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COST-EFFECTIVENESS OF DEMENTIA PREVENTION INTERVENTIONS

 
I. McRae1, L. Zheng2,4, S. Bourke3, N. Cherbuin1, K.J. Anstey2,4
 

1. Centre for Research on Ageing Health and Wellbeing, Research School of Population Health, The Australian National University, Canberra, ACT, Australia; 2. Neuroscience Research Australia, Margarete Ainsworth Building, Barker Street, Randwick, Sydney NSW, Australia; 3..Department of Health Services Research and Policy, Research School of Population Health, The Australian National University, Canberra, ACT, Australia; 4. Ageing Futures Institute, School of Psychology, University of New South Wales, Sydney, NSW, Australia

Corresponding Author: Dr Ian McRae, Centre for Research on Ageing Health and Wellbeing, Research School of Population Health, The Australian National University, Canberra, ACT 2600, Australia, Email: Ian.S.McRae@anu.edu.au, Ph: +61 431 929 750

J Prev Alz Dis 2020;
Published online December 15, 2020, http://dx.doi.org/10.14283/jpad.2020.71

 
 


Abstract

Background: Assessment of cost-effectiveness of interventions to address modifiable risk factors associated with dementia requires estimates of long-term impacts of these interventions which are rarely directly available and must be estimated using a range of assumptions.
OBJECTIVES: To test the cost-effectiveness of dementia prevention measures using a methodology which transparently addresses the many assumptions required to use data from short-term studies, and which readily incorporates sensitivity analyses.
DESIGN: We explore an approach to estimating cost-effective prices which uses aggregate data including estimated lifetime costs of dementia, both financial and quality of life, and incorporates a range of assumptions regarding sustainability of short- term gains and other parameters.
SETTING: The approach is addressed in the context of the theoretical reduction in a range of risk factors, and in the context of a specific small-scale trial of an internet-based intervention augmented with diet and physical activity consultations.
MEASUREMENTS: The principal outcomes were prices per unit of interventions at which interventions were cost-effective or cost-saving.
RESULTS: Taking a societal perspective, a notional intervention reducing a range of dementia risk-factors by 5% was cost-effective at $A460 per person with higher risk groups at $2,148 per person. The on-line program costing $825 per person was cost-effective at $1,850 per person even if program effect diminished by 75% over time.
CONCLUSIONS: Interventions to address risk factors for dementia are likely to be cost-effective if appropriately designed, but confirmation of this conclusion requires longer term follow-up of trials to measure the impact and sustainability of short-term gains.

Key words: Dementia, risk factors, cost-effectiveness, interventions, sustainability.


 

Background

While many studies have addressed the association of lifestyle and vascular factors with dementia, few have addressed whether interventions designed to reduce risk factors are cost-effective (1). This is in part because dementia risk reduction programs are implemented well before the usual age of dementia onset. This means that economic evaluation using simulation modelling requires parameters relevant to a long-term time frame. As most intervention studies to date have 5 years or less of follow-up (1) (exceptions include the planned trials of multi-domain interventions (2)), cost-effectiveness studies require model parameters to be extrapolated well beyond the data observed. Reviews of model-based economic evaluations of dementia interventions (1, 3) have identified very few methods which assess prevention strategies. The types of non-pharmaceutical interventions identified in these reviews mainly focused on early assessment of dementia, screening or diagnosis rather than reduction in risk factors (3).
Short-term cost-effectiveness studies (4) and methodologies have been published which address cost-effectiveness of transitions from mild cognitive impairment (MCI) to dementia (5). However, assessing cost-effectiveness of programs which reduce or treat risk factors (many of which occur in mid-life) requires modelling the impact of interventions over longer time frames (1, 3, 5-9) and requires assumptions on how trial results are sustained over the longer term. In the absence of robust estimates of many of the parameters needed for full Markov or other simulation models, we suggest an alternate approach to estimating the price at which programs are cost-effective. This approach provides transparency in estimating the sensitivity of these prices with highly uncertain parameter estimates.
A 2019 review of health economic evaluations of primary prevention programs for dementia (1) identified three analyses of prevention strategies (6, 8, 9) which modelled dementia progress and costs over the long-term. Noting the range of uncertainties, the review recommended that “extensive sensitivity analysis to examine the impact of assumptions” be implemented. This included assumptions regarding long-term vs short-term outcomes of interventions, the impact of optimal program targeting, and discounting (1). Two of the analyses were partial evaluations which addressed potential cost savings from reductions in dementia levels, but did not address health benefits (usually measured by Quality Adjusted Life Years (QALYs)), so cost-effectiveness was not testable(6, 8). While including an extensive sensitivity analysis, the study which addressed cost-effectiveness (9) required a range of assumptions to estimate parameters including annual risk rates, mortality rates for those with and without dementia and QALY levels by age for people with dementia (9).
Estimated age/gender specific incidence rates(10) for dementia are available for Australia, but the impact of interventions on incidence of dementia at each age is not known, nor are age-specific costs or QALY estimates. Hence, there is value in exploring non-simulation approaches to estimate the cost-effectiveness of interventions which address dementia risk factors using aggregate data. We use an approach based on average lifetime costs of dementia and losses in quality of life per individual who develops dementia. Until long-term parameters can be obtained with confidence, this approach avoids the need for transition probabilities and cost and QALY measures by age. It also gives a direct means of linking costs and benefits and provides a transparent means of undertaking sensitivity analyses of all factors, including parameters reflecting the sustainability of improvements in risk factors, program targeting and discounting.
To demonstrate the proposed approach we draw on two examples (11, 12): (1) a study that estimated the effects of risk reduction through population attributable risk(PAR) and (2) a recent randomized control trial (RCT) which assessed the impact of an on-line dementia prevention program. The RCT has a relatively short follow-up (15 months), so to estimate the long term cost-effective and cost-saving prices we provide a range of different assumptions including the degree to which gains in risk reduction are sustained and how well the program is targeted to people with high likelihoods of progressing to dementia.

