**4. Conclusion**

Prevention is a newer area in dementia/AD research, and the shift from observation to action has occurred only in the last decade, with several intervention studies now ongoing, and other RCTs starting soon. Although the pathogenesis of dementia is not fully elucidated, primary prevention seems possible, as most factors involved in dementia onset and progression are modifiable or amenable to management. The recent AHRQ/NIH report shows that develop‐ ment of successful preventive strategies requires a more refined knowledge on risk and protective factors for dementia and AD, as well as a validation of the observational studies with large intervention studies [19]. AD and VaD share several risk factors, and most dementia cases are attributable to both vascular and neurodegenerative brain damage. Furthermore, population-based neuropathological studies have shown that both subclinical neurodegener‐ ative (amyloid plaques, neurofibrillary tangles, Lewy bodies) and vascular lesions are common in the brains of cognitively normal elderly individuals, as is their co-occurrence [9]. In light of this, preventive strategies aiming to postpone the onset of dementia syndrome have great potential.

The first initiatives with an international perspective have already been established, for example the Leon Thal Symposia [160], Prevent Alzheimer's Disease by 2020 (PAD2020, http:// www.pad2020.org), and the European Dementia Prevention Initiative (EDPI, http:// www.edpi.org). It has been suggested that a worldwide database could be built by integrating

Prevention of Alzheimer's Disease: Intervention Studies

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The ongoing RTCs on dementia prevention will have to take into account the "window of opportunity hypothesis" when evaluating the results of interventions. In fact, efficacy of preventive actions may vary by age. Thus, implementation of interventions at the appropriate time in the life course is crucial for successful prevention. Refining of prognostic tools, which can be used for early detection of subjects at risk of dementia in the general population, will also help to better plan intervention studies. Also, when targeting elderly individuals, the frequent coexistence of chronic diseases needs to be considered, since it can negatively impact cognitive performance and limit adherence to preventive interventions. On the other hand, appropriate management of morbidity can help improve cognitive performance and delay dementia onset. For instance, although stroke is a known risk factor for dementia, it has been recently reported that about 25% of stroke patients discontinued one or more of their prescri‐ bed secondary prevention medications within 3 months of hospitalization for acute stroke [161-163]. Improving long-term adherence to post-stroke treatment can prevent recurrent cerebrovascular diseases and contribute to preventing or delaying clinical expression of dementia syndrome. Additionally, there is evidence of inadequate management of hyperten‐ sion and hypercholesterolemia in the older adults [146]. Similar situations exist for heart failure, which increases the risk of dementia among older adults [68], and diabetes mellitus, which accelerates the progression from mild cognitive impairment to dementia by more than 3 years [164]. Preliminary results from the PreDIVA study showed that 87% of the study participants have at least one modifiable risk factor amenable to intervention, proving the

and expanding already existing cohorts and registries [160].

presence of a window of opportunity for improved risk management [146].

In conclusion, prevention of dementia is now moving from observational to interventional studies to verify hypotheses and define tools that can be applied in the general population. Epidemiological and preclinical studies will continue to provide new information on risk/ protective factors and pathological mechanisms. The international collaboration among research teams involved in ongoing multidomain RCTs will allow the sharing of experiences and discussions on methodological aspects of these studies. This can help in interpretation of results, identification and solution of problems related to intervention strategies, and refine‐ ment of preventative approaches. The multidomain intervention RCTs are at one end of the current spectrum of intervention trials in AD/cognitive impairment. At the other end are RCTs testing disease-modifying drugs (i.e. anti-amyloid therapy) in genetically at-risk groups or those with established biomarker burden. The shift towards pre-symptomatic and predementia stages of AD has brought prevention and treatment RCTs much closer to each other than before. Since a cure for dementia is not yet available, finding effective preventive strategies is essential for a sustainable society in an aging world. As dementia, cardiovascular diseases, stroke and diabetes mellitus – all major public health problems – share several risk

Epidemiological research suggests that the most effective strategy may be to encourage the implementation of multiple preventive measures throughout the life course, including high educational attainment in childhood and early adulthood; active control of vascular factors and disorders over adulthood; and maintenance of mentally, physically, and socially active lifestyles during middle age and later in life. It has been estimated that half of AD cases worldwide are potentially attributable to modifiable risk factors, and a 10-25% reduction in these factors could potentially prevent 3 million AD cases worldwide, with a reduction in all risk factors having the greatest impact on dementia prevalence [70]. However, RCTs are indispensable to confirm the effect of risk reduction strategies targeting multiple risk factors. Multidomain interventional RCTs are now ongoing and will provide new insights into prevention of cognitive impairment and dementia. Full implementation of the life-course approach is more challenging, due to the difficulties of carrying out RCTs over many decades. Such long-term studies would require very large sample sizes and huge financial resources, and a pragmatic way to assess the effect of long-term interventions within a RCT has not yet been established. Furthermore, several risk and protective factors are not appropriate for intervention trials, due to unethical reasons, thus evidence about these factors rely on con‐ ducting rigorous observational studies (e.g., placebo-controlled trials for high blood pressure or cholesterol are not possible because such treatments are known to protect against cardio/ cerebrovascular diseases) [35]. Methodological alternatives to RCTs have been proposed to obtain robust evidence on AD and dementia prevention [37, 159].

