Aluminium and Alzheimer's disease: An epidemiological approach Christopher N. Martyn MRC Environmental Epidemiology Unit, Southampton General Hospital, Tremona Road, Southampton S09 4XY, England. Abstract Epidemiological methods have an important role in the investigation of the postulated connection between exposure to aluminium and the development of Alzheimer's disease. We have examined the usefulness of existing data on prevalence and mortality as a resource for studying variations in the rate of the disease with time and geography. Unfortunately, methodological differences between prevalence surveys and errors and biases in mortality data are large. No reliable conclusions can be drawn from these data about geographical differences in rates of dementia in England and Wales nor about time trends in the disease. Aluminium salts are widely used in the UK for the treatment of drinking water. Residual aluminium concentrations vary more than ten fold between different parts of the country. We have estimated diagnostic rates of pre-senile Alzheimer's disease in seven geographical areas and examined the correlation between rates of Alzheimer's disease and water aluminium concentration.
Introduction Since it is impossible to administer aluminium containing compounds to humans under experimental conditions the hypothesis that links exposure to aluminium with the development of Alzheimer's disease can only be tested by epidemiological techniques. Collection of the sort of data necessary for most epidemiological studies is time consuming and expensive and as a first approach it is sensible to try to make use of information that is already available. Two sources of data relevant to Alzheimer's disease exist; the first is routinely collected mortality data, derived from the information recorded on death certificates by the doctor certifying death; the second is the numerous surveys that have been carried out to determine the local prevalence of dementia. Either might prove to be a resource that would allow investigation of geographical variation in the rate of Alzheimer's disease and its relation to differences in the population exposure to aluminium. Estimates of mortality derived from death certificates are subject to errors and biases from a variety of sources and preliminary investigations are needed to assess their likely m a g n i t u d e . In this p a p e r we d e s c r i b e our investigations of the usefulness of existing data as a way of examining geographical variation in the prevalence of and mortality from Alzheimer's disease in England and Wales.
Prevalence Surveys Recent prevalence surveys of dementia have been well reviewed by Henderson (1986) and by Ineichen (1987). Prevalence rates varied from 2.5% in people aged over 65 years in London (Gurland et al., 1983) to 25% in people
over 60 years in the USSR (Sternberg and Gawrilova, 1978). At least part of this variation is due to differences in methodology. There are three main ways in which differences in survey methods are likely to influence the estimate of prevalence: the method of case-finding used, the definition of dementia that was employed and the population that was sampled.
Case-finding Surveys which have employed an interviewer to administer a psychometric test or questionnaire to all or a sample of the elderly population in a community are more likely to achieve completeness of ascertainment of cases of dementia than those that have relied on review of cases already known to hospital-based services or general practices. An example where this sort of methodological difference may have had an effect on the estimate of prevalence is easy to find. In Kay's survey in Newcastle in 1970 all people over the age of 65 in the community were sampled; the prevalence of severe dementia was 6.2%. In contrast, in the survey of Adolfsson et al. (1981) that relied on counting cases under institutionalised care, the estimate of prevalence was only 2%.
Definition of dementia Until recently there were no generally agreed and workable definitions for dementia or criteria for the diagnosis of Alzheimer's disease. Investigators were therefore obliged to construct empirical definitions for themselves. Often, these definitions did not attempt to distinguish between different diseases underlying dementia so that prevalence estimates of dementia cannot be equated with the prevalence of Alzheimer's disease. It is also obvious that those surveys which aimed to detect cases of mild dementia as well as more severely demented people will obtain a
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higher prevalence rate than surveys that considered only those cases where dementia was severe. Kay et al. (1985) have discussed in detail the effect that different working definitions of dementia and different psychometric instruments for the detection of dementia are likely to have on prevalence estimates.
Population sampled Most surveys have excluded young or middle aged people from the study population because the prevalence of dementia is so low in these age groups. Above the age of 65 years, however, the prevalence of dementia increases very quickly. In many countries the proportion of very elderly people in the population is growing rapidly. Unless age standardisation has been carded out it is difficult to compare surveys from different countries because the populations surveyed may have had a very different age structure. Another difficulty is that some surveys included only people living at home, while others took a random sample of the whole population over a certain age. Cases of dementia cared for in institutions will be excluded from the former type of survey. Statistical power One further problem in the interpretation of prevalence surveys arises because the numbers of cases that were detected in some of them were fairly small. Small numbers affect the precision of the estimate of prevalence. For example, although the prevalence of dementia measured in Hobart was twice that obtained from a similar study in London, the confidence intervais around these estimates are such that the possibility that this was a chance finding cannot be excluded (Kay et al., 1985). Even if we consider only those surveys which employed similar methods of case finding and similar definitions of dementia the inferences that can be drawn from differences in the prevalence of dementia are very limited. No unequivocal evidence yet exists to show geographical variation in rates of Alzheimer's disease.
Mortality Data In England and Wales the Office of Population Surveys and Censuses (OPCS) extracts, from the information recorded on death certificates, the underlying cause of death and codes this diagnosis according to the International Classification of Diseases. These data have recently been used to examine the geographical distribution of mortality from a number of diseases including dementia (Gardner et a/., 1984). Mortality from dementia showed considerable variation over different parts of the country. Data derived from death certificates, however, are known to contain a number of inaccuracies. We carded out a series of studies to evalute whether the apparent geographical variation in mortaliy from dementia reflected real differences in the rates of the disease (Martyn and Pippard, 1988).
What proportion of cases of dementia have this diagnosis recorded as the underlying cause of death? Using the d i a g n o s t i c register m a i n t a i n e d at the psychogeriatric clinic at Newcastle General Hospital, Newcastle upon Tyne we identified 197 patients diagnosed
as being demented during the years 1980 and 1981. In 1986, when this study was carded out, 140 of these patients had died. OPCS were able to provide the death certificates of 137 of these 140. In less than 25% was the underlying cause of death coded as dementia or Alzheimer's disease (ICD Numbers 290 or 331). In only 58% was dementia, Alzheimer's disease or a related diagnosis recorded on either part of the death certificate by the doctor certifying death.
Are patients who do have dementia coded as the underlying cause of death unusual? Because so small a proportion of patients who are diagnosed during life as being demented have a diagnosis of Alzheimer's disease or a related condition coded as the underlying cause of death, it seemed likely that these patients might be atypical. We therefore examined a sample of death certificates, again provided by OPCS, in which the underlying cause of death had been coded as pre-senile or senile dementia. The sample of 200 death certificates represented approximately one in two of all deaths certified as due to dementia in people under the age of 76 for the year 1978. Two facts of importance emerged; first, most of the patients had died in hospitals with long-stay beds; second, the most common terminal event by far was bronchopneumonia. Geographical analysis of mortality from dementia The mortality data for 1968 - 1978 consisting of extracts from all death Certificates for England and Wales were examined. Mortality rates for each sex for each local authority area were calculated from 1971 census data which were grouped according to local authority boundaries. Death rates were expressed as standardised mortality ratios. There were 140 areas which had a significantly higher than average (P
Introduction Since it is impossible to administer aluminium containing compounds to humans under experimental conditions the hypothesis that links exposure to aluminium with the development of Alzheimer's disease can only be tested by epidemiological techniques. Collection of the sort of data necessary for most epidemiological studies is time consuming and expensive and as a first approach it is sensible to try to make use of information that is already available. Two sources of data relevant to Alzheimer's disease exist; the first is routinely collected mortality data, derived from the information recorded on death certificates by the doctor certifying death; the second is the numerous surveys that have been carried out to determine the local prevalence of dementia. Either might prove to be a resource that would allow investigation of geographical variation in the rate of Alzheimer's disease and its relation to differences in the population exposure to aluminium. Estimates of mortality derived from death certificates are subject to errors and biases from a variety of sources and preliminary investigations are needed to assess their likely m a g n i t u d e . In this p a p e r we d e s c r i b e our investigations of the usefulness of existing data as a way of examining geographical variation in the prevalence of and mortality from Alzheimer's disease in England and Wales.
Prevalence Surveys Recent prevalence surveys of dementia have been well reviewed by Henderson (1986) and by Ineichen (1987). Prevalence rates varied from 2.5% in people aged over 65 years in London (Gurland et al., 1983) to 25% in people
over 60 years in the USSR (Sternberg and Gawrilova, 1978). At least part of this variation is due to differences in methodology. There are three main ways in which differences in survey methods are likely to influence the estimate of prevalence: the method of case-finding used, the definition of dementia that was employed and the population that was sampled.
