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Do we know enough to begin prevention interventions for dementia?
Alzheimer’s & Dementia 3 (2007) S86 –S88
Do we know enough to begin prevention interventions for dementia? Peter V. Rabins* Johns Hopkins School of Medicine, Baltimore, MD, USA
Abstract
This article reviews prior examples of successful prevention interventions and reviews whether comparable data are available to support a prevention campaign targeting later life cognitive decline and dementia. The evidence that risk factors for vascular disease— hypertension, hyperlipidemia, and diabetes mellitus—increase the incidence of dementia supports a prevention campaign now. © 2007 The Alzheimer’s Association. All rights reserved.
Keywords:
Dementia; Alzheimer’s disease; Prevention
Prevention is the ultimate goal of medicine, and the twentieth century saw several examples that have had significant public health impact [1]: ● Vaccination has eliminated smallpox several infectious diseases and almost eliminated polio, diphtheria, tetanus, and whooping cough (pertussis). ● Food fortification eliminated pellagra in the U.S. [2]. ● Water purification has greatly lessened water-borne infectious diseases such as giardiasis and cholera. ● Water fluoridation has made dental caries and tooth loss much less prevalent [3]. ● The treatment of hypertension, hypercholesterolemia, and diabetes, falling rates of cigarette smoking, the adoption by some individuals of a more active lifestyle, and the adoption by some of a diet lower in fat and salt have resulted in 30% or more declines in stroke and heart attack. From these successes and from other failed experiences, several general principles have been identified: ● Many successful prevention strategies are passive, that is, they require no or little effort on the part of individuals. Water purification and water fluoridation are examples. ● Many successful preventive interventions have significant effects on the rates of disorder at the population
*Corresponding author. Tel.: 410-955-6736; Fax: 410-614-1094. E-mail address: [email protected]
level but small benefits for any one individual. Rose [4] called this the “prevention paradox.” ● Interventions that require persistent behavior change are more difficult to establish and sustain than those that require one-time actions (such as inoculations) or passive strategies (such as water purification or fluoridation). Nevertheless, dropping rates of cigarette smoking—the result of public education, physician instruction, and, perhaps, pharmacologic strategies that help some individuals stop smoking-associated behaviors—and lower rates of syphilis and human immunodeficiency virus infection—the result of casefinding strategies, biologic therapies (penicillin for syphilis), and public education about safer sexual practices such as the use of barriers that prevent spread (condoms)—suggest that widespread adoption of behavior-centered prevention can lessen rates of disorder. Recent experience also demonstrates the types of evidence that should be required before prevention strategies should be instituted at the population level. For example, although a large number of well-designed epidemiologic studies supported the conclusion that women who had taken hormone replacement therapy (HRT) and both men and women who had taken nonsteroidal anti-inflammatory drugs (NSAIDS) had a lower likelihood of developing dementia than matched individuals who had not taken these drugs, these were not demonstrated in prospective, randomized control trials. “Naturalistic” studies that rely on whether individuals chose to or were prescribed medications, behav-
1552-5260/07/$ – see front matter © 2007 The Alzheimer’s Association. All rights reserved. doi:10.1016/j.jalz.2007.01.006
P.V. Rabins / Alzheimer’s & Dementia 3 (2007) S86 –S88
iors, or other activities and that look backward at samples of individuals collected for these studies or for other studies cannot adequately control for the differences between the groups, even when investigators attempt to do so statistically. Said another way, there appears to be no way, at least at present, to replicate the benefits of random assignment and unawareness of who is receiving the active and inactive treatments, when these conditions are not inherent to the initial design of the study. However, although the recent prospective intervention studies failed to find a preventive benefit of either of two NSAIDS (naproxen and celecoxib) or an estrogen/progesterone formulation of HRT on dementia in individuals at high risk for dementia (because of a family history of dementia), these negative studies did not rule out the possibility that these medications have preventive activity in individuals younger than 60 years of age, that other drugs in the class such as the NSAID ibuprofen or estrogen alone might be preventive, or in individuals at high risk on the basis of genetic factors such as having an APOE e4 allele. In addition to the questions left unanswered by these trials, the expense of these trials, the difficulty of enrolling subjects, and the very long time that would be needed to demonstrate a benefit in young or middle-aged individuals demonstrate the difficulties that will be faced in proving the effectiveness of prevention strategies for dementia. On the other hand, success in preventing dementia dates back to the development of aggressive case-finding strategies and the introduction of penicillin and other antibiotics and the resultant dramatic declines in the incidence of neurosyphilis by the 1940s. A more recent example is the demonstration in a small sample that individuals randomized to aspirin after stroke compared with those randomized to placebo had lower rates of cognitive impairment and higher brain blood flow [5]. Interest in the prevention of dementia heightened through the 1990s [6] as the ability to identify precursor or early emergent states of dementia developed, particularly through the pioneering work of Ronald Petersen at the Mayo Clinic and his refinement of the construct of mild cognitive impairment. Interest among the public in the potential preventive effects of so-called nutriceuticals and health food supplements such as ginkgo biloba, curcumin, and fish oil has also fueled research. Establishing prevention strategies for dementia also faces challenges similar to those faced by chronic illnesses such as cardiovascular disease. The likelihood is that their etiology is multifactorial, that both genetic and non-genetic factors contribute to pathogenesis, that there is a long period of risk before any manifestation of illness, and that repeated exposure to the prevention strategy will be necessary. Nevertheless, the dramatic drops in death rates from stroke and myocardial infarction during the past 30 years suggest that prevention is not only a possibility, but that research on this topic is timely.