 

Methods and Data

Approach

We used available estimates of the proportion of adults aged 65 and over who are expected to develop dementia and then estimated the reduction in prevalence of dementia for a target population from the two example interventions. Savings in costs and QALYs per person generated by the interventions were estimated using the average per person life-time costs of dementia and loss of QALY due to dementia. This enabled us to estimate the maximum price per person for an intervention to be cost saving or cost effective.
The standard measure of cost-effectiveness (technically cost-utility) is the incremental cost per QALY gained (i.e. the Incremental Cost-Effectiveness Ratio or ICER). For the purposes of this study, an intervention with an ICER below $50,000 is considered cost-effective. While Australia has no formal ICER thresholds this is the level most commonly quoted and is consistent with UK, Australian (13) and American(14) literature.
Apart from sensitivity analysis for uncertain parameters, we examined: (1) the impact of program targeting, as an intervention targeted at the highest risk groups has a greater opportunity to reduce dementia prevalence, (2) the impact of “decay” which reflects reduction in the gains from an intervention over time, and (3) the impact of different levels of discounting. Discounting is a means of “valuing down” (1) future financial and health costs as people may prefer to save money (or gain health benefits) now rather than in the future.

Lifetime Costs of Developing Dementia

Lifetime costs for people with dementia are the product of average annual costs of treatment/care and the duration of care. While estimates of duration of dementia vary widely depending mainly on age at diagnosis, international evidence and reviews suggest that a mean of 5 years is appropriate for the duration of care for dementia (15, 16) (noting this may not be the same as the actual duration of dementia) (17)).
The available estimates of costs of dementia take several perspectives. An American study (18) including direct healthcare costs and costs of informal care estimated $260,000 per person in 2015 (all costs in Australian Dollars); while a 2016 Australian analysis found average annual costs of $35,550 per person including indirect costs such as loss of productivity of both patients and carers (10). With 5 years life with dementia, this becomes $177,750 lifetime cost per person. A later Australian study (19) of people with dementia in residential care with a markedly different methodology estimated higher annual costs of $88,000 per year for residential care compared to $55,000 from the earlier study(10). Given the varying results from these studies, we used a figure of $200,000 as baseline, with a range from $150,000 to $300,000 used for sensitivity analyses.

Loss of Quality Adjusted Life Years by People Developing Dementia

The lifetime loss of QALYs for people with dementia includes the loss due to poorer quality of life and the loss due to premature mortality. A conservative median estimated years of life lost to dementia used here as a baseline is 5 years. This is consistent with previous studies (20) and an Australian systematic review (15). Some estimates as high as 9 years of life have been found (7, 21); we use this as the upper limit for sensitivity analysis purposes.
Few generally applicable estimates of QALY values for people with dementia are available (22). Most studies deriving QALYs in a dementia context relate to specific RCTs with specific populations rather than comparing average people with and without dementia. We draw on estimates of average QALYs for people with dementia and the wider aged population (7, 23). With 5 years of life with dementia, and 5 years loss of life due to dementia there is an average loss 1.5 QALYs while alive and 4.2 QALYS due to premature mortality giving a lifetime loss of 5.7 QALYs from the dementia. A previous estimate (7) based on 6 years with dementia and 9 years loss of life led to an estimated 9.4 QALYs lost which we use as an upper level for sensitivity testing.

Prevalence of dementia

Population prevalence data is not required for Example 1 as the predicted outcomes are explicitly in prevalence terms, although it is required for Example 2. While “Australian data on dementia prevalence are lacking” (AIHW 2018 p138 (24)), we use an estimate of 10% for people aged 65 or over from a study using Australian data (10), which is marginally above estimates combining Australian and international data (10, 24). For Example 2, we assume that any reduction in risk will lead to an equivalent reduction in prevalence when the cohort reaches age 65 or over, and that this reduction will apply to the estimated 10% prevalence of dementia in this age group.

Discounting

People generally value future costs and effects less than current costs and effects and the value diminishes the further into the future they are expected to occur (25). Hence, economic evaluations adjust the value of costs and benefits for the time at which they occur, using discounting (25). Discounting over long periods has major impacts on results of cost-effectiveness studies (1), particularly when comparing program costs at midlife to medical and other savings in later life (26). A range of discount levels are used by different organisations including: a) the use of 3% for both costs and QALYs (9), b) discount rates of 4% for costs and 1.5% for QALYs( 1), c) the use of 5% for both costs and QALYs in Australia by the Medicare Services Advisory Committee (25), and d) a UK recommendation that 3.5% be applied to both costs and QALYs (25).
In the light of extremely low interest rates in Australia and many other countries at present, and the long durations of discounting in this study, we use baseline discount rates of 3% for both costs and QALYs. For sensitivity analysis we include the Australian standard of 5% for both costs and QALYs, and the 4%/1.5% applied in Holland (1).
Simulation approaches apply discounting each year. However, assuming on average no differences between treated and untreated groups before onset of dementia, the discounting will have no material impact on the differences between treatment groups prior to diagnosis (note that while in principle costs change at onset, they are only measured from diagnosis). We, therefore, discount from the average age of commencement of the intervention to approximately the mid-point of the dementia period. To establish the period of discounting we take an average age of diagnosis as being in the early 80s (27-29). Most studies addressing average age at diagnosis show averages from the high 70s to mid 80s, but most commence with aged populations which may lead to some upward bias. We, therefore, include some alternate discounting periods for sensitivity analysis.

Example 1 – Estimates of Dementia Prevention using Population Attributable Risk

Ashby-Mitchell et al.(2017) (11) explored the aggregate Population Attributable Risk (PAR) from a set of known correlates of dementia (midlife obesity, physical inactivity, smoking, low educational attainment, diabetes mellitus, midlife hypertension, depression). They used PAR values to estimate the impact of uniform reductions in these correlates on dementia prevalence. They concluded that a uniform 5% improvement across all risks would, over 20 years, lead to a reduction in the prevalence of dementia of 3.2% or 17,454 people in Australia.
Any intervention which aimed to reduce the risk factors addressed in Example 1 would need to improve obesity levels and hypertension in mid-life so we assume an intervention targeted at the population aged 45 years and over with an average age of around 65 years. Consistent with the modelling in Example 1 this gives a 20-year period from average age at intervention to average age of dementia diagnosis (early 80s) which we use for discounting (15 years used for sensitivity testing).

Example 2 – BBL-GP Intervention

The Body-Brain-Life in General Practice program (BBL-GP) aims to reduce known dementia risk factors using a mixture of on-line training and face-to-face consultations with dietitians and exercise physiologists (12). Results are assessed using an aggregate measure combining a range of known risk factors (the ANU-ADRI (30)) with program participants compared to an active control group. After 62 weeks the BBL-GP participants showed a decline in ANU-ADRI scores of 4.62 units more than the active controls (12). For a population of Australians aged 60-64 years at baseline, a difference in baseline values of 1 point of ANU-ADRI is associated with a difference of 8% in people developing mild cognitive decline (MCI) or dementia after 12 years (31). This suggests a BBL-GP effect of 37% if the 4.62 units improvement is sustained.
This is an upper limit. Firstly, it is unlikely all the gains in risk factors will be sustained (e.g. maintaining weight loss). Secondly, the evidence of the impact of one point of ANU-ADRI on MCI and dementia may be the same as the long-term impact on dementia, but need not be, as there is likely to be a bias towards reducing MCI in those who are least likely to go forward to dementia. In this case the 8% impact of one ADRI point would be an overstatement. Finally, it is not clear if differences in the index obtained from an intervention have the same effect as differences brought about by lifetime experiences. The size of “decay” for any particular intervention is, therefore, driven by a range of factors including the time period between the intervention and the age at which dementia diagnosis is likely. For sensitivity analysis we test a range of different levels of reduction in impact of the BBL-GP program on actual dementia risk, beginning with a 50% reduction and increasing to a 95% reduction. We term this “decay” to reflect both the difficulty in sustaining the intervention’s short-term gains and the other issues described.
The trial population in Example 2 had an average age of 51 years (12), so for discounting purposes there is approximately 30 years to the average age of dementia diagnosis (20 years used for sensitivity testing). The average cost per participant in the BBL-GP trial relative to an active control was $2,700 including set-up costs. The number of participants in this trial was small, and while there are fixed costs of around $200 per person, other expenditures was almost independent of participant numbers. If more fully implemented the program would be expected to be at least quadrupled in size and costs would become $825 per person. We use this figure to assess cost-effectiveness. With a larger implementation, average costs would be further reduced.

 

Results

Table 1 shows baseline estimates for Example 1 with a target population of all people aged 45 years or over. This suggests that, ignoring program costs and discounting, over the lifetimes of the people protected from dementia by the lifestyle changes there would be savings of $3.5b and 99,488 QALYs. While these savings are large, with a targeting across the whole population, the savings per targeted person are only $342. After allowing for discounting, the maximum cost per targeted person which could lead to a cost saving program is $189, while a cost less than $460 would achieve a cost-effective incremental cost per QALY gained (the ICER) of less than $50,000.

Table 1. Example 1 – PAR – Baseline costing

1. (10)= ((4) + (9)*(5))/(6)
 
Table 2 provides estimates of maximum costs per person for a program to be cost saving or cost-effective under different assumptions on target size, lifetime costs, QALY losses and discount rates. Tests 1-3 show relatively little sensitivity in cost-effective or cost-saving prices to changes in estimated lifetime costs and lifetime QALY losses to dementia, with greater effects of QALY increases than cost increases on the cost-effective price. Test 4 assumes the intervention targets only half the population aged 45 and over and assumes the targeting is so well focused on those at higher risk that the number of people avoiding dementia is unchanged. This generates a much greater change in the maximum acceptable costs than shown in Tests 1-3. Test 5 assumes an intervention targeted at a population of only 10,000 who are at very high risk of developing dementia (25% prevalence rate), and again with 3.2% of the anticipated cases “saved” from dementia (11). The cost-effective price increases to $2,069 (after discounting), more than 4 times the baseline estimate. With such precise targeting the percentage saved would probably be greater than 3.2%, and any increase in this parameter would increase the cost-effective prices proportionately. Table 2 also shows the impact of different discounting rates, with the 4%/1.5% levels having broadly similar results to baseline, but the 5%/5% showing acceptable prices around 60% of 3%/3% meaning interventions are considerably less likely to be cost-effective. Should the duration of discounting (the period from the intervention to average age of diagnosis) be reduced, for the 3%/3% calculation the maximum cost-effective price would increase by 15% meaning more expensive interventions would be cost-effective.

Table 2. Example 1 – PAR Costings – Sensitivity analyses

NOTE: * shows variation from baseline
 
Table 3 provides baseline estimates for Example 2. For presentation purposes the assumed population is 10,000 but results are independent of this number. The discounted program prices at baseline of $3,052 per person to be cost saving and $7,401 per person for the program to be cost-effective are well above the average price per participant of $825 relative to the active control.

Table 3. Example 2- BBL-GP – Baseline Costing

 
Table 4 provides sensitivity testing which in addition to the factors tested for Example 1 tests levels of “decay”, and shows that the targeting, decay and discounting assumptions have the greatest impact on the overall outcomes. The targeting level of 60% was chosen as the trial participants were mainly people with obesity, with the relative risk of developing dementia of 1.6 (11). With an average price of $825, results discounted at 3% and all other factors at baseline level, a decay of up to 88% would be cost-effective, although not 95% (Test 3). With a 60% loading for targeting and the maximum levels of cost savings from preventing dementia and QALY lost to dementia, the intervention would be cost-effective at 95% decay (Test 7). Test 8 shows that with the 60% loading for targeting and other factors at baseline, even at 93% decay from the short term results the program would be cost-effective.

Table 4. Example 2 – BBL-GP Costing – Sensitivity Analyses

NOTE: * shows variation from baseline
 
The patterns in these tables show that results are linear with respect to both targeting and “decay”, and less than linear with respect to estimated lifetime costs and QALYs lost to dementia. As for Example 1, discounting has a major impact on the results, although even with relatively high levels of “decay” (80% with all other factors at baseline) the intervention is likely to remain cost-effective with 5%/5% discounting. Should the duration of discounting be reduced, the maximum cost-effective price would increase by 34% for the 3%/3% discounting, although this does not lift any of these prices above $825 for the examples in Table 4.

 

Discussion

Our results suggest that multi-domain programs such as the BBL-GP in Example 2 are likely to be cost-effective (unless program impacts decay almost completely over time), while the more generic approach of Example 1 requires tight targeting to at-risk populations to be cost-effective. These results are consistent with prior studies (1, 32) in showing the importance of targeting and sustainability of observed results beyond the period of study follow-up.
The estimated cost of $825 per person in Example 2 would be reduced with wider implementation. Previous studies have estimated cost of dementia risk reduction programs of $200 to $500 per person (9, 33). If Example 2 could be conducted at these lower costs it is more likely to be cost-effective even at high levels of “decay”. Should the duration from intervention to diagnosis of dementia be less than the assumed levels, the effect of discounting would be reduced, and maximum cost-effective program prices increased.
Recalling that “decay” includes other factors as well as the need for participants to maintain lifestyle changes over many years, high levels of decay are possible. Studies with long follow-up are needed to assess actual program effects. Programs which continue to interact with the participants continuously over time are likely to improve effects but increase costs. We also note that improving dementia risk factors would improve a range of other health outcomes (e.g. cardiovascular health, diabetes, mild cognitive impairment), in addition to dementia related outcomes. If the total benefits of risk reduction programs were included, they would be even more likely to be cost-effective.

Limitations

The main limitation in this and any other analysis of cost-effectiveness of dementia prevention interventions is the uncertainty in many parameters, which has required extensive sensitivity analysis to assess a reasonable range of outcomes. However, the approach taken here integrates sensitivity analysis and facilitates estimation of outcomes under varied assumptions.
The study assumed binary outcomes of dementia against no dementia and did not address the benefit of delay in onset of dementia, which also reduced the likelihood of finding cost-effective outcomes. Dementia related QALY losses prior to diagnosis were not included in the study, leading to a further conservative bias in estimates.
Like all approaches to cost-effectiveness modelling for dementia prevention interventions this study is limited by having only short-term program outcomes (1). The baseline calculations assume (1) in the case of Example 1, that well-established associations between risk factors and dementia are causative; (2) for both examples, changes in risk factors driven by interventions have the same effect as if the level of the risk factor was achieved ”naturally” (e.g. reversing midlife obesity with an intervention has the same effect as achieving a normal weight at midlife without intervention) and; (3) changes in risk from a short-term intervention are sustained over time(e.g. weight does not revert to previous levels). The approach used here however provides a simple and transparent way to test the impact of these ongoing concerns.

 

Conclusion

To explore the cost-effectiveness of interventions aimed at dementia risk reduction requires a means of extrapolating outcomes from what, to date, have been relatively short-term trials. We examined lifetime costs (in both dollar and QALY terms) of dementia and applied these to projected changes in risks of dementia from two example studies. The results suggest that the multi-domain approach of BBL-GP is highly likely to be cost-effective.
The approach shows further the importance of targeting programs to “at risk” portions of the population and the sensitivity to the sustainability or otherwise of trial results. While these factors are well-known, the approach provides a means of estimating the orders of magnitude of program impacts and reinforces the need for longer-term studies to measure all relevant factors to enable assessment of cost-effectiveness with greater confidence.

 

Funding Sources: This research was undertaken as part of the Centre for Research Excellence in Cognitive Health, which was funded by the National Health and Medical Research Council grant #1100579. Anstey is funded by NHMRC Fellowship #1102694, Zheng is part supported by the NHMRC Dementia Centre for Research Collaboration. The funders had no role in the design and conduct of this study; in the analysis and interpretation of the data; in the preparation of the manuscript; or in the review or approval of the manuscript.
Acknowledgements: We acknowledge the ARC Centre of Excellence in Population Ageing Research.

Conflict of Interest: Dr McRae, Dr Zheng, Dr Bourke, and Professor Cherbuin declare that they have no conflict of interest. Professor Anstey reports personal fees from StaySharp, outside the submitted work.

Ethical standards: The authors followed the ethical guidelines of the Journal for this manuscript.

 

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FACTORS ASSOCIATED WITH ALZHEIMER’S DISEASE: AN OVERVIEW OF REVIEWS

 

M. Rochoy1,2, V. Rivas1, E. Chazard1,3, E. Decarpentry1, G. Saudemont1, P.-A. Hazard1, F. Puisieux1, S. Gautier1,2, R. Bordet1,2

 

1. Univ. Lille, F-59000 Lille, France; 2. INSERM, U1171-Degenerative and Vascular Cognitive Disorders, F-59000 Lille, France; 3. EA2694, Public Health Department, Univ Lille, CHU Lille, F-59000 Lille, France

Corresponding Author: Michaël Rochoy, 20 rue André Pantigny, 62230 Outreau, France. +33667576735, michael.rochoy@gmail.com

J Prev Alz Dis 2019;2(6):121-134
Published online February 11, 2019, http://dx.doi.org/10.14283/jpad.2019.7

 


Abstract

Alzheimer’s disease (AD) is a frequent pathology, with a poor prognosis, for which no curative treatment is available in 2018. AD prevention is an important issue, and is an important research topic.
In this manuscript, we have synthesized the literature reviews and meta-analyses relating to modifiable risk factors associated with AD. Smoking, diabetes, high blood pressure, obesity, hypercholesterolemia, physical inactivity, depression, head trauma, heart failure, bleeding and ischemic strokes, sleep apnea syndrome appeared to be associated with an increased risk of AD. In addition to these well-known associations, we highlight here the existence of associated factors less described: hyperhomocysteinemia, hearing loss, essential tremor, occupational exposure to magnetic fields.
On the contrary, some oral antidiabetic drugs, education and intellectual activity, a Mediterranean-type diet or using Healthy Diet Indicator, consumption of unsaturated fatty acids seemed to have a protective effect.
Better knowledge of risk factors for AD allows for better identification of patients at risk. This may contribute to the emergence of prevention policies to delay or prevent the onset of AD.

Key words: Alzheimer’s disease, prevention, risk factors, early intervention.

List of abbreviations: AD: Alzheimer’s disease; OR: Odds-Ratio; RR: Relative Ratio


 

Background

The prevalence of dementia is estimated to be over 45 million people and could reach 115 million by 2050 (1). Alzheimer’s disease (AD) accounts for 60-70% of dementias (2). The prevalence of dementia is increasing as the population ages (3). Nevertheless, several studies showed a decrease in the prevalence rate of dementia or severe cognitive impairment after the age of 65 over the last 10 to 30 years in the United States (4–7) and Europe (8–13). The decrease in the prevalence rate could be explained by prevention and better management of risk factors (14).
The main risk factor for AD is age. Another known risk factor is heredity; thus, many genetic determinants have been studied, notably ApoE4, ApoE3 or presenilin S1 and S2 (15, 16).
In 2018, AD remains incurable and prevention is essential: it is based on the management of modifiable risk factors.
Many studies focused on AD “risk factors”. In response to the large number of articles, systematic literature reviews focused on classes of risk factors (genetic, environmental, infectious, etc.). For clinicians, it seems important to synthesize these numerous studies and reviews, and provide an overview of literature reviews.
Our aim was to summarize the literature reviews conducted on modifiable risk factors for AD.

 

Methods

This overview of literature reviews was conducted using the PubMed search engine (MEDLINE database), with the equation: “Alzheimer disease”[MeSH] AND “risk factor” [All Fields] AND (Meta-Analysis[ptyp] OR Review[ptyp]). The research was carried out in February 2017 and checked in November 2017.
The inclusion criteria were literature review or meta-analysis of epidemiological articles.
There was no time limit on the reviews and meta-analyses included.
The exclusion criteria were:
–     Descriptive literature reviews
–     Literature reviews that do not detail the populations studied
–    Pathophysiological literature reviews
–     Animal model studies
–     Articles not accessible in full
–     Articles in a language other than English or French

An additional search was performed on the UpToDate® site. The literature reviews cited, not found via the PubMed query, have been added.
A second additional search was carried out on the French Health Scientific Literature search engine (LiSSa) to look for other risk factors that were not noticed during the initial searches, via literature reviews published in journals not indexed on MEDLINE.
When the same association was covered by several reviews, we excluded the oldest ones.
As the purpose of this work is to provide an up-to-date synthesis of the literature reviews, most of the main and/or relevant results of the studies have been extracted.

 

Results

We identified 668 literature reviews and included 86 from PubMed. We included 5 articles with additional research (UpToDate® and LiSSa). Reviews and meta-analysis included are summarized in Table 1.

Table 1. Summary of reviews and meta-analysis

Table 1. Summary of reviews and meta-analysis

There are many modifiable risk factors for AD, summarized in Table 2. Levels of evidence are resumed in Table 3.

Table 2. Modifiable factors associated with AD

Table 2. Modifiable factors associated with AD

 

Table 3. Summary of evidences concerning associated factors for Alzheimer’s dementia

Table 3. Summary of evidences concerning associated factors for Alzheimer’s dementia

 

Cardiovascular

Several literature reviews established a link between hypertension at different life stages and an increased risk of AD (17–21).
A systematic review summarized the findings from population-based observational studies and randomized clinical trials addressing the relations of blood pressure to cognitive function and dementia (20). Concerning “late-life” hypertension, seven longitudinal studies reported an association with AD, three longitudinal studies and two cross-sectional studies found no association, five cross-sectional studies reported an inverse association (potentially protective) (20). Concerning “mid-life” hypertension, an association with AD has been reported in four of five longitudinal studies (20).
Barnes and Yaffe associated «mid-life» hypertension and AD with OR = 1.61 (CI95 [1.16 – 2.24]). «Late-life» hypertension was not associated with an increased risk of AD in 8 of the 13 studies included (22). In another literature review, patients with the highest coefficient of variation in blood pressure were more likely to have an increased risk of cognitive impairment or dementia (17).
In 2006, another review highlighted a link between low diastolic BP (between 65 and 80 mmHg) and increased risk of AD (18).
Most published studies demonstrate associations between atrial fibrillation and impaired cognition, but no atrial fibrillation treatment has yet been associated with a reduced incidence of cognitive decline or dementia (23).
Heart failure was associated with 60% increased dementia risk (RR = 1.60 ; CI95 [1.19-2.13]) (24). Heart failure is associated with increased radiologic brain damage, particularly in the limbic system (which includes the hippocampus), similar to objective damage in AD patients (25).
A meta-analysis o associated hyperhomocysteinemia (> 15 µmol/L) and AD: OR = 3.37 (CI95% [1.90 – 5.95]) (26). This association is suggested in other reviews MA (27, 28). The link between vitamin deficiency (B9 or B12) and hyperhomocysteinemia is known and this could constitute a confounding bias.
Kivipelto et al. associated risk of AD and «mid-life» hypercholesterolemia (not in «late life») (29). In another review, 5 prospective studies were studied: 3 showed a significant association between AD and hypercholesterolemia; on the other hand, 1 study showed no significant association, while the last showed, conversely, a protective effect with a RR estimated at 0.4 (CI95 [0.2 – 0.8]) (18).
Hemorrhagic and ischemic stroke was also considered as risk factors for dementia: an increase in the risk of dementia by 10% after a first episode, and up to more than 20% after several episodes (30). Subclinical brain microbleeds (4 or more) were associated with an increase in cognitive impairment (HR = 2.10 ; CI95 [1.21 – 3.64]) (31).
One review analyzed different types of antihypertensive agents and their possible association with AD: there was no difference between control group, diuretic group or angiotensin 2 antagonist. In contrast, the authors report a decrease in RR dementia in patients using a calcium channel blocker (RR = 0.55; CI95 [0.24 – 0.73]) (32). For ACE inhibitors, the authors reported, at the conclusion of their review, a significant difference between the treatment and control groups in the incidence of cognitive impairment, but no significant difference in the occurrence of dementia (32).
In the review by Miida et al., the included cross-sectional studies showed a significant decrease in the risk of AD in patients using statins; but 3 out of 4 prospective studies did not show a significant decrease in the risk of AD, as did the 8 randomized controlled trials (RCTs) (33).

Habitus, social contact and educational level

Physical activity was associated with a decreased risk of cognitive impairment in 21 of 24 cohorts included (87.5%) and 100% of cross-sectional studies; a meta-analysis of 8 studies reported RR at 0.58 (CI95 [0.49 – 0.70]) for high vs low physical activity (34). In 2011, Barnes and Yaffe concluded that there is an association between physical inactivity and increased risk of dementia in the various reviews and meta-analyses included in their study (19). Wheeler et al. suggest that reducing and replacing sedentary behavior with intermittent light-intensity physical activity may protect against cognitive decline by reducing glycemic variability (35).
Active smoking (versus never smoking) was associated with an increased risk of dementia: RR = 1.79 (CI95 [1.43 – 2.23]) (22). In 2014, Beydoun et al. published a literature review with somewhat more nuanced results on this relationship between smoking and cognitive impairment: 16 of the 29 cohort epidemiological studies included (55.2%) found an association between smoking and increased risk of cognitive impairment, as 2 of the 7 cross-sectional studies included. In a meta-analysis of 9 of 29 studies, the authors calculated a RR of AD for current and former smokers compared to never smokers at 1.37 (CI95 [1.23 – 1.52]) (28).
Concerning alcohol, Beydoun et al. noted an association between alcohol and increased cognitive impairment in 44% of cohorts included and 75% of cross-sectional studies (28).
In 2009, Anstey et al. published a meta-analysis of 15 cohorts whose results suggest that alcohol consumption is associated with a decreased risk of AD: RR = 0.66 (CI95 [0.47 – 0.94]) (36). Confounding factors were possible, particularly due to alcohol-related comorbidities.
There was a moderate association between caffeine consumption and decreased risk of cognitive problems: in one review, 4 of the 7 cross-sectional studies and 3 of the 11 cohorts included found this association. Five other cohorts among the 11 identified this link in a partial way in the subgroup analyses (for example, only among women) (28).
Frequent social contact and cognitive stimulation would be protective factors (37).
A lower educational level was associated with an increased risk of AD, with an RR estimated at 1.80 (CI95 [1.43 – 2.27]) (38) or 1.99 (CI95 [1.30 – 3.04]) in Beydoun’s meta-analysis (knowing that low educational level here means less than 8 years of education) (28).

Pneumology

A meta-analysis of 6 cohort studies (19,940 patients) associated sleep apnea syndrome and dementia (RR = 1.69; CI95 [1.34 – 2.13]). The association is also found in subgroup analyses, with or without polysomnography, adjusted or not on ApoE4 (39).

Infectiology

One of 3 case-control studies and 2 epidemiological studies showed a possible link between Chlamydia pneumoniae infection and AD possibly through chronic neuronal inflammation (40).
The prevalence of Helicobacter pylori was increased in patients with AD in case-control studies; in cohorts patients with H. pylori often have poorer cognitive performance (confounding bias). However, the authors conclude their narrative review with a lack of longitudinal studies to support the association between infection and AD, to explain more precisely the mechanism by which H. pylori would actually intervene in pathogenesis, and to determine the utility of eradication of the bacterium in patients with AD or cognitive disorders (41).
A review of 12 case-control studies did not associated Herpes Simplex Virus 1 infection and AD (40). In the same review, it is suggested that HHV6 is not an independent risk factor for AD. Nevertheless, its presence could increase the neuronal damage caused by HSV1 in patients with ApoE4.

Endocrinology and metabolism

The risk of dementia (especially AD) increased in cases of «mid-life» underweight (BMI < 18.5) or «mid-life» obesity (between 45 and 64 years of age according to the authors); this association is not present after 64 years of age, in late life (42). «Mid-life» obesity was associated with an increased risk of dementia : RR = 1.59 (CI95 [1.02 – 2.48]) (22).
Diabetes is also a risk factor for AD in most studies, with an estimated RR of 1.53 (CI95 [1.42 – 1.63]), or slightly higher in so-called «eastern» populations, with an RR of 1.62 (CI95 [1.49 – 1.75]) (43). Mid-life and late-life diabetes were associated with AD (42); interaction is possible with cerebrovascular risk (18).
The impact of metformin use on the occurrence of cognitive impairment is unclear: protective role in a cohort, risk factor in a case-control study. In one studiy, metformin + hypoglycemic sulfonamide combination therapy is associated with a decrease in AD compared to untreated diabetic patients (HR = 0.65; CI95 [0.56 – 0.74]) (44).
Hypotestosteronemia in elderly men would be associated with an increase in AD (RR = 1.48; CI95 [1.12 – 1.96]). However, the authors do not detail their definition of «elderly male» and report that the studies included in their meta-analysis have different definitions for hypotestosteronemia (45)

Psychiatry, neurology and anesthesia

A meta-analysis associated history of depression and increased risk of AD: RR = 1.90 (CI95 [1.55 – 2.33]) in cohort studies (46). Late-life depression is associated with increased risk of AD (37).
In 2015, Harrington et al. studied the relationship between depression and Aβ plaques in a healthy, older adult population. The majority of included studies found a significant increase in Aβ levels in depressed patients. However, the authors mentioned many biases in the 19 cross-sectional studies included (47).
Long-term benzodiazepine users had an increased risk of dementia compared with never users: RR = 1.49 (CI95 [1.30 – 1.72]). The risk of dementia increased by 22% for every additional 20 defined daily dose per year (RR = 1.22 ; CI95 [1.18 – 1.25]) (48).
Peripheral and central hearing impairment were associated with a risk of AD (49). The RR was estimated at 2.82 (CI95 [1.47 – 5.42]) between hearing impairment and risk of cognitive impairment (50).
Head injury with loss of consciousness could also be a risk factor for AD, according to several studies, with an estimated RR of 1.82 (CI95 [1.26 – 2.67]) (51). In a subgroup analysis, OR is significant only for men (OR = 2.29 ; CI95 [1.47 – 2.06]), not for women (52).
A review of 6 epidemiological studies reports that an essential tremor would be associated with an increased risk of AD (53).
A meta-analysis of 15 case-control studies did not associated general anesthesia and AD (OR = 1.05; CI95 [0.93 – 1.19]) (54).

Environmental

Several literature reviews have highlighted a possible link between AD and exposure to extremely low frequency electromagnetic fields, particularly in a professional context (electrician, electronics technician, welder…) (55–57). The latest meta-analysis (20 studies) highlighted the numerous biases (particularly publication bias) and heterogeneity of the populations being compared, without a dose-response relationship. They suggested a higher risk for train drivers (RR = 2.94; CI95 [1.15 – 7.51]) than for welders (RR = 1.54; CI95 [1.00 – 2.38]) or electricians (RR = 1.18; CI95 [1.01 – 1.37]) (58).
A positive association was observed between pesticide exposure and AD (OR = 1.34; CI95 [1.08 – 1.67]) (59).

Diet, nutrients

Regular use of anti-acids (with aluminium) has no relationship with increased risk of AD: a meta-analysis estimated OR for case-control studies at 1.0 (CI95 [0.8 – 1.2]) and for prospective studies at 0.8 (CI95 [0.4 – 1.8]) (60). A review highlighted a possible relationship between aluminium in drinking water and AD, but noted inconsistencies (61).
A review showed no association or inconsistent associations between vitamin B12 intake and cognitive function (62).
A literature review of 57 studies concluded that there is no evidence to support a possible recommendation for the preventive use of zinc for AD (63).
A decrease in manganese plasma levels may also be associated with an increased risk of AD (64).
In one review, magnesium was not associated with AD, but a lowered level of magnesium within the cerebrospinal fluid increased the risk of AD (65).
A combined meta-analysis of 3 meta-analyses estimates an HR of 0.92 (CI95 [0.88 – 0.97]) in favour of an inverse (protective) relationship between mediterranean diet and risk of AD (66). In 2017, Yusufov et al. published a systematic review of the literature in which 10 of the 12 studies included found an association between Mediterranean diet and reduction in the risk of AD (67).
Van de Rest et al. studied the impact of the Healthy Diet Indicator diet, based on World Health Organization recommendations: 6 of the 6 cross-sectional studies and 6 of the 8 longitudinal studies included found an association between diet adequate to HDI recommendations and decreased risk of cognitive impairment (66).
The intake of unsaturated fatty acids (notably via fish consumption) is associated with a reduction in the risk of AD and dementia (68). This association is mainly found in cross-sectional studies (5/5), less in cohorts (7/18); a meta-analysis of 5 studies estimated RR at 0.67 (CI95 [0.47 – 0.95]) (28). A role of the intestinal flora has been mentioned in the pathogenesis of Alzheimer’s disease (69).
In the review by Yusufov et al. 7 of the 9 studies included found that dietary intake of vitamin E was associated with a decreased risk of AD (67). Beydoun et al. report a similar association, but in 9 of 21 cohort studies and 2 of 6 cross-sectional studies included in their review (34).
An overview of systematic review suggested that Ginkgo biloba extract has potentially beneficial effects for people with dementia when it is administered at doses greater than 200mg/day for at least 5 months (70).
Yusufov et al. note that 4 of the 5 included studies found an association between folate (vitamin B9) intake and decreased risk of AD (67).
Plasma vitamin D concentration greater than 560 ng/mL is associated with minimal gain at the MMSE level estimated at 1.16 points (CI95 [0.46 – 1.85]) in a meta-analysis (71). Several confounding biases are possible, including better sun exposure of non-dementia patients.
An other meta-analysis showed significantly lower plasma levels of folate, vitamin A, vitamin B12, vitamin C, and vitamin E (P < .001), non-significantly lower levels of zinc (P = .050) and vitamin D (P = .075) in AD patients, and non-significant differences for plasma levels of copper and iron; this lower plasma nutrient levels could indicate that patients with AD have impaired systemic availability of several nutrients (72).

 

Discussion

Principal results

Cardiovascular risk factors are an important part of the reviews selected in this research work. Thus, most of the journals included report an association between the different cardiovascular risk factors and the occurrence of AD.
Medically, several reviews suggest that a history of depressive syndrome is associated with an increased risk of AD. Hearing, central or peripheral impairment also seems to increase the risk of AD. However, the studies do not allow us to conclude whether the risk is corrected with the use of hearing aids.
On the environmental level, intellectual inactivity and low educational level (less than 8 years of study) seem to be the most associated factors in this research with an increased risk of AD.
Unlike intellectual inactivity and low educational level, the authors of the reviews hypothesize that a higher level of education would be associated with a lower risk of AD.
On the drug side, it would appear that the use of calcium channel blockers is associated with a decrease in dementia (but not in AD in particular). For IECs, the results point to a decrease in cognitive disorders, but not in the occurrence of dementia.
In terms of diet, the Mediterranean diet is the most studied, and seems to be associated with a decrease in the risk of AD. The results of the various reviews also seem to point towards a protective role for a diet rich in unsaturated fatty acids ω.
Dietwise, no relationship has been found between plasma or cerebrospinal zinc levels and the incidence of dementia or AD. Similarly, there is no reported link between zinc supplementation and the prevention of AD.
The same applies to vitamin B or vitamin E supplementation. Plasma magnesium levels also do not appear to be associated with a risk of AD.
The absorption of aluminum, through drinking water or medication, does not appear to be associated with the development of AD or dementia.
Medically, the use of ARB2 or diuretics does not appear to affect the onset of dementia. More anecdotally, general anesthesia did not show an association with the occurrence of AD either.
From an environmental perspective, it appears that HSV1 and HHV6 infections are not associated with the occurrence of AD.
Alcohol consumption presents contradictory results. Some studies tend to show a protective effect of alcohol on the occurrence of dementia and AD, while others suggest the opposite relationship.

Strengths and limitations

Alzheimer’s disease is a frequent pathology, with a poor prognosis, without curative treatment available in 2018. Knowing how to prevent it better is an important issue, and a lot of research is being carried out in this direction. The large number of literature reviews and meta-analyses carried out on the subject can make a global approach difficult. Our synthesis is intended to be an overview of the various literature reviews in 2018, in order to take stock of what seems likely, what seems doubtful and what is not yet well studied. This is a substantial work based on 90 literature reviews and meta-analyses. Our results are consistent with the previous syntheses carried out on the same subject.
It is likely that the initial research equation may have caused a selection bias in the results presented by the PubMed database.
A publication bias is to be mentioned; in order to limit it, we completed our research with a search in the encyclopedia «UpToDate» and in French-speaking journals not indexed via LiSSa.
An «interpretation» bias is possible in the inclusion of the different reviews.
This study assumes that all included reviews and meta-analyses are of equal quality and value, which is not the case. The various reviews may be sources of bias, which may have influenced the results presented. Many confounding biases can exist in studies and be amplified by literature reviews.
Moreover, the subject matter is vast and complicated, it is not easy to approach it in its entirety, through very heterogeneous publications, which highlight different pathophysiological hypotheses in order to explain in a rational and scientific way the possible suspected association.

Perspectives

We have only studied literature reviews; risk or protective factors may exist, have been studied in retrospective or prospective studies that have not yet been reviewed.
As studies and reviews progress, some clearly identified risk factors can be modified, particularly in the cardiovascular and environmental fields. It may be interesting to study the impact of prevention on targeted modifiable risk factors in order to assess the impact on the incidence of AD and dementia.
On the other hand, some of the factors studied appear to be «doubtful», and it seems appropriate to carry out additional studies. For example, it may be relevant to study the impact of H. pylori eradication on the occurrence of AD, in order to determine whether systematic treatment can be an axis of AD prevention.

 

Conclusions

Specifying the risk factors for AD is a major issue to better prevent or delay its appearance. Current studies identify many modifiable risk factors. The impact of these modifiable factors appears to be greater and more reliable than genetic factors. Risk factors can induce AD, anticipate it or aggravate it; protective factors can have a specific effect or an effect limiting the impact of a pathology (antidepressant, anti-hypertensive…). To our knowledge, the cumulative effect of the various risk factors has not been studied.
Identifying patients at risk is important in order to prevent or delay the onset of AD, and also to limit high-risk behaviors (driving, treatment management, gas handling), anticipate dependency, limit financial risks (legal protection) or integrate a research protocol.
Synthesizing the literature reviews also highlights doubtful risk factors and unstudied risk factors. In addition, some risk factors have emerged in recent articles, but have not yet been studied in literature reviews. Studying these factors also makes it possible to make physiopathological assumptions that will lead to a better understanding of the mechanisms involved in the development of AD.

 

Ethics approval and consent to participate: Not applicable.

Consent for publication: Not applicable.

Availability of data and material: Not applicable / all articles used in this overview are cited in the text.

Competing interests: The authors declare that they have no competing interests.

Funding: Not applicable.

Authors’ contributions: MR, VR reviewed the literature and were involved in manuscript preparation and revision. EC, ED, GS, PAH, FP, SG, RB were involved in manuscrit revision. All authors read and approved the final manuscript.

Acknowledgements: The authors acknowledge fellow colleagues for the discussions. We apologize to authors whose studies were not cited due to space constraints.

 

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AN ACTION PLAN TO FACE THE CHALLENGE OF DEMENTIA: INTERNATIONAL STATEMENT ON DEMENTIA FROM IAP FOR HEALTH

 

H. Chertkow, on behalf of the Research Executive Committee of the Canadian Consortium on Neurodegeneration in Aging* and the International IAP committee on Dementia**

 

Corresponding Author: H Chertkow, 3755 chemin de la Côte-Ste-Catherine, Montréal (Québec), Canada, H3T 1E2, 514 340-8222, howard.chertkow@mcgill.ca

* The following individuals are members of the Research Executive Committee of the Canadian Consortium on Neurodegeneration in Aging: Drs. Howard Chertkow, Professor of Neurology, McGill University, Montreal, Canada; David B. Hogan, Professor of Geriatric Medicine, University of Calgary, Calgary, Canada; Sandra Black, Professor of Medicine, University of Toronto, Toronto, Canada; Howard Feldman, Professor of Neurology, University of British Columbia, British Columbia, Canada, and University of California, San Diego, San Diego, CA; Serge Gauthier, Professor of Neurology, McGill University, Montreal, Canada; Kenneth Rockwood, Professor of Medicine, Dalhousie University, Halifax, Canada; Mario Masellis, Associate Professor of Medicine, University of Toronto, Toronto, Canada; Katherine McGilton, Senior Scientist, Toronto Rehabilitation Institute, University of Toronto, Toronto, Canada; Mary C. Tierney, Professor, Department of Family and Community Medicine, University of Toronto, Toronto, Canada; Jane Rylett, Professor of Physiology and Pharmacology, Western University, London, ON, Canada; Dr. Pascale Léon, Lady Davis Institute, Montreal, Canada; Victor Whitehead, Lady Davis Institute, Montreal, Canada.

** The following individuals are members of the International IAP committee on Dementia: Ama de-Graft Aikins, Professor of Social Psychology, Dean International Programmes Regional Institute for Population Studies (RIPS), University of Ghana, Accra, Ghana; Liaquat Ali, Fellow, BAS and Vice Chancellor, Bangladesh University of Health Sciences, Dhaka, Bangladesh; Laila Asmal, Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch, South Africa; Hayrunnisa Bolay Belen, Professor of Neurology, Algology, Head of Algology, Director of Neuropsychiatry Centre & Director of Neuroscience PhD Program, Ankara, Turkey; Carol Brayne, Professor of Public Health Medicine, Director, Institute of Public Health, University of Cambridge, Cambridge, UK; Josef Priller, Deputy Director, Department of Psychiatry und Psychotherapy CCM, Charité – Universitätsmedizin Berlin, Germany; Lars Lannfelt, Professor, Department Public Health and Caring Sciences/Geriatrics, Uppsala University, Uppsala, Sweden; Alan Leshner, Chief Executive Officer, Emeritus, American Association for the Advancement of Science, Washington DC, USA; Ninoslav Mimica, Head of Department for Biological Psychiatry and Psychogeriatrics, University Psychiatric Hospital Vrapče, School of Medicine, University of Zagreb, Zagreb, Croatia; Maryam Noroozian, Professor of Neurology, Founder & Director: Memory and Behavioral Neurology Division, Department of Psychiatry, Faculty of Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran; Adesola Ogunniyi, Professor of Medicine, College of Medicine, University of Ibadan, Ibadan, Nigeria; Juha Rinne, Professor of Neurotransmission, University of Turku and Turku University Hospital, Turku, Finland; Paolo Maria Rossini, Full-Professor of Neurology, Chair of Institute of Neurology at the Faculty of Medicine, Catholic University, University Policlinic A. Gemelli Foundation, Rome, Italy; Jonas Alex Morales Saute, Neurogeneticist at Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; Philip Scheltens, Director of the Alzheimer Centre, VU University Medical Center Amsterdam, Amsterdam, Netherlands; Ales Stuchlik, Head, Department of Neurophysiology of Memory Institute of Physiology, the Czech Academy of Sciences, Prague, Czech Republic.

J Prev Alz Dis 2018;5(3):207-212
Published online June 20, 2018, http://dx.doi.org/10.14283/jpad.2018.27

 


Abstract

An international committee set up through the IAP for Health met to develop an action plan for dementia. Comprehensive international and national initiatives should move forward with calls for action that include increased public awareness regarding brain health and dementia, support for a broad range of dementia research objectives, and investment in national health care systems to ensure timely competent person-centred care for individuals with dementia. The elements of such action plans should include: 1) Development of national plans including assessment of relevant lifecourse risk and protective factors; 2) Increased investments in national research programs on dementia with approximately 1% of the national annual cost of the disease invested; 3) Allocating funds to support a broad range of biomedical, clinical, and health service and systems research; 4) Institution of risk reduction strategies; 5) Building the required trained workforce (health care workers, teachers, and others) to deal with the dementia crisis; 6) Ensuring that it is possible to live well with dementia; and 7) Ensuