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Epidemiology of neurological diseases in elderly people: what did we learn from the Rotterdam Study?
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Epidemiology of neurological diseases in elderly people: what did we learn from the Rotterdam Study? Albert Hofman, Paulus T V M de Jong, Cornelia M van Duijn, Monique M B Breteler
The Rotterdam Study is a prospective cohort study that has been ongoing since 1990 in the city of Rotterdam, the Netherlands, among 7983 people aged 55 years or older. One part of the study targets neurological diseases, others deal with cardiovascular, ophthalmological, and endocrine diseases. The findings of the Rotterdam Study have been presented in some 500 research articles and reports. Here we give the reasons for the study and its design, and present a summary of what has been learned about the frequencies and causes of neurological diseases. Perhaps the most important message from the Rotterdam Study is the great potential for prevention or postponement of neurological diseases in elderly people. The time for preventive nihilism is over.
Introduction
Design of the Rotterdam Study
In the mid 1980s, when we were designing the study that we refer to now as the Rotterdam Study, the demographic changes that would lead to a substantial increase in the proportion of elderly people in the population were already quite clear. Nearly 20 years later, Oeppen and Vaupel1 summarised the increase in life expectancy at birth in countries with the highest life expectancy with a slope of 0·23 years per year. This finding suggested that for every 4 years lived, about 1 year was added—or, roughly, when you live a week, you gain a weekend. This pattern will quite clearly produce a large rise in the number of elderly people living with disease because most diseases cluster at the end of life. This trend is not because these diseases are the result of ageing, but is because nearly all diseases in elderly people are the consequence of harmful factors that accumulate over time. As Peto and Doll2 suggested: “There is no such thing as aging.” This reasoning implies that to find the causes of these diseases one has to find the harmful influences that work over a lifetime or for substantial parts of it. Thus to establish the causes of diseases in the elderly population the risk factors for those diseases would clearly need to be studied. The main approach to identify causes is the prospective follow-up study—a trick of epidemiologists that has proven effective in finding causes of heart disease and cancer. Remarkably, around 1985, very few follow-up studies focused on elderly people, and follow-up studies of neurological diseases in other age-groups were also uncommon. There was another factor that led to the Rotterdam Study (figure 1), namely that “the epidemiologist” does not exist. In our academic environment, and most likely in that of others as well, there are epidemiologists for cardiovascular diseases, cancer, and many other diseases, and they have a tendency to seek the company of their subject-matter peers (oncologists and cardiologists) rather than their object-matter colleagues (epidemiologists). So, to force a minimum of contact among epidemiologists, a follow-up study with various disease outcomes that uses one joint population seemed a good place to start and data gathering began in 1990.3
The basic design of the study was straightforward: a prospective cohort study of 7983 people living in a welldefined district in the city of Rotterdam, the Netherlands (78% of 10 215 invitees). Participants were all 55 years of age or older and the oldest at the start was 106 years. Participants were all thoroughly examined at baseline. They were interviewed at home for 2 h and then had an extensive set of assessments (a total of 5 h) in a specially built research facility in the centre of their district. Examinations focused on possible causes of invalidating diseases in elderly people, in a clinically state-of-the-art manner as far as the circumstances allowed. The emphasis was on imaging (of heart, blood vessels, eyes, skeleton, and brain) and obtaining samples of bodily fluids to enable further indepth molecular and genetic analyses. These investigations were repeated every 3–4 years for characteristics that could change over time: we had examination cycles from 1990 to 1993, from 1994 to 1997, from 1998 to 2000, and from 2001 to 2004. In 1999, 3011 participants (out of 4472 invitees) who turned 55 years of age or who moved into the study district since the start of the study were added to the cohort. Participants were followed up for signs of various diseases that are common in elderly people (and many
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Lancet Neurol 2006; 5: 545–50 Department of Epidemiology Biostatistics, Erasmus Medical Centre, Rotterdam, Netherlands (A Hofman MD, P T V M de Jong MD, C M van Duijn PhD, M M B Breteler MD) Correspondence to: Prof Albert Hofman [email protected]
For a list of publications see http://www.epib.nl/ergo.htm
Figure 1: The Rotterdam Study logo
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Prevalence (%)
Dementia 45 40 35 30 25 20 15 10 5 0
5·0 4·5 4·0 3·5 3·0 2·5 2·0 1·5 1·0 0·5 0
Given the increased risk of these diseases with age and the probable continued increase in life expectancy, we expect these prevalence figures to substantially rise in the next decade, both in absolute numbers and in proportions of the population affected. Although the specific prevalences might vary in different places and populations, the general pattern of a rise in prevalence is likely to be closely similar. This pattern is not just happening in North America and western Europe, but is a worldwide trend (with the unfortunate exception of sub-Saharan Africa), and in absolute numbers the rise in Alzheimer’s disease and Parkinson’s disease will be led by China and India.12
Stroke 10 9 8 7 6 5 4 3 2 1 0 AMD
Parkinson’s disease 10 9 8 7 6 5 4 3 2 1 0 55
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Figure 2: Prevalence of dementia, stroke, Parkinson’s disease, and age-related macular degeneration (AMD) in the Rotterdam Study
that are also common in younger adults): coronary heart disease and stroke, Parkinson’s disease, Alzheimer’s disease and other dementias, macular degeneration and glaucoma, diabetes mellitus, and osteoporosis.