Case-finding Surveys which have employed an interviewer to administer a psychometric test or questionnaire to all or a sample of the elderly population in a community are more likely to achieve completeness of ascertainment of cases of dementia than those that have relied on review of cases already known to hospital-based services or general practices. An example where this sort of methodological difference may have had an effect on the estimate of prevalence is easy to find. In Kay's survey in Newcastle in 1970 all people over the age of 65 in the community were sampled; the prevalence of severe dementia was 6.2%. In contrast, in the survey of Adolfsson et al. (1981) that relied on counting cases under institutionalised care, the estimate of prevalence was only 2%.
Definition of dementia Until recently there were no generally agreed and workable definitions for dementia or criteria for the diagnosis of Alzheimer's disease. Investigators were therefore obliged to construct empirical definitions for themselves. Often, these definitions did not attempt to distinguish between different diseases underlying dementia so that prevalence estimates of dementia cannot be equated with the prevalence of Alzheimer's disease. It is also obvious that those surveys which aimed to detect cases of mild dementia as well as more severely demented people will obtain a
170
Aluminium and Alzheimer's disease
higher prevalence rate than surveys that considered only those cases where dementia was severe. Kay et al. (1985) have discussed in detail the effect that different working definitions of dementia and different psychometric instruments for the detection of dementia are likely to have on prevalence estimates.
Population sampled Most surveys have excluded young or middle aged people from the study population because the prevalence of dementia is so low in these age groups. Above the age of 65 years, however, the prevalence of dementia increases very quickly. In many countries the proportion of very elderly people in the population is growing rapidly. Unless age standardisation has been carded out it is difficult to compare surveys from different countries because the populations surveyed may have had a very different age structure. Another difficulty is that some surveys included only people living at home, while others took a random sample of the whole population over a certain age. Cases of dementia cared for in institutions will be excluded from the former type of survey. Statistical power One further problem in the interpretation of prevalence surveys arises because the numbers of cases that were detected in some of them were fairly small. Small numbers affect the precision of the estimate of prevalence. For example, although the prevalence of dementia measured in Hobart was twice that obtained from a similar study in London, the confidence intervais around these estimates are such that the possibility that this was a chance finding cannot be excluded (Kay et al., 1985). Even if we consider only those surveys which employed similar methods of case finding and similar definitions of dementia the inferences that can be drawn from differences in the prevalence of dementia are very limited. No unequivocal evidence yet exists to show geographical variation in rates of Alzheimer's disease.
Mortality Data In England and Wales the Office of Population Surveys and Censuses (OPCS) extracts, from the information recorded on death certificates, the underlying cause of death and codes this diagnosis according to the International Classification of Diseases. These data have recently been used to examine the geographical distribution of mortality from a number of diseases including dementia (Gardner et a/., 1984). Mortality from dementia showed considerable variation over different parts of the country. Data derived from death certificates, however, are known to contain a number of inaccuracies. We carded out a series of studies to evalute whether the apparent geographical variation in mortaliy from dementia reflected real differences in the rates of the disease (Martyn and Pippard, 1988).
What proportion of cases of dementia have this diagnosis recorded as the underlying cause of death? Using the d i a g n o s t i c register m a i n t a i n e d at the psychogeriatric clinic at Newcastle General Hospital, Newcastle upon Tyne we identified 197 patients diagnosed
as being demented during the years 1980 and 1981. In 1986, when this study was carded out, 140 of these patients had died. OPCS were able to provide the death certificates of 137 of these 140. In less than 25% was the underlying cause of death coded as dementia or Alzheimer's disease (ICD Numbers 290 or 331). In only 58% was dementia, Alzheimer's disease or a related diagnosis recorded on either part of the death certificate by the doctor certifying death.
Are patients who do have dementia coded as the underlying cause of death unusual? Because so small a proportion of patients who are diagnosed during life as being demented have a diagnosis of Alzheimer's disease or a related condition coded as the underlying cause of death, it seemed likely that these patients might be atypical. We therefore examined a sample of death certificates, again provided by OPCS, in which the underlying cause of death had been coded as pre-senile or senile dementia. The sample of 200 death certificates represented approximately one in two of all deaths certified as due to dementia in people under the age of 76 for the year 1978. Two facts of importance emerged; first, most of the patients had died in hospitals with long-stay beds; second, the most common terminal event by far was bronchopneumonia. Geographical analysis of mortality from dementia The mortality data for 1968 - 1978 consisting of extracts from all death Certificates for England and Wales were examined. Mortality rates for each sex for each local authority area were calculated from 1971 census data which were grouped according to local authority boundaries. Death rates were expressed as standardised mortality ratios. There were 140 areas which had a significantly higher than average (P