S87
Reports in this supplement present the results of a Centers for Disease Control and Prevention– directed effort to determine whether there is currently adequate scientific evidence to support a campaign to target preventive strategies for dementia. Several approaches were considered: First, evidence that vascular risk factors predispose to the development of vascular dementia and evidence that vascular risk factors might also independently increase the risk of developing Alzheimer’s disease led to a careful assessment of the evidence that they be targeted in a prevention campaign. Second, a developing literature linking higher levels of physical activity to lower rates of dementia incidence raises questions about physical activity levels and exercise as prevention strategies. Third, associations between higher levels of social and cognitive (“mental”) activity raise it as a possible target. What does the evidence show? First, epidemiologic data reviewed by Rockwood [7] show an association between physical activity broadly defined, physical exercise more narrowly defined, and lower rates of dementia. The plausibility of a link between higher levels of physical activity and greater brain structure/function is supported by the studies reviewed by Kramer [8], which demonstrate improvement in brain structure and function in animals and humans after exercise programs. However, the epidemiologic studies are subject to the above reviewed limits of observational studies, and the studies of brain structure and function are in very small samples and do not demonstrate prevention of dementia. Thus, there is not yet the type of evidence that would support a conclusion that the hypothesis has been proved and that a public campaign should be mounted. Nonetheless, I agree with Rockwood that, “In the [interim], there is no good reason not to lead a life of physical activity (and intellectual stimulation, and rich social networks).” The evidence linking vascular disease to subsequent cognitive decline is stronger, whereas that linking physical and social inactivity to cognitive decline is even weaker. Moss [9] presents evidence that hypertension can lead to the brain changes associated with poorer cognitive performance as well as with poorer cognitive performance in animals. These data support a causal link, although not directly with the plaques and tangles characteristic of human Alzheimer’s disease. Grodstein [10] reviews the epidemiologic data linking the known risk factors for vascular disease and stroke, mid-life hypertension, dyslipidemia, and diabetes mellitus to poorer cognitive performance later in life, and McKhann [11] presents emerging data that the increased risk of cognitive decline after coronary artery bypass surgery is due to progression vascular disease not surgery-associated factors, further strengthening the association. Still, no intervention studies have yet demonstrated that the incidence of dementia can be delayed or prevented by treatment (secondary prevention) of these risk factors. Nonetheless, the demonstrated efficacy of interventions targeting these risk factors for stroke and myocardial infarction suggests that adding
S88
P.V. Rabins / Alzheimer’s & Dementia 3 (2007) S86 –S88
dementia prevention as a goal of already existing or planned prevention efforts targeting hypertension, dyslipidemia, and diabetes is appropriate. At what point in the lifespan will such interventions need to take place? The epidemiologic evidence is strongest for showing a linkage between mid-life hypertension and latelife dementia. If this means that all preventive interventions will need to be targeted toward mid-life rather than late life, then studies will be very expensive and take so long that they are unlikely to be done. However, with the standards used to develop the current campaign to increase activity and exercise levels for the prevention of cardiovascular disease, the conclusion by Rockwood [7] that physical, social, and cognitive activity can be encouraged now seems in order. In summary, the evidence that cardiovascular disease and diabetes mellitus contribute to the pathogenesis of dementia, particularly vascular dementia and Alzheimer’s disease, is moderately strong. The evidence that strategies targeting the risk factors for cardiovascular disease— hypertension, hyperlipidemia, inactivity, and immoderate salt intake— have reduced the rates of myocardial infarction and stroke is strong. Therefore, targeting these risk factors for the prevention of dementia seems appropriate at this time. However, little is known about the best strategies for dissemination when targeting dementia [12,13]. The time has come for studies of both efficacy and dissemination, but design challenges remain to be solved.
