers than when ex-smokers were included. A prospective Taiwanese study following almost a million people over ten years found an association between baseline ozone but not particulate matter up to 2.5 μm in diameter (PM 2.5 ) and incident Alzheimer's dementia [33]. However, change in exposure to both pollutants during follow up was associated with a two-to-three-fold increased risk of incident AD. A final cross-sectional study of 871 people in Taiwan also examined both particulate matter (PM 10 ) and ozone concentration at the participant's home address, finding increased Alzheimer's dementia risk in the second and third tertiles of PM 10 concentrations (adjusted OR, 95 % CI: 1.68, 0.94-3.00; 4.17, 2.31-7.54; P trend < 0.001) but only in the highest tertile of ozone concentrations (0.60, 0.33-1.09; 2.00, 1.14-3.50; P trend = 0.03) [34]. They found similar patterns of association with vascular dementia.
Thus, the evidence for airborne environmental risk factors for dementia is consistent in the direction of association for all exposures and the overall strength of evidence, while based on relatively few studies, is moderate to strong. Table 4 summarises the studies linking toxic heavy metals to dementia risk. There were two studies of arsenic, one of which was of grade-B quality and found no association with dementia; the grade-C study found increased rates of dementia in areas with higher soil arsenic levels but this country-level simulation is less informative about risk factors in individuals [35,36]. A case-control study with 129 people in each group found that an excess of people with Alzheimer's dementia were born in areas with higher than average lead concentrations [37].

Toxic heavy metals
Overall, there was relatively little extant evidence for an association between toxic heavy metals and dementia risk. Table 5 summarises the studies focused on other metals and dementia risk. Aluminium was the most studied metal, with sixteen studies investigating its relationship with dementia including almost 22,000 people with dementia. The only high quality studya prospective cohort study of almost four thousand older adults in south-west France (the PAQUID study [38])found that levels of aluminium consumption in drinking water in excess of 0.1 mg per day were associated with a doubling of dementia risk and a three-fold increase in the risk of Alzheimer's dementia [39]. Of the remaining thirteen moderate quality studies, six found an association between increased aluminium levels in drinking water and increased dementia risk [40][41][42][43][44][45], four found no association [37,[46][47][48], and one found a protective effect of higher soil levels of aluminium [49]. In general, the larger studies showed a positive association and the smaller studies showed a null effect.

Other metals
A prospective cohort study compared calcium levels in tap water with risk of developing Alzheimer's dementia. However, it is unclear if their not mentioning calcium as a predictor means that they failed to examine it or if it did not emerge from the models as an independent predictor. A cross-sectional study found no association between cobalt and dementia risk [37,50]. Two case-control studies and one review article summarising 101 studies considered copper and iron in relation to dementia [24,37,49]. The findings regarding copper were inconclusive. However, they reported that higher soil levels of iron were associated with an increased risk of dementia [37,49]. The review article was inconclusive [24].
An excess of people with Alzheimer's dementia were born in areas with higher than average levels of manganese in a cross-sectional study [37]. The same study found no evidence for an association between molybdenum, nickel, uranium, or zinc with dementia risk [37]. However, another study found that higher zinc levels in the soil was associated with an increased risk of Alzheimer's dementia [49].
It is challenging to synthesise the published reports on the association between metals and dementia, and the published evidence for an individual element is often weak and/or contradictory. However, there is at least some evidence that calcium, cobalt, molybdenum, nickel, and Strength of evidence is assessed according to the criteria outlined in Table 1 c Increased levels of the exposure are associated with: ↑ an increased risk of dementia; ↓ a decreased risk of dementia; ↕ mixed results on dementia risk; andno substantial effect on dementia risk  129 individuals with AD (clinically diagnosed by standard medical services) who were born in SLSJ.
Cross-sectional study: principal components analysis. Samples of aquatic sediment were analysed for geochemical variables. AD cases were identified from a registry.
15 individuals with AD were born in areas with lower than average concentration of lead; 49 were born in areas with higher than average concentrations. This difference was statistically significant (P < 0.05).

B
AD Alzheimer's dementia, CI confidence interval, SD standard deviation, SEM standard error of the mean          Case-cohort study: Cox PH models. Exposure based on self-report. Dementia status ascertained using death certification. Person-years at risk were calculated from a randomly-selected sub-cohort.
Exposure to any pesticides was not associated with an increased risk of non-VaD mortality in men or women. The same pattern was seen when disaggregating the effect of insecticides, herbicides, and fungicides in men. In women, high exposure to herbicides and fungicides was associated with an increased risk of non- Fourteen studies are reviewed (2 on cognitive performance, 1 mild cognitive dysfunction, 7 AD, 1 FTD, 2 VaD, and 1 PD).
Narrative review. Of the 7 AD studies, 5 demonstrated an increased risk of AD (plus one which did so weakly) and one showed no association.
-"Information from the literature [on VaD] is scant; however, occupational exposure to pesticides or fertilizers conferred a two-fold increased risk of developing vascular dementia in the Canadian Study of Health and Aging." (p. 7).
"Due to the relative rarity of [FTD] at the population level, pesticide exposure has been studied as a contributing factor to FTD onset in relatively few studies and no association was found." (p. 7). Cross-sectional study (case-control): logistic regression. Risk factor exposure was based on self-report.
Solvent exposure was associated with an increased odds ratio of dementia in men (adjusted OR, 95 % CI: 6.3, 2.2-18.1) but not in women (0.6, 0.2-1.9). In men, a significant effect of exposure duration was observed. Case-cohort study: Cox PH models. Exposures based on self-report. Dementia status ascertained using death certification. Person-years at risk were calculated from a randomly-selected sub-cohort.
High exposure to any solvents compared to no exposure was associated with an increased risk of non-VaD mortality in men (adjusted HR, 95 % CI 1.20, 0.90-1.61) but not women. High exposure to aromatic solvents was associated with increased non-VaD mortality in women (3.46, 0.59-20.5) but not men. High exposure to chlorinated solvents was associated with increased risk in men (1.33, 0.96-1.83) and women (2.08, 0.60-7.14), as was low exposure in men (1.25, 0.89-1.76).

A
The hazard associated with cumulative exposure to chlorinated solvents showed a significant trend (P = 0.01).

Santibanez et al., 2007 [68]
Solvents Systematic review of studies linking occupational exposures and AD.
Twenty four studies: 3 cohort and 21 case-control studies.
Systematic review. "For solvents, only two out of the 11 studies analysing this exposure found a significant association with AD." (p. 730) -AD Alzheimer's disease, CI confidence interval, ELF-MF Extremely low frequency magnetic fields, FTD fronto-temporal dementia, HR hazard ratio; OR odds ratio, PD Parkinson's disease, RR relative risk, VaD vascular dementia  uranium are not associated with an increased risk of dementia, but this is often based on minimal evidence. One prospective study and the larger cross-sectional studies tend to support an association between aluminium and dementia risk [39][40][41]44].
Other trace elements Table 6 shows the studies investigating links between other trace elements and dementia. A cross-sectional study extrapolated from the medical records of 160 people to estimate annual dementia incidence and found the area with the highest fluoride concentrations in public water supplies had the lowest incidence [51]. Selenium has been the focus of a number of studies. The included review article [23] referred to a randomised, controlled trial of selenium supplementation to reduce dementia risk, the PREADVISE trial, but this seems to have converted into an observational study and is yet to report on selenium levels [52][53][54]. The review also referred to a conference abstract reporting a prospective cohort study [55], but subsequent reports do not focus on selenium [56]. In general, this review article reported mixed findings from 15 case-control studies and 24 autopsy studies [23]. One cross-sectional study found no differences in average levels of silicon in drinking water between a group of people with Alzheimer's dementia and several neurological control groups [46]. On the other hand, two prospective cohort studies found an association between higher levels of silica in drinking water and dementia incidence [39,57]. However, a case-control study did not corroborate these findings [48].
The evidence for other trace elements is again mixed and generally weak in strength. Table 7 summarises the individual studies relating occupational exposures to dementia risk. Four studies investigated occupational exposure to aluminium in relation to dementia [58][59][60][61]. These tended to be small with consequently low statistical power. Their results were mixed. The prospective Manitoba Study of Health and Aging studied a variety of exposures but the only robust association they found was an increased risk of dementia in relation to self-reported exposure to defoliants/fumigants [62]. The same study reported null associations in all other exposures studied, apart from a protective effect of excessive noise and increased risk associated with radiation exposure. However, in both these cases, only one person with dementia had been exposed to noise or radiation and so there is very limited statistical power. A case-cohort study of 1552 people dying with non-vascular dementia found no association between exposure to diesel motor exhaust fumes and dementia but mixed evidence for extremely low frequency magnetic fields or electric shocks [63]. Two reviews concluded that exposure to pesticides was associated with an increased risk of dementia which was corroborated by the prospective Canadian Study of Health and Aging, Cache County Study, the PAQUID study, and to some extent a retrospective British study of farmers but not by the Manitoba study or a case-control study from Québec; a study from the Netherlands had mixed findings [62][63][64][65][66][67][68][69][70]. A systematic review found no support for an association between occupational exposure to lead and dementia and mixed evidence (predominantly null) between solvent exposure and dementia [68]. A case-control study from the USA found an association between solvent exposure and AD, at least in men [71]. However, a case-cohort study from the Netherlands found mixed associations between solvents and dementia, perhaps reflecting the diversity of chemicals described as solvents [63].

Occupational-related exposures
The evidence linking occupational exposures and dementia is frequently weak. Aside from the mixed evidence for solvents, the strongest evidence is for exposure to pesticides, but even findings in that literature are mixed. However, there seems to be no published evidence suggesting that occupational exposure to diesel motor exhaust, lead, inks/dyes, paints/stains/varnishes, gasoline/ fuels/oils, liquid plastics/rubbers, or vibratory tools affect dementia risk. Table 8 summarises studies linking miscellaneous environmental exposures and dementia. One study reported no association between climate and dementia admissions [72]. Two systematic reviews examined low and extremely low frequency electric and magnetic fields and, while the evidence is mixed, there seems to be an association with dementia risk and this was corroborated by a prospective study in Switzerland which found that living close to power lines for over 15 years was associated with a doubling of Alzheimer's disease mortality (but not the occupational study mentioned above [63]) [73,74]. Its findings are difficult to interpret, but a prospective study in Denmark found that mobile phone subscription was associated with a decreased risk of subsequent hospital admission with dementia [75]. Three high quality prospective studies (including 11,884 people of whom 691 developed dementia) examined the association between vitamin D and dementia and all found that lower vitamin D levels at baseline were associated with an increased risk of developing dementia [76][77][78]. However, this finding was not corroborated by a small case-control study (40 in each group) of people with mild dementia [79]. Finally, one study noted that the area with the highest dementia mortality had the lowest drinking water pH [42].

Miscellaneous environmental factors
Out of the miscellaneous exposures considered in this section, there seems to be strong evidence that vitamin D deficiency is associated with increased risk of dementia and moderate evidence implicating electric and magnetic fields. There is no published evidence supporting any role for weather parameters in dementia risk.

Main findings
In summary, we found moderate evidence for air pollution exposures being related to dementia risk, particularly nitrogen oxides, particulate matter, and ozone. There was little evidence that toxic heavy metals, or indeed most metals, influence dementia risk, apart from aluminiumwhere larger, better quality studies suggested an association. Other than silicon, there was little evidence for other trace elements affecting dementia risk, though selenium remains an interesting element. Of the occupational exposures, there was little strong evidence, but the evidence suggests that exposure to some pesticides and, possibly, metals may affect dementia risk. Finally, there was strong evidence for vitamin D deficiency being associated with raised dementia risk and moderate evidence for electromagnetic fields, though this complicated exposure requires some unpicking.