Lessons from the study Common diseases One thing became very clear in the first phase of the study: neurological diseases in elderly people are extremely common. Figure 2 shows the the prevalence of stroke, dementia (Alzheimer’s disease and other dementias combined), Parkinson’s disease, and macular degeneration, by age.4–8 We summarised these findings, with other prevalence studies, in 2000;9 the table shows these data extrapolated to the current European Union. A more recent analysis has provided similar findings.10As an example, more than 40% of participants aged 95 years and older had a clinical diagnosis of dementia (assessed with a detailed clinical neurological work-up). This finding is likely to be an underestimate of disease frequency; although we had a high participation rate, the prevalence of dementia is probably even higher in those who did not take part because patients with dementia are less likely to participate in population studies.11 Men
Women
Total
Dementia
1 550 000
2 980 000
4 530 000
Stroke
1 620 000
1 690 000
3 310 000
Macular degeneration
720 000
1 210 000
1 930 000
Parkinson’s disease
490 000
660 000
1 150 000
Table: Absolute number of neurological diseases in the elderly population of the European Union8,9
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The force of morbidity (or incidence rate) of neurological diseases is strong, which translates into a high risk of these diseases. Incidence rates for stroke, dementia, Parkinson’s disease, and macular degeneration increase with age (figure 3).13–18 This finding should not surprise us much in view of the rise in prevalence, except that the rise in incidence seems to continue in very old people; there is no evidence of levelling off of the occurrence of new cases of dementia, stroke, or Parkinson’s disease at a very old age. There are few data like these, but if confirmed this finding is important. The increase, which could be due in part to the changing mortality patterns in other diseases, suggests that there is not a specific window of exposure (ie, a certain age) and that the cause is such that the diseases are not running out of suitable candidates— ie, susceptibles—over time. It also means that if an individual does not have dementia at the age of 90 years, they are not immune and are still at risk of the disease.
Imaging The more imaging we did in the population, the more we saw that not all abnormal pathological changes shown on the scans had direct harmful consequences.19 Most of the brain infarcts were silent, like most myocardial infarctions in elderly people, and most white-matter lesions did not seem to have any direct effects; a person can have substantial brain atrophy and many plaques in the carotid arteries before clinical symptoms emerge. However, this finding does not mean that all pathological signs are harmless. On the contrary, in the long term silent braininfarcts predict clinical stroke, dementia, and depression; white-matter lesions predict cognitive decline, dementia, and depression; increased thickness of the intima-media wall predicts stroke and dementia; and brain atrophy predicts dementia and depression.20–28
Genes In 1991, John Hardy, with the help of many others, published the first evidence for a mutation in the amyloid precursor protein gene on chromosome 21 that is associated with Alzheimer’s disease29 and cerebral haemorrhage.30 Subsequently, mutations in two other http://neurology.thelancet.com Vol 5 June 2006
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Was Kraepelin right? The idea that abnormalities in circulation play a part in dementia is at least a century old. In his memoirs written in the second decade of the 20th century, Emil Kraepelin35 (figure 4) wrote that although his colleague and co-worker Alois Alzheimer had found important neuropathological correlates of dementia, most cases were due to arteriosclerosis. Our search for vascular causes of dementia can therefore be summarised with the question: “Was Kraepelin right?” The first evidence for a strong involvement of vascular factors, not only in vascular dementia but also in Alzheimer’s disease, came from the cross-sectional observations that atherosclerosis was strongly associated with cerebral white-matter lesions, cardiovascular clinical disease with cognitive function, and atherosclerosis at various sites with Alzheimer’s disease.36–38 Longitudinal studies made clear that silent and non-silent strokes predict dementia and that stroke is often a precursor of dementia.22 Follow-up in the Rotterdam Study showed a strong predictive value of diabetes mellitus and concentrations of insulin-like growth factor-1 for Alzheimer’s disease http://neurology.thelancet.com Vol 5 June 2006
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Dementia
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5·0 4·0 4·0 3·0 3·0 2·0 2·0 1·0 1·0 0.5 0
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major genes were implicated in Alzheimer’s disease (presenilin 1 and presenilin 2). Van Duijn and co-authors31 showed that the mutation in these major genes—ie, amyloid precursor protein gene, presenilin 1, and presenilin 2 combined—amounted to less than 0·5% of all dementia cases in the population. In quantitative terms the apolipoprotien E polymorphism was more promising, although it probably does not account for more than 10–15% of all cases. Other genes are being investigated and are likely to explain some of the underlying mechanisms of the disease, probably jointly with non-genetic risk factors. Thinking about the cause of Parkinson’s disease has been somewhat of a roller coaster. In the 1970s, genes were implicated (based on a few small twin studies), then in the 1980s, 1-methyl-4-phenyl-tetrahydropyridine (MPTP) exposure made the environmental case. In the 1990s, thinking reverted back to genetic causes with the discovery of the alpha-synuclein and Parkin genes and later Park7 and many other genes. More recently the environmental hypothesis has made a comeback through findings in the Rotterdam Study and in other studies. Until quite recently, our view was, in common with most epidemiologists, that a single gene would never explain much of the major disease in the elderly population and that even genetic polymorphisms are unlikely to play a large part in these complex diseases. That was until a significant role of the Y402H allele of the complement factor H gene in age-related macular degeneration was identified, with a population attributable risk in The Rotterdam Study of more than 50%, major associations with all stages of macular degeneration, and interaction with smoking and inflammatory markers.32–34
Parkinson’s disease
6
AMD
5 4 3 2 1 0 55 60
65
70