References [1] Russell LB. Is prevention better than cure? Washington: The Brookings Institution; 1986. [2] Park YK, Sempos CT, Barton CN, Vanderveen JE, Yetley EA. Effectiveness of food fortification in the United States: the case of pellagra. Am J Public Health 2000;90:727–38. [3] MMWR 1999;48.933– 40. [4] Rose G. The strategy of preventive medicine. Oxford: Oxford University Press; 1992. [5] Meyer JS, Rogers RL, McClintic K. Randomized clinical trial of daily aspirin therapy in multi-infarct dementia. J Am Geriatr Soc 1989;37: 549 –55. [6] Rabins PV. Prevention of mental disorders in the elderly: current perspectives and future prospects. J Am Geriatr Soc 1992;40:727–33. [7] Rockwood K, Middleton L. Physical activity and the maintenance of cognitive function. Alzheimers Dement 2007;3:S38 – 44. [8] Kramer A, Erickson KI. Effects of physical activity on cognition, well-being, and brain: human interventions. Alzheimers Dement 2007;3:S45–51. [9] Moss MB, Jonak E. Cerebrovascular disease and dementia: a primate model of hypertension and cognition. Alzheimers Dement 2007;3: S6 –15. [10] Grodstein F. Cardiovascular risk factors and cognitive function. Alzheimers Dement 2007;3:S16 –22. [11] McKhann GM, Selnes OA. Vascular cognitive change: perspective from neurology. Alzheimers Dement 2007;3:S23–9. [12] O’Loughlin JL, Paradis G, Gray-Donald K, Renaud L. The impact of a community-based heart disease prevention program in a low-income, inner-city neighborhood. Am J Public Health 1999;89:1819 – 26. [13] Shea S. Community health, community risks, community action. Am J Public Health 1992;82:785–7.
Do we know enough to begin prevention interventions for dementia? Peter V. Rabins* Johns Hopkins School of Medicine, Baltimore, MD, USA
Abstract
This article reviews prior examples of successful prevention interventions and reviews whether comparable data are available to support a prevention campaign targeting later life cognitive decline and dementia. The evidence that risk factors for vascular disease— hypertension, hyperlipidemia, and diabetes mellitus—increase the incidence of dementia supports a prevention campaign now. © 2007 The Alzheimer’s Association. All rights reserved.
Keywords:
Dementia; Alzheimer’s disease; Prevention
Prevention is the ultimate goal of medicine, and the twentieth century saw several examples that have had significant public health impact [1]: ● Vaccination has eliminated smallpox several infectious diseases and almost eliminated polio, diphtheria, tetanus, and whooping cough (pertussis). ● Food fortification eliminated pellagra in the U.S. [2]. ● Water purification has greatly lessened water-borne infectious diseases such as giardiasis and cholera. ● Water fluoridation has made dental caries and tooth loss much less prevalent [3]. ● The treatment of hypertension, hypercholesterolemia, and diabetes, falling rates of cigarette smoking, the adoption by some individuals of a more active lifestyle, and the adoption by some of a diet lower in fat and salt have resulted in 30% or more declines in stroke and heart attack. From these successes and from other failed experiences, several general principles have been identified: ● Many successful prevention strategies are passive, that is, they require no or little effort on the part of individuals. Water purification and water fluoridation are examples. ● Many successful preventive interventions have significant effects on the rates of disorder at the population
*Corresponding author. Tel.: 410-955-6736; Fax: 410-614-1094. E-mail address: [email protected]