Platforms for early intervention could be established by incorporating the classical clinical trial approach to disease into a public health model, with long-term longitudinal databases including large populations. Establishing comprehensive databases for studies on aging can create the opportunity to formulate and validate tools for early detection of people who are at increased risk of late-life cognitive impairment, to identify important targets (risk factors) for preventive interventions, and to test such interventions in RCTs.

The first initiatives with an international perspective have already been established, for example the Leon Thal Symposia [160], Prevent Alzheimer's Disease by 2020 (PAD2020, http:// www.pad2020.org), and the European Dementia Prevention Initiative (EDPI, http:// www.edpi.org). It has been suggested that a worldwide database could be built by integrating and expanding already existing cohorts and registries [160].

**4. Conclusion**

468 Understanding Alzheimer's Disease

potential.

Prevention is a newer area in dementia/AD research, and the shift from observation to action has occurred only in the last decade, with several intervention studies now ongoing, and other RCTs starting soon. Although the pathogenesis of dementia is not fully elucidated, primary prevention seems possible, as most factors involved in dementia onset and progression are modifiable or amenable to management. The recent AHRQ/NIH report shows that develop‐ ment of successful preventive strategies requires a more refined knowledge on risk and protective factors for dementia and AD, as well as a validation of the observational studies with large intervention studies [19]. AD and VaD share several risk factors, and most dementia cases are attributable to both vascular and neurodegenerative brain damage. Furthermore, population-based neuropathological studies have shown that both subclinical neurodegener‐ ative (amyloid plaques, neurofibrillary tangles, Lewy bodies) and vascular lesions are common in the brains of cognitively normal elderly individuals, as is their co-occurrence [9]. In light of this, preventive strategies aiming to postpone the onset of dementia syndrome have great

Epidemiological research suggests that the most effective strategy may be to encourage the implementation of multiple preventive measures throughout the life course, including high educational attainment in childhood and early adulthood; active control of vascular factors and disorders over adulthood; and maintenance of mentally, physically, and socially active lifestyles during middle age and later in life. It has been estimated that half of AD cases worldwide are potentially attributable to modifiable risk factors, and a 10-25% reduction in these factors could potentially prevent 3 million AD cases worldwide, with a reduction in all risk factors having the greatest impact on dementia prevalence [70]. However, RCTs are indispensable to confirm the effect of risk reduction strategies targeting multiple risk factors. Multidomain interventional RCTs are now ongoing and will provide new insights into prevention of cognitive impairment and dementia. Full implementation of the life-course approach is more challenging, due to the difficulties of carrying out RCTs over many decades. Such long-term studies would require very large sample sizes and huge financial resources, and a pragmatic way to assess the effect of long-term interventions within a RCT has not yet been established. Furthermore, several risk and protective factors are not appropriate for intervention trials, due to unethical reasons, thus evidence about these factors rely on con‐ ducting rigorous observational studies (e.g., placebo-controlled trials for high blood pressure or cholesterol are not possible because such treatments are known to protect against cardio/ cerebrovascular diseases) [35]. Methodological alternatives to RCTs have been proposed to

Platforms for early intervention could be established by incorporating the classical clinical trial approach to disease into a public health model, with long-term longitudinal databases including large populations. Establishing comprehensive databases for studies on aging can create the opportunity to formulate and validate tools for early detection of people who are at increased risk of late-life cognitive impairment, to identify important targets (risk factors) for

obtain robust evidence on AD and dementia prevention [37, 159].

preventive interventions, and to test such interventions in RCTs.

The ongoing RTCs on dementia prevention will have to take into account the "window of opportunity hypothesis" when evaluating the results of interventions. In fact, efficacy of preventive actions may vary by age. Thus, implementation of interventions at the appropriate time in the life course is crucial for successful prevention. Refining of prognostic tools, which can be used for early detection of subjects at risk of dementia in the general population, will also help to better plan intervention studies. Also, when targeting elderly individuals, the frequent coexistence of chronic diseases needs to be considered, since it can negatively impact cognitive performance and limit adherence to preventive interventions. On the other hand, appropriate management of morbidity can help improve cognitive performance and delay dementia onset. For instance, although stroke is a known risk factor for dementia, it has been recently reported that about 25% of stroke patients discontinued one or more of their prescri‐ bed secondary prevention medications within 3 months of hospitalization for acute stroke [161-163]. Improving long-term adherence to post-stroke treatment can prevent recurrent cerebrovascular diseases and contribute to preventing or delaying clinical expression of dementia syndrome. Additionally, there is evidence of inadequate management of hyperten‐ sion and hypercholesterolemia in the older adults [146]. Similar situations exist for heart failure, which increases the risk of dementia among older adults [68], and diabetes mellitus, which accelerates the progression from mild cognitive impairment to dementia by more than 3 years [164]. Preliminary results from the PreDIVA study showed that 87% of the study participants have at least one modifiable risk factor amenable to intervention, proving the presence of a window of opportunity for improved risk management [146].

In conclusion, prevention of dementia is now moving from observational to interventional studies to verify hypotheses and define tools that can be applied in the general population. Epidemiological and preclinical studies will continue to provide new information on risk/ protective factors and pathological mechanisms. The international collaboration among research teams involved in ongoing multidomain RCTs will allow the sharing of experiences and discussions on methodological aspects of these studies. This can help in interpretation of results, identification and solution of problems related to intervention strategies, and refine‐ ment of preventative approaches. The multidomain intervention RCTs are at one end of the current spectrum of intervention trials in AD/cognitive impairment. At the other end are RCTs testing disease-modifying drugs (i.e. anti-amyloid therapy) in genetically at-risk groups or those with established biomarker burden. The shift towards pre-symptomatic and predementia stages of AD has brought prevention and treatment RCTs much closer to each other than before. Since a cure for dementia is not yet available, finding effective preventive strategies is essential for a sustainable society in an aging world. As dementia, cardiovascular diseases, stroke and diabetes mellitus – all major public health problems – share several risk factors, public health efforts promoting healthier lifestyle have the potential to enhance health status in advanced age.

heimer's Association workgroups on diagnostic guidelines for Alzheimer's disease.

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[5] Fratiglioni, L, & Qiu, C. Prevention of common neurodegenerative disorders in the

[6] Qiu, C, Kivipelto, M, & Von Strauss, E. Epidemiology of Alzheimer's disease: occur‐ rence, determinants, and strategies toward intervention. Dialogues in clinical neuro‐

[7] Stephan, B. C, Matthews, F. E, Ma, B, Muniz, G, Hunter, S, Davis, D, et al. Alzheimer and vascular neuropathological changes associated with different cognitive States in

[8] Schneider, J. A, Arvanitakis, Z, Bang, W, & Bennett, D. A. Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology.

[9] Sonnen, J. A. Santa Cruz K, Hemmy LS, Woltjer R, Leverenz JB, Montine KS, et al. Ecology of the aging human brain. Archives of neurology. (2011). Aug;, 68(8),

[10] Mckhann, G, Drachman, D, Folstein, M, Katzman, R, Price, D, & Stadlan, E. M. Clini‐ cal diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alz‐

[11] Mangialasche, F, Solomon, A, Winblad, B, Mecocci, P, & Kivipelto, M. Alzheimer's disease: clinical trials and drug development. Lancet neurology. (2010). Jul;, 9(7),

[12] Morris, J. C. Early-stage and preclinical Alzheimer disease. Alzheimer disease and

[13] Petersen, R. C, Doody, R, Kurz, A, Mohs, R. C, Morris, J. C, Rabins, P. V, et al. Cur‐ rent concepts in mild cognitive impairment. Arch Neurol. (2001). Dec;, 58(12),

[14] Harvey, R, Fox, N, & Rossor, M. Dementia Handbook. London: Martin Dunitz;

[15] Albert, M. S, Dekosky, S. T, Dickson, D, Dubois, B, Feldman, H. H, Fox, N. C, et al. The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommen‐ dations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. (2011). May;,

[16] Mckhann, G. M, Knopman, D. S, Chertkow, H, Hyman, B. T, & Jack, C. R. Jr., Kawas CH, et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diag‐

elderly. Experimental gerontology. (2009). Jan-Feb;44(1-2):46-50.

a non-demented sample. J Alzheimers Dis. (2012). , 29(2), 309-18.

heimer's Disease. Neurology. (1984). Jul;, 34(7), 939-44.

associated disorders. (2005). Jul-Sep;, 19(3), 163-5.

Alzheimers Dement. (2011). May;, 7(3), 257-62.

science. (2009). , 11(2), 111-28.

(2007). Dec 11;, 69(24), 2197-204.

1049-56.

702-16.

1985-92.

(1999).

7(3), 270-9.