75 80 85 Age (years)
90
95
55 60
65
70
75 80 85 Age (years)
90
95
Figure 3: Incidence of dementia, stroke, Parkinson’s disease, and age-related macular degeneration (AMD) in the Rotterdam Study
and of insulin concentrations for cognitive function.39–41 Atrial fibrillation was associated with an increased risk of white-matter lesions, stroke, and dementia. Blood pressure predicted white-matter lesions, especially deep periventricular lesions.42 The association of blood pressure with dementia was less straightforward. We observed a positive association before the age of 80 years and a negative one in people aged 80 years or older. Most cardiovascular risk factors were predictive of Alzheimer’s disease and other dementias. Low intake of antioxidants was associated with increased dementia risk.43 Serum homocysteine levels predicted dementia as well as white-matter lesions and silent brain-infarcts.44–46 Smoking was shown to be associated with an increased risk of dementia. Overall, risk was doubled compared with that of non-smokers, and this risk increased in a dose-
Figure 4: On the Starnberg lake, from left to right: Alzheimer, Kraepelin, Gaupp, and Nissl Reproduced with permission of Springer-Verlag.35
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response fashion.47 Alcohol consumption was inversely related to dementia;48 this finding lent support to an earlier finding in the Paquid study, which was done in Bordeaux, France.49 Kraepelin was a fanatic teetotaller, which brought him into conflict with many Bavarians, including the king, and he probably would not have liked this inverse association with alcohol. But it seems that he was right in that vascular factors play a major part in dementia.
Inflammation and oxidative stress The idea that the inflammatory process is implicated in the development of atherosclerosis, and thus of cardiovascular disease,50 has spurred the search for links between various markers of inflammation and atherosclerosis, stroke, Alzheimer’s disease and other dementias, and Parkinson’s disease.51 In the Rotterdam Study, plasma concentrations of inflammatory proteins were increased before clinical onset of dementia, both in Alzheimer’s disease and in vascular dementia. In particular, high concentrations of α1-antichymotrypsin and interleukin 6 were associated with an increased risk of dementia.52 Another promising marker linked with stroke and dementia is lipoprotein-associated phospholipase A2, an enzyme that plays an important part in the cholesterol pathway and atherosclerosis.53,54 Inflammatory processes may also be implicated in Alzheimer’s disease. In the Rotterdam Study the use of non-steroidal anti-inflammatory drugs for more than a month was associated with a substantial reduction in the risk of Alzheimer’s disease.55,56 There are suggestions that a particular anti-amylogenic subset of non-steroidals is specifically associated with the reduction in risk of Alzheimer’s disease, but this observation is currently based on too few events. Another general pathway that has been implicated in both cardiovascular diseases and dementia is oxidative stress. Since Linus Pauling’s grand theory of oxidative stress as a source of cumulative harm for all cells and tissues and thereby of a major cause of disease and death, much effort has been invested in studying the putative effects of antioxidants in foods and plasma on major diseases. Dietary antioxidants are associated with Alzheimer’s disease, Parkinson’s disease, macular degeneration, and ischaemic stroke.57–61 The associations are not always similarly observed with concentrations of antioxidants in plasma. Various hormonal determinants have been investigated for a link with dementia. In the Rotterdam Study a longer reproductive period was not associated with a reduced risk of dementia in postmenopausal women. Serum concentrations of endogenous oestradiol in women were not associated with dementia, and raised oestrogen concentrations were not associated with larger hippocampi and improved memory performance.62–64 These observational findings were consistent with the later observation in a major randomised trial of increased risk of dementia in women on hormone therapy.65 548
Comorbidity and aetiology Diseases with late onset cluster more than those with early onset because they have passage of time in common as well as several joint causal pathways—ie, inflammation, oxidative stress, and atherosclerosis. There are three reasons why diseases cluster in elderly people. First, they can simply be linked by age. Upon controlling for age the association disappears. Second, diseases can cluster because they have a joint cause or joint causes. By controlling for the joint cause, the association between the two diseases disappears. The third option is that one disease causes another. The Rotterdam Study provided evidence that the link between stroke and both subtypes of dementia—vascular dementia and Alzheimer’s disease—is directly causal and not just the result of atherosclerosis as a joint cause. By contrast, no association was reported between Alzheimer’s disease and age-related macular degeneration, although macular degeneration has been proposed to be be an ocular manifestation of Alzheimer’s disease.66
Prevention An important and largely unexpected lesson from the Rotterdam Study is the large potential for prevention of diseases in elderly people, or at least for postponement of the clinical manifestation of these diseases. The main possibilities are in vascular factors, oxidative stress, and inflammatory factors. The vascular factors that could be targeted to prevent neurological diseases in elderly people, especially dementia, include the classic cardiovascular risk factors (such as blood pressure, cholesterol, and smoking), atherosclerosis and conditions that contribute to it (such as diabetes mellitus), and atrial fibrillation. Current strategies to prevent atherosclerosis and ischaemic stroke probably also contribute to the prevention of Alzheimer’s disease, other dementias, and macular degeneration. The potential of prevention of dementia and macular degeneration through increased intake of antioxidants seems large, although experience with prevention programmes for cardiovascular disease suggests a need for moderation of optimism. Intervention strategies that include inflammatory factors also have large potential for the postponement of many diseases in elderly people. The role of various imaging techniques in early identification of elderly individuals at possible high risk for neurological diseases is still largely to be established, and various studies are currently underway, such as the Rotterdam Scan Study, a spin-off of the Rotterdam Study.