level but small benefits for any one individual. Rose [4] called this the “prevention paradox.” ● Interventions that require persistent behavior change are more difficult to establish and sustain than those that require one-time actions (such as inoculations) or passive strategies (such as water purification or fluoridation). Nevertheless, dropping rates of cigarette smoking—the result of public education, physician instruction, and, perhaps, pharmacologic strategies that help some individuals stop smoking-associated behaviors—and lower rates of syphilis and human immunodeficiency virus infection—the result of casefinding strategies, biologic therapies (penicillin for syphilis), and public education about safer sexual practices such as the use of barriers that prevent spread (condoms)—suggest that widespread adoption of behavior-centered prevention can lessen rates of disorder. Recent experience also demonstrates the types of evidence that should be required before prevention strategies should be instituted at the population level. For example, although a large number of well-designed epidemiologic studies supported the conclusion that women who had taken hormone replacement therapy (HRT) and both men and women who had taken nonsteroidal anti-inflammatory drugs (NSAIDS) had a lower likelihood of developing dementia than matched individuals who had not taken these drugs, these were not demonstrated in prospective, randomized control trials. “Naturalistic” studies that rely on whether individuals chose to or were prescribed medications, behav-
1552-5260/07/$ – see front matter © 2007 The Alzheimer’s Association. All rights reserved. doi:10.1016/j.jalz.2007.01.006
P.V. Rabins / Alzheimer’s & Dementia 3 (2007) S86 –S88
iors, or other activities and that look backward at samples of individuals collected for these studies or for other studies cannot adequately control for the differences between the groups, even when investigators attempt to do so statistically. Said another way, there appears to be no way, at least at present, to replicate the benefits of random assignment and unawareness of who is receiving the active and inactive treatments, when these conditions are not inherent to the initial design of the study. However, although the recent prospective intervention studies failed to find a preventive benefit of either of two NSAIDS (naproxen and celecoxib) or an estrogen/progesterone formulation of HRT on dementia in individuals at high risk for dementia (because of a family history of dementia), these negative studies did not rule out the possibility that these medications have preventive activity in individuals younger than 60 years of age, that other drugs in the class such as the NSAID ibuprofen or estrogen alone might be preventive, or in individuals at high risk on the basis of genetic factors such as having an APOE e4 allele. In addition to the questions left unanswered by these trials, the expense of these trials, the difficulty of enrolling subjects, and the very long time that would be needed to demonstrate a benefit in young or middle-aged individuals demonstrate the difficulties that will be faced in proving the effectiveness of prevention strategies for dementia. On the other hand, success in preventing dementia dates back to the development of aggressive case-finding strategies and the introduction of penicillin and other antibiotics and the resultant dramatic declines in the incidence of neurosyphilis by the 1940s. A more recent example is the demonstration in a small sample that individuals randomized to aspirin after stroke compared with those randomized to placebo had lower rates of cognitive impairment and higher brain blood flow [5]. Interest in the prevention of dementia heightened through the 1990s [6] as the ability to identify precursor or early emergent states of dementia developed, particularly through the pioneering work of Ronald Petersen at the Mayo Clinic and his refinement of the construct of mild cognitive impairment. Interest among the public in the potential preventive effects of so-called nutriceuticals and health food supplements such as ginkgo biloba, curcumin, and fish oil has also fueled research. Establishing prevention strategies for dementia also faces challenges similar to those faced by chronic illnesses such as cardiovascular disease. The likelihood is that their etiology is multifactorial, that both genetic and non-genetic factors contribute to pathogenesis, that there is a long period of risk before any manifestation of illness, and that repeated exposure to the prevention strategy will be necessary. Nevertheless, the dramatic drops in death rates from stroke and myocardial infarction during the past 30 years suggest that prevention is not only a possibility, but that research on this topic is timely.