Limitations of the review and risk of bias within and across studies
The broad search and systematic methodology of this review is likely to have identified all the available literature. Our exclusion of studies without dementia as their outcome resulted in the exclusion of high quality studies examining the association between environmental risk factors and, for example, cognition or brain structure [80,81]. Such studies may shed some light on the pathogenesis of dementia since cognitive or brain changes are important features of dementia but they are not specific to this syndrome. We excluded papers measuring levels of a particular substance (often trace elements) in brain areas or in serum since these physiological changes could not be directly linked to environmental exposure. Our other exclusion criteria (case studies, animal or nutritional studies) are unlikely to have resulted in the exclusion of relevant papers or introduced bias. As mentioned above, we did exclude papers examining the effect of rurality or urbanicity since we have previously reviewed this literature and found in a meta-analysis an increased risk of dementia (particularly Alzheimer's dementia) in rural areas, particularly living in rural areas early in life [16]. One unavoidable bias is that, despite the projected increase in dementia rates occurring disproportionately in low-to-middle income countries [4], the majority of the research was conducted in high-income countries.
One of the major challenges in trying to synthesise such a broad selection of papers is the diversity of methodologies used. When considering Bradford Hill's criteria for inferring a causal association (strength, consistency, specificity, temporality, biological gradient, plausibility, and coherence), one clearly cannot satisfy the temporality criterion with a cross-sectional study, and thus a longitudinal study will provide more robust evidence for the role of a risk factor in the pathogenesis of dementia [82]. Since many of the included studies are cross-sectional, it is often not possible to infer a causal relationship. However, attrition in longitudinal studies can be non-random which can introduce selection bias [83]. Furthermore, no study measured exposures at more than one time point (though some measured the average exposure in a period), which will give a more accurate picture of true exposure over time and is essential in order to test whether there are critical or sensitive periods within the life course [84].
The fact that a number of exposures were only studied in a single study (see Table 2) also weakens support for them as it is impossible to examine the consistency of the association in multiple studies. However, exposures which were investigated in more than one study were also measured in a variety of ways, sometimes with variable quality. For example, many exposures were inferred from an address. This may be reasonable when it is not possible to measure an individual's exposure directly, but the timing of measurement of the exposure is crucial, as will be discussed below. One strength of this approach is that it allows cumulative exposure to be estimated, given the participant's residential history. A more robust measure of an individual's exposure is direct measurement. This will clearly make a study more costly and will also not solve the problem of the timing of the exposure. Less robust, but frequently used for occupational exposures, in particular, is self-report. This does avoid the problem of temporality as different points in the life course can be covered, but will be limited in detail and prone to recall bias [85]. Finally, direct measurement of levels of a substance in the brain is likely to be the most accurate, but is also the most difficult to link to dementia riskparticularly for substances present in healthand thus these studies were excluded from the presence of the review. Alzheimer's disease in the brain and the overt clinical symptoms of Alzheimer's dementia are parallel, related phenomena [9] and the fact that approximately a third of people dying without dementia can have moderate or severe Alzheimer's disease in their brains further complicates the interpretation of autopsy studies [86]. Returning to Bradford Hill's criteria, a number of included studies grouped their exposures into multiple categories, allowing the exploration of a biological gradient in any association observedfor example nitrogen oxides [27] which can strengthen any inference of a causal relationship.
Where possible, we reported the most-adjusted model in a particular study. Most studies adjusted for age and sex and some for other relevant known risk factors for dementia such as educational attainment or comorbidity but adjustment beyond that was highly variable. The possibility of residual confounding still remains.
There was a similar diversity of methodologies (and diagnostic criteria) used to identify people with dementia and it is important to consider whether any of these may introduce bias. Most robust is direct clinical assessment of individuals (often combined with a preliminary screening phase to minimise costs), either specifically for a research project or sourced from medical records. Two-phase screening seems to provide an accurate measure of dementia [87], but screening non-participation may introduce selection bias [88]. A substantial number of studies used dementia mortality as their outcome. This has previously been criticised [89], but more recent studies suggest that dementia reporting is improving, for example 72 % of a memory clinic cohort had dementia correctly diagnosed on their death certificates [90]. Importantly, death certification of dementia did not seem to be related to premorbid intelligence or area-level deprivation in that study (unpublished results available from the author on request). Another study using multiple sources from electronic health records to identify cases of dementia found that death certificates alone identified 83 % of the total number of cases identified by any source [17]. An additional important point is the adequacy of controls in case-control studiesthere was some variability in the extent of matching with people with dementia.
Since we know that dementia is a condition which is affected by risk and protective factors throughout the life course [1], when the exposure is measured is crucial. Within life course epidemiology, there are three models of the association between a risk factor and an outcome: accumulation of risk, sensitive periods, and critical periods [91,92]. Sensitive periods refer to a period of the life course when an exposure has a greater effect than other times. A critical period is the only time when a particular exposure has its effect; it does not affect risk if encountered at a different point in life. Crucially for dementiawhich is now indisputably considered a condition of the life course [93] the exposure in a study must be measured sufficiently early in life plausibly to be involved in the pathogenesis of a condition which begins years or even decades before the clinical onset of symptoms [94]. For example, we have found evidence above for an association between air pollution and dementia but it is not clear at what stage of life exposure is important. A recent study found a biomarker which has been proposed for Alzheimer's disease (reduced cerebrospinal fluid levels of Aβ 1-42 [95]) in children in Mexico City who had been exposed to high levels of air pollution in utero and throughout their life compared to controls [96]. The issue of timing of exposures has been rather neglected by the published literature on potential environmental risk factors for dementia and should be considered in much richer detail in the future.

Comparison with previous literature
To the best of our knowledge, this is the first comprehensive systematic review of environmental risk factors for dementia. A review article was recently published on environmental risk factors for Parkinson's disease and Alzheimer's disease [20]. However, this article did not take the systematic approach or focus on dementia of the present reviewthe author included an extremely broad range of risk factors, including some environmental risk factors alongside clinical, lifestyle, and dietary factors. The findings of that review generally agreed with ours and it concluded that there was robust evidence for an increased risk of Alzheimer's disease in relation to exposure to pesticides and that there was weak evidence for an increased risk in relation to levels of aluminium in drinking water and electromagnetic fields.
An older review summarised the literature relating to a number of risk and protective factors and concluded that there was evidence that occupational exposure to solvents, pesticides, and electromagnetic fields as well high levels of aluminium in drinking water were hazardous [21]. A brief review article from around the same time considered young-onset Alzheimer's dementia and highlighted a number of deficiencies in the literature, many of which remain, which frequently consisted of small studies with limited measurements of environmental data, particularly in relation to the life course and what would now be referred to as the 'preclinical' period [97].

Implications
As mentioned above, if a modifiable environmental risk factor for dementia could be identified and modified, the implications for public health, the economic cost of dementia, and individuals' suffering could be profound. We have reported, albeit with many caveats, a short list of environmental factors which may be related to dementia riskair pollution (all types); aluminium; silicon; selenium; pesticides; vitamin D; and electric and magnetic fieldsand it is reasonable to speculate about possible mechanisms which might underlie these associations, if they were to prove causal. These mechanisms could be examined in more detail using methodologies such as Mendelian randomization [98].
Air pollution has been shown to be associated with reduced cerebral blood flow [99] and seems to be neurotoxic [100]. As shown above, brain changesincluding cognitive changes and biomarkerscan be identified in children living in areas with high levels of air pollution compared to controls [96]. Aluminium has been found in amyloid plaques and neurofibrillary tangles (pathological features of Alzheimer's disease) and, in rat models, aluminium intake increases amyloid expression [101,102]. Furthermore, it has been suggested that relatively small amounts of aluminium could be neurotoxic and levels could accumulate selectively in certain brain tissues [103]. Silica may reduce absorption or increase excretion of aluminium [39]. Copper could be implicated in the pathogenesis of Alzheimer's disease in a number of ways, including promoting Aβ aggregation and hyperphosphorylation and aggregation of tau [104]. The role of selenium in human physiology is complex [105] and it is involved in multiple molecular pathways relevant to the development of Alzheimer's disease [23]. Pesticides form a heterogeneous group but some seem to be neurotoxic. Organophosphates, for example, may disrupt cholinergic neurotransmission through inhibition of acetylcholinesterase [69]. Chronic exposure to some pesticides has been linked to multiple neurological conditions, though specific mechanisms remain unclear. Vitamin D has numerous effects relevant to the pathogenesis of Alzheimer's disease, including stimulating macrophages to clear amyloid plaques, reducing amyloid-induced cytotoxicity, as well as maintenance of cerebrovascular function [78]. Electric and magnetic fields have been proposed to affect the brain in a variety of mechanismsincluding oxidative stress, apoptosis and necrosis of neurons, and even cytogenetic effectsbut no firm mechanistic link with dementia has been made [73,106]. It can be seen that several of these putative risk factors could act through multiple routes and it may become even more difficult to disentangle the relative importance of Alzheimer's disease pathology and cerebrovascular disease in causing clinical dementia.

Conclusions
In conclusion, the published evidence concerning specific environmental risk factors for dementia is generally not strong. However, there seems to be little role for most metals or other trace elements, occupational exposure to lead, inks/dyes, paints/stains/varnishes, gasoline/fuels/oils, liquid plastics/rubbers, vibratory tools, or climate in determining dementia risk. There is at least moderate evidence consistently supporting air pollution, aluminium, silicon, selenium, pesticides, vitamin D, and electromagnetic fields as putative environmental risk factors for dementia. More and better research is needed and we suggest that this shortlist should form the initial focus of attention.