Conclusion In looking back on 15 years of study of neurological diseases in the Rotterdam Study a few final observations seem pertinent. First, the study has helped to prevent the fragmentation of epidemiology. In fact, this approach—ie, one population studied by various specialist groups—could http://neurology.thelancet.com Vol 5 June 2006
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have more general merit than previous studies in a specialised academic environment. Second, through the joint study of various diseases, detailed investigation of clustering, comorbidity, and joint causes has been possible. Third, implementation of new technologies, as far as possible, in the epidemiological approach has been largely successful. This point applies in particular to research on vascular components of Alzheimer’s disease, the use of modern imaging as a surrogate for pathological lesions, and the application of genetic techniques at the population level. Fourth, much work is waiting for translation of the findings from genetic and imaging studies to diagnostic and therapeutic progress. This work is largely done by the many young and inspired colleagues who work as residents and PhD students on the Rotterdam Study. In fact, one of the more important contributions of the Rotterdam Study has been in in-service researcher training. Finally, and perhaps most importantly the possibilities of prevention or postponement of diseases in elderly people seem vast. In particular, this idea is quite recent for dementia and macular degeneration. Until less than a decade ago the general view on these diseases was that they were the inescapable consequences of ageing and the medical approach to them was consequently rather nihilistic. Now, some building blocks for testing preventive programmes are in place, and before long, some recommendations for prevention could be made. There is no longer room for preventive nihilism.
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Contributors AH has been principal investigator of the Rotterdam Study since its start, and principal investigator for neurological diseases from 1990 to 1996; PTVMdJ is principal investigator for ophthalmological diseases; CMvD is principal investigator for genetic epidemiology; MB has been involved in the Rotterdam Study since its start and has been principal investigator for neurological diseases since 1996. AH wrote this Personal View and the other authors contributed significantly to the final version.
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Conflicts of interest We have no conflicts of interest. Acknowledgments More than 50 organisations have financially supported the Rotterdam Study over the years. No financial support was obtained for writing this Personal View. References 1 Oeppen J, Vaupel JW. Broken limits to life expectancy. Science 2002; 296: 1029–31. 2 Peto R, Doll R. There is no such thing as aging. BMJ 1997; 315: 1030–32. 3 Hofman A, Grobbee DE, de Jong PTVM, van den Ouweland FA. Determinants of disease and disability in the elderly: the Rotterdam Study. Eur J Epidemiol 1991; 7: 403–22. 4 Bots ML, Looman SJ, Koudstaal PJ, Hofman A, Hoes AW, Grobbee DE. Prevalence of stroke in the general population. Stroke 1996; 27: 1499–501. 5 Bots ML, van Wilk EC, Koudstaal PJ, Hofman A, Grobbee DE. Typical and atypical transient ischaemic attacks in the general population: the Rotterdam Study. Stroke 1997; 28: 768–72. 6 Ott A, Breteler MMB, van Harskamp F, et al. Prevalence of Alzheimer’s disease and vascular dementia: association with education: the Rotterdam Study. BMJ 1995; 310: 970–73. 7 de Rijk MC, Breteler MMB, Graveland GA, et al. Prevalence of Parkinson disease in the elderly: the Rotterdam Study. Neurology 1995; 45: 2143–46.
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For a listing of sponsors of The Rotterdam Study see http:// www.epib.nl/ergo.htm
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Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med 1999; 340: 115–26. van der Meer IM, de Maat MP, Hak AE, et al. C-reactive protein predicts progression of atherosclerosis measured at various sites in the arterial tree: the Rotterdam Study. Stroke 2002; 33: 2750–55. Engelhart MJ, Geerlings MI, Meijer J, et al. Inflammatory proteins in plasma and the risk of dementia: the Rotterdam Study. Arch Neurol 2004; 61: 668–72. Oei HHS, van der Meer IM, Hofman A, et al. Lipoproteinassociated phospholipase A2 activity is associated with risk of coronary heart disease and ischemic stroke: the Rotterdam Study. Circulation 2005; 111: 570–75. van Oijen M, van der Meer IM, Hofman A, Witteman JCM, Koudstaal PJ, Breteler MMB. Lipoprotein-associated phospholipase A2 is associated with risk of dementia. Ann Neurol 2006; 59: 139–44. Andersen K, Launer LJ, Ott A, Hoes AW, Breteler MMB, Hofman A. Do nonsteroidal anti-inflammatory drugs decrease the risk for Alzheimer’s disease? The Rotterdam Study. Neurology 1995; 45: 1441–45. in t’ Veld BA, Ruitenberg A, Hofman A, et al. Nonsteroidal antiinflammatory drugs and the risk of Alzheimer’s disease. N Engl J Med 2001; 345: 1515–21. Jama JW, Launer LJ, Witteman JCM, et al. Dietary antioxidants and cognitive function in a population-based sample of older pesons: the Rotterdam Study. Am J Epidemiol 1996; 144: 275–80. de Rijk MC, Breteler MMB, den Breeijen JH, et al. Dietary antioxidants and Parkinson’s disease: the Rotterdam Study. Arch Neurol 1997; 54: 762–65. Vokó Z, Hollander M, Hofman A, Koudstaal PJ, Breteler MMB. Dietary antioxidants and the risk of ischemic stroke: the Rotterdam Study. Neurology 2003; 61: 1273–75. Engelhart MJ, Geerlings, MI, Ruitenberg A, et al. Dietary intake of antioxidants and risk of Alzheimer’s disease: the Rotterdam Study. JAMA 2002; 287: 3223–29. van Leeuwen R, Boekhoorn S, Vingerling JR, et al. Dietary intake of anti-oxidants and risk of age-related macular degeneration: the Rotterdam Study. JAMA 2005; 294: 3101–07. Geerlings MI, Ruitenberg A, Witteman JCM, et al. Reproductive period and risk of dementia in postmenopausal women. JAMA 2001; 285: 1475–81. Geerlings MI, Launer LJ, de Jong FH, et al. Endogenous estradiol and risk of dementia in women and men: the Rotterdam Study. Ann Neurol 2003; 53: 607–15. den Heijer T, Geerlings MI, Hofman A, et al. Higher estrogen levels are not associated with larger hippocampi and better memory performance. Arch Neurol 2003; 60: 213–20. Shumaker SA, Legault C, Kuller L, et al. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women. JAMA 2004; 291: 2947–58. Ikram MK, Vingerling JR, Hofman A, Breteler MMB, de Jong PTVM. Aging macular disease in relation to Alzheimer’s disease and brain atrophy. Am J Epidemiol (in press).
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Epidemiology of neurological diseases in elderly people: what did we learn from the Rotterdam Study? Albert Hofman, Paulus T V M de Jong, Cornelia M van Duijn, Monique M B Breteler
The Rotterdam Study is a prospective cohort study that has been ongoing since 1990 in the city of Rotterdam, the Netherlands, among 7983 people aged 55 years or older. One part of the study targets neurological diseases, others deal with cardiovascular, ophthalmological, and endocrine diseases. The findings of the Rotterdam Study have been presented in some 500 research articles and reports. Here we give the reasons for the study and its design, and present a summary of what has been learned about the frequencies and causes of neurological diseases. Perhaps the most important message from the Rotterdam Study is the great potential for prevention or postponement of neurological diseases in elderly people. The time for preventive nihilism is over.
Introduction
Design of the Rotterdam Study
In the mid 1980s, when we were designing the study that we refer to now as the Rotterdam Study, the demographic changes that would lead to a substantial increase in the proportion of elderly people in the population were already quite clear. Nearly 20 years later, Oeppen and Vaupel1 summarised the increase in life expectancy at birth in countries with the highest life expectancy with a slope of 0·23 years per year. This finding suggested that for every 4 years lived, about 1 year was added—or, roughly, when you live a week, you gain a weekend. This pattern will quite clearly produce a large rise in the number of elderly people living with disease because most diseases cluster at the end of life. This trend is not because these diseases are the result of ageing, but is because nearly all diseases in elderly people are the consequence of harmful factors that accumulate over time. As Peto and Doll2 suggested: “There is no such thing as aging.” This reasoning implies that to find the causes of these diseases one has to find the harmful influences that work over a lifetime or for substantial parts of it. Thus to establish the causes of diseases in the elderly population the risk factors for those diseases would clearly need to be studied. The main approach to identify causes is the prospective follow-up study—a trick of epidemiologists that has proven effective in finding causes of heart disease and cancer. Remarkably, around 1985, very few follow-up studies focused on elderly people, and follow-up studies of neurological diseases in other age-groups were also uncommon. There was another factor that led to the Rotterdam Study (figure 1), namely that “the epidemiologist” does not exist. In our academic environment, and most likely in that of others as well, there are epidemiologists for cardiovascular diseases, cancer, and many other diseases, and they have a tendency to seek the company of their subject-matter peers (oncologists and cardiologists) rather than their object-matter colleagues (epidemiologists). So, to force a minimum of contact among epidemiologists, a follow-up study with various disease outcomes that uses one joint population seemed a good place to start and data gathering began in 1990.3
The basic design of the study was straightforward: a prospective cohort study of 7983 people living in a welldefined district in the city of Rotterdam, the Netherlands (78% of 10 215 invitees). Participants were all 55 years of age or older and the oldest at the start was 106 years. Participants were all thoroughly examined at baseline. They were interviewed at home for 2 h and then had an extensive set of assessments (a total of 5 h) in a specially built research facility in the centre of their district. Examinations focused on possible causes of invalidating diseases in elderly people, in a clinically state-of-the-art manner as far as the circumstances allowed. The emphasis was on imaging (of heart, blood vessels, eyes, skeleton, and brain) and obtaining samples of bodily fluids to enable further indepth molecular and genetic analyses. These investigations were repeated every 3–4 years for characteristics that could change over time: we had examination cycles from 1990 to 1993, from 1994 to 1997, from 1998 to 2000, and from 2001 to 2004. In 1999, 3011 participants (out of 4472 invitees) who turned 55 years of age or who moved into the study district since the start of the study were added to the cohort. Participants were followed up for signs of various diseases that are common in elderly people (and many
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Lancet Neurol 2006; 5: 545–50 Department of Epidemiology Biostatistics, Erasmus Medical Centre, Rotterdam, Netherlands (A Hofman MD, P T V M de Jong MD, C M van Duijn PhD, M M B Breteler MD) Correspondence to: Prof Albert Hofman [email protected]
For a list of publications see http://www.epib.nl/ergo.htm
Figure 1: The Rotterdam Study logo
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Dementia 45 40 35 30 25 20 15 10 5 0
5·0 4·5 4·0 3·5 3·0 2·5 2·0 1·5 1·0 0·5 0
Given the increased risk of these diseases with age and the probable continued increase in life expectancy, we expect these prevalence figures to substantially rise in the next decade, both in absolute numbers and in proportions of the population affected. Although the specific prevalences might vary in different places and populations, the general pattern of a rise in prevalence is likely to be closely similar. This pattern is not just happening in North America and western Europe, but is a worldwide trend (with the unfortunate exception of sub-Saharan Africa), and in absolute numbers the rise in Alzheimer’s disease and Parkinson’s disease will be led by China and India.12
Stroke 10 9 8 7 6 5 4 3 2 1 0 AMD
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Figure 2: Prevalence of dementia, stroke, Parkinson’s disease, and age-related macular degeneration (AMD) in the Rotterdam Study
that are also common in younger adults): coronary heart disease and stroke, Parkinson’s disease, Alzheimer’s disease and other dementias, macular degeneration and glaucoma, diabetes mellitus, and osteoporosis.
Lessons from the study Common diseases One thing became very clear in the first phase of the study: neurological diseases in elderly people are extremely common. Figure 2 shows the the prevalence of stroke, dementia (Alzheimer’s disease and other dementias combined), Parkinson’s disease, and macular degeneration, by age.4–8 We summarised these findings, with other prevalence studies, in 2000;9 the table shows these data extrapolated to the current European Union. A more recent analysis has provided similar findings.10As an example, more than 40% of participants aged 95 years and older had a clinical diagnosis of dementia (assessed with a detailed clinical neurological work-up). This finding is likely to be an underestimate of disease frequency; although we had a high participation rate, the prevalence of dementia is probably even higher in those who did not take part because patients with dementia are less likely to participate in population studies.11 Men
Women
Total
Dementia
1 550 000
2 980 000
4 530 000
Stroke
1 620 000
1 690 000
3 310 000
Macular degeneration
720 000
1 210 000
1 930 000
Parkinson’s disease
490 000
660 000
1 150 000
Table: Absolute number of neurological diseases in the elderly population of the European Union8,9
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The force of morbidity (or incidence rate) of neurological diseases is strong, which translates into a high risk of these diseases. Incidence rates for stroke, dementia, Parkinson’s disease, and macular degeneration increase with age (figure 3).13–18 This finding should not surprise us much in view of the rise in prevalence, except that the rise in incidence seems to continue in very old people; there is no evidence of levelling off of the occurrence of new cases of dementia, stroke, or Parkinson’s disease at a very old age. There are few data like these, but if confirmed this finding is important. The increase, which could be due in part to the changing mortality patterns in other diseases, suggests that there is not a specific window of exposure (ie, a certain age) and that the cause is such that the diseases are not running out of suitable candidates— ie, susceptibles—over time. It also means that if an individual does not have dementia at the age of 90 years, they are not immune and are still at risk of the disease.
Imaging The more imaging we did in the population, the more we saw that not all abnormal pathological changes shown on the scans had direct harmful consequences.19 Most of the brain infarcts were silent, like most myocardial infarctions in elderly people, and most white-matter lesions did not seem to have any direct effects; a person can have substantial brain atrophy and many plaques in the carotid arteries before clinical symptoms emerge. However, this finding does not mean that all pathological signs are harmless. On the contrary, in the long term silent braininfarcts predict clinical stroke, dementia, and depression; white-matter lesions predict cognitive decline, dementia, and depression; increased thickness of the intima-media wall predicts stroke and dementia; and brain atrophy predicts dementia and depression.20–28
Genes In 1991, John Hardy, with the help of many others, published the first evidence for a mutation in the amyloid precursor protein gene on chromosome 21 that is associated with Alzheimer’s disease29 and cerebral haemorrhage.30 Subsequently, mutations in two other http://neurology.thelancet.com Vol 5 June 2006
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Was Kraepelin right? The idea that abnormalities in circulation play a part in dementia is at least a century old. In his memoirs written in the second decade of the 20th century, Emil Kraepelin35 (figure 4) wrote that although his colleague and co-worker Alois Alzheimer had found important neuropathological correlates of dementia, most cases were due to arteriosclerosis. Our search for vascular causes of dementia can therefore be summarised with the question: “Was Kraepelin right?” The first evidence for a strong involvement of vascular factors, not only in vascular dementia but also in Alzheimer’s disease, came from the cross-sectional observations that atherosclerosis was strongly associated with cerebral white-matter lesions, cardiovascular clinical disease with cognitive function, and atherosclerosis at various sites with Alzheimer’s disease.36–38 Longitudinal studies made clear that silent and non-silent strokes predict dementia and that stroke is often a precursor of dementia.22 Follow-up in the Rotterdam Study showed a strong predictive value of diabetes mellitus and concentrations of insulin-like growth factor-1 for Alzheimer’s disease http://neurology.thelancet.com Vol 5 June 2006
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major genes were implicated in Alzheimer’s disease (presenilin 1 and presenilin 2). Van Duijn and co-authors31 showed that the mutation in these major genes—ie, amyloid precursor protein gene, presenilin 1, and presenilin 2 combined—amounted to less than 0·5% of all dementia cases in the population. In quantitative terms the apolipoprotien E polymorphism was more promising, although it probably does not account for more than 10–15% of all cases. Other genes are being investigated and are likely to explain some of the underlying mechanisms of the disease, probably jointly with non-genetic risk factors. Thinking about the cause of Parkinson’s disease has been somewhat of a roller coaster. In the 1970s, genes were implicated (based on a few small twin studies), then in the 1980s, 1-methyl-4-phenyl-tetrahydropyridine (MPTP) exposure made the environmental case. In the 1990s, thinking reverted back to genetic causes with the discovery of the alpha-synuclein and Parkin genes and later Park7 and many other genes. More recently the environmental hypothesis has made a comeback through findings in the Rotterdam Study and in other studies. Until quite recently, our view was, in common with most epidemiologists, that a single gene would never explain much of the major disease in the elderly population and that even genetic polymorphisms are unlikely to play a large part in these complex diseases. That was until a significant role of the Y402H allele of the complement factor H gene in age-related macular degeneration was identified, with a population attributable risk in The Rotterdam Study of more than 50%, major associations with all stages of macular degeneration, and interaction with smoking and inflammatory markers.32–34
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AMD
5 4 3 2 1 0 55 60
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55 60
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75 80 85 Age (years)
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Figure 3: Incidence of dementia, stroke, Parkinson’s disease, and age-related macular degeneration (AMD) in the Rotterdam Study
and of insulin concentrations for cognitive function.39–41 Atrial fibrillation was associated with an increased risk of white-matter lesions, stroke, and dementia. Blood pressure predicted white-matter lesions, especially deep periventricular lesions.42 The association of blood pressure with dementia was less straightforward. We observed a positive association before the age of 80 years and a negative one in people aged 80 years or older. Most cardiovascular risk factors were predictive of Alzheimer’s disease and other dementias. Low intake of antioxidants was associated with increased dementia risk.43 Serum homocysteine levels predicted dementia as well as white-matter lesions and silent brain-infarcts.44–46 Smoking was shown to be associated with an increased risk of dementia. Overall, risk was doubled compared with that of non-smokers, and this risk increased in a dose-
Figure 4: On the Starnberg lake, from left to right: Alzheimer, Kraepelin, Gaupp, and Nissl Reproduced with permission of Springer-Verlag.35
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response fashion.47 Alcohol consumption was inversely related to dementia;48 this finding lent support to an earlier finding in the Paquid study, which was done in Bordeaux, France.49 Kraepelin was a fanatic teetotaller, which brought him into conflict with many Bavarians, including the king, and he probably would not have liked this inverse association with alcohol. But it seems that he was right in that vascular factors play a major part in dementia.
Inflammation and oxidative stress The idea that the inflammatory process is implicated in the development of atherosclerosis, and thus of cardiovascular disease,50 has spurred the search for links between various markers of inflammation and atherosclerosis, stroke, Alzheimer’s disease and other dementias, and Parkinson’s disease.51 In the Rotterdam Study, plasma concentrations of inflammatory proteins were increased before clinical onset of dementia, both in Alzheimer’s disease and in vascular dementia. In particular, high concentrations of α1-antichymotrypsin and interleukin 6 were associated with an increased risk of dementia.52 Another promising marker linked with stroke and dementia is lipoprotein-associated phospholipase A2, an enzyme that plays an important part in the cholesterol pathway and atherosclerosis.53,54 Inflammatory processes may also be implicated in Alzheimer’s disease. In the Rotterdam Study the use of non-steroidal anti-inflammatory drugs for more than a month was associated with a substantial reduction in the risk of Alzheimer’s disease.55,56 There are suggestions that a particular anti-amylogenic subset of non-steroidals is specifically associated with the reduction in risk of Alzheimer’s disease, but this observation is currently based on too few events. Another general pathway that has been implicated in both cardiovascular diseases and dementia is oxidative stress. Since Linus Pauling’s grand theory of oxidative stress as a source of cumulative harm for all cells and tissues and thereby of a major cause of disease and death, much effort has been invested in studying the putative effects of antioxidants in foods and plasma on major diseases. Dietary antioxidants are associated with Alzheimer’s disease, Parkinson’s disease, macular degeneration, and ischaemic stroke.57–61 The associations are not always similarly observed with concentrations of antioxidants in plasma. Various hormonal determinants have been investigated for a link with dementia. In the Rotterdam Study a longer reproductive period was not associated with a reduced risk of dementia in postmenopausal women. Serum concentrations of endogenous oestradiol in women were not associated with dementia, and raised oestrogen concentrations were not associated with larger hippocampi and improved memory performance.62–64 These observational findings were consistent with the later observation in a major randomised trial of increased risk of dementia in women on hormone therapy.65 548
Comorbidity and aetiology Diseases with late onset cluster more than those with early onset because they have passage of time in common as well as several joint causal pathways—ie, inflammation, oxidative stress, and atherosclerosis. There are three reasons why diseases cluster in elderly people. First, they can simply be linked by age. Upon controlling for age the association disappears. Second, diseases can cluster because they have a joint cause or joint causes. By controlling for the joint cause, the association between the two diseases disappears. The third option is that one disease causes another. The Rotterdam Study provided evidence that the link between stroke and both subtypes of dementia—vascular dementia and Alzheimer’s disease—is directly causal and not just the result of atherosclerosis as a joint cause. By contrast, no association was reported between Alzheimer’s disease and age-related macular degeneration, although macular degeneration has been proposed to be be an ocular manifestation of Alzheimer’s disease.66
Prevention An important and largely unexpected lesson from the Rotterdam Study is the large potential for prevention of diseases in elderly people, or at least for postponement of the clinical manifestation of these diseases. The main possibilities are in vascular factors, oxidative stress, and inflammatory factors. The vascular factors that could be targeted to prevent neurological diseases in elderly people, especially dementia, include the classic cardiovascular risk factors (such as blood pressure, cholesterol, and smoking), atherosclerosis and conditions that contribute to it (such as diabetes mellitus), and atrial fibrillation. Current strategies to prevent atherosclerosis and ischaemic stroke probably also contribute to the prevention of Alzheimer’s disease, other dementias, and macular degeneration. The potential of prevention of dementia and macular degeneration through increased intake of antioxidants seems large, although experience with prevention programmes for cardiovascular disease suggests a need for moderation of optimism. Intervention strategies that include inflammatory factors also have large potential for the postponement of many diseases in elderly people. The role of various imaging techniques in early identification of elderly individuals at possible high risk for neurological diseases is still largely to be established, and various studies are currently underway, such as the Rotterdam Scan Study, a spin-off of the Rotterdam Study.
Conclusion In looking back on 15 years of study of neurological diseases in the Rotterdam Study a few final observations seem pertinent. First, the study has helped to prevent the fragmentation of epidemiology. In fact, this approach—ie, one population studied by various specialist groups—could http://neurology.thelancet.com Vol 5 June 2006
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have more general merit than previous studies in a specialised academic environment. Second, through the joint study of various diseases, detailed investigation of clustering, comorbidity, and joint causes has been possible. Third, implementation of new technologies, as far as possible, in the epidemiological approach has been largely successful. This point applies in particular to research on vascular components of Alzheimer’s disease, the use of modern imaging as a surrogate for pathological lesions, and the application of genetic techniques at the population level. Fourth, much work is waiting for translation of the findings from genetic and imaging studies to diagnostic and therapeutic progress. This work is largely done by the many young and inspired colleagues who work as residents and PhD students on the Rotterdam Study. In fact, one of the more important contributions of the Rotterdam Study has been in in-service researcher training. Finally, and perhaps most importantly the possibilities of prevention or postponement of diseases in elderly people seem vast. In particular, this idea is quite recent for dementia and macular degeneration. Until less than a decade ago the general view on these diseases was that they were the inescapable consequences of ageing and the medical approach to them was consequently rather nihilistic. Now, some building blocks for testing preventive programmes are in place, and before long, some recommendations for prevention could be made. There is no longer room for preventive nihilism.
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Contributors AH has been principal investigator of the Rotterdam Study since its start, and principal investigator for neurological diseases from 1990 to 1996; PTVMdJ is principal investigator for ophthalmological diseases; CMvD is principal investigator for genetic epidemiology; MB has been involved in the Rotterdam Study since its start and has been principal investigator for neurological diseases since 1996. AH wrote this Personal View and the other authors contributed significantly to the final version.
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Conflicts of interest We have no conflicts of interest. Acknowledgments More than 50 organisations have financially supported the Rotterdam Study over the years. No financial support was obtained for writing this Personal View. References 1 Oeppen J, Vaupel JW. Broken limits to life expectancy. Science 2002; 296: 1029–31. 2 Peto R, Doll R. There is no such thing as aging. BMJ 1997; 315: 1030–32. 3 Hofman A, Grobbee DE, de Jong PTVM, van den Ouweland FA. Determinants of disease and disability in the elderly: the Rotterdam Study. Eur J Epidemiol 1991; 7: 403–22. 4 Bots ML, Looman SJ, Koudstaal PJ, Hofman A, Hoes AW, Grobbee DE. Prevalence of stroke in the general population. Stroke 1996; 27: 1499–501. 5 Bots ML, van Wilk EC, Koudstaal PJ, Hofman A, Grobbee DE. Typical and atypical transient ischaemic attacks in the general population: the Rotterdam Study. Stroke 1997; 28: 768–72. 6 Ott A, Breteler MMB, van Harskamp F, et al. Prevalence of Alzheimer’s disease and vascular dementia: association with education: the Rotterdam Study. BMJ 1995; 310: 970–73. 7 de Rijk MC, Breteler MMB, Graveland GA, et al. Prevalence of Parkinson disease in the elderly: the Rotterdam Study. Neurology 1995; 45: 2143–46.
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For a listing of sponsors of The Rotterdam Study see http:// www.epib.nl/ergo.htm
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