S87
Reports in this supplement present the results of a Centers for Disease Control and Prevention– directed effort to determine whether there is currently adequate scientific evidence to support a campaign to target preventive strategies for dementia. Several approaches were considered: First, evidence that vascular risk factors predispose to the development of vascular dementia and evidence that vascular risk factors might also independently increase the risk of developing Alzheimer’s disease led to a careful assessment of the evidence that they be targeted in a prevention campaign. Second, a developing literature linking higher levels of physical activity to lower rates of dementia incidence raises questions about physical activity levels and exercise as prevention strategies. Third, associations between higher levels of social and cognitive (“mental”) activity raise it as a possible target. What does the evidence show? First, epidemiologic data reviewed by Rockwood [7] show an association between physical activity broadly defined, physical exercise more narrowly defined, and lower rates of dementia. The plausibility of a link between higher levels of physical activity and greater brain structure/function is supported by the studies reviewed by Kramer [8], which demonstrate improvement in brain structure and function in animals and humans after exercise programs. However, the epidemiologic studies are subject to the above reviewed limits of observational studies, and the studies of brain structure and function are in very small samples and do not demonstrate prevention of dementia. Thus, there is not yet the type of evidence that would support a conclusion that the hypothesis has been proved and that a public campaign should be mounted. Nonetheless, I agree with Rockwood that, “In the [interim], there is no good reason not to lead a life of physical activity (and intellectual stimulation, and rich social networks).” The evidence linking vascular disease to subsequent cognitive decline is stronger, whereas that linking physical and social inactivity to cognitive decline is even weaker. Moss [9] presents evidence that hypertension can lead to the brain changes associated with poorer cognitive performance as well as with poorer cognitive performance in animals. These data support a causal link, although not directly with the plaques and tangles characteristic of human Alzheimer’s disease. Grodstein [10] reviews the epidemiologic data linking the known risk factors for vascular disease and stroke, mid-life hypertension, dyslipidemia, and diabetes mellitus to poorer cognitive performance later in life, and McKhann [11] presents emerging data that the increased risk of cognitive decline after coronary artery bypass surgery is due to progression vascular disease not surgery-associated factors, further strengthening the association. Still, no intervention studies have yet demonstrated that the incidence of dementia can be delayed or prevented by treatment (secondary prevention) of these risk factors. Nonetheless, the demonstrated efficacy of interventions targeting these risk factors for stroke and myocardial infarction suggests that adding
S88
P.V. Rabins / Alzheimer’s & Dementia 3 (2007) S86 –S88
dementia prevention as a goal of already existing or planned prevention efforts targeting hypertension, dyslipidemia, and diabetes is appropriate. At what point in the lifespan will such interventions need to take place? The epidemiologic evidence is strongest for showing a linkage between mid-life hypertension and latelife dementia. If this means that all preventive interventions will need to be targeted toward mid-life rather than late life, then studies will be very expensive and take so long that they are unlikely to be done. However, with the standards used to develop the current campaign to increase activity and exercise levels for the prevention of cardiovascular disease, the conclusion by Rockwood [7] that physical, social, and cognitive activity can be encouraged now seems in order. In summary, the evidence that cardiovascular disease and diabetes mellitus contribute to the pathogenesis of dementia, particularly vascular dementia and Alzheimer’s disease, is moderately strong. The evidence that strategies targeting the risk factors for cardiovascular disease— hypertension, hyperlipidemia, inactivity, and immoderate salt intake— have reduced the rates of myocardial infarction and stroke is strong. Therefore, targeting these risk factors for the prevention of dementia seems appropriate at this time. However, little is known about the best strategies for dissemination when targeting dementia [12,13]. The time has come for studies of both efficacy and dissemination, but design challenges remain to be solved.
References [1] Russell LB. Is prevention better than cure? Washington: The Brookings Institution; 1986. [2] Park YK, Sempos CT, Barton CN, Vanderveen JE, Yetley EA. Effectiveness of food fortification in the United States: the case of pellagra. Am J Public Health 2000;90:727–38. [3] MMWR 1999;48.933– 40. [4] Rose G. The strategy of preventive medicine. Oxford: Oxford University Press; 1992. [5] Meyer JS, Rogers RL, McClintic K. Randomized clinical trial of daily aspirin therapy in multi-infarct dementia. J Am Geriatr Soc 1989;37: 549 –55. [6] Rabins PV. Prevention of mental disorders in the elderly: current perspectives and future prospects. J Am Geriatr Soc 1992;40:727–33. [7] Rockwood K, Middleton L. Physical activity and the maintenance of cognitive function. Alzheimers Dement 2007;3:S38 – 44. [8] Kramer A, Erickson KI. Effects of physical activity on cognition, well-being, and brain: human interventions. Alzheimers Dement 2007;3:S45–51. [9] Moss MB, Jonak E. Cerebrovascular disease and dementia: a primate model of hypertension and cognition. Alzheimers Dement 2007;3: S6 –15. [10] Grodstein F. Cardiovascular risk factors and cognitive function. Alzheimers Dement 2007;3:S16 –22. [11] McKhann GM, Selnes OA. Vascular cognitive change: perspective from neurology. Alzheimers Dement 2007;3:S23–9. [12] O’Loughlin JL, Paradis G, Gray-Donald K, Renaud L. The impact of a community-based heart disease prevention program in a low-income, inner-city neighborhood. Am J Public Health 1999;89:1819 – 26. [13] Shea S. Community health, community risks, community action. Am J Public Health 1992;82:785–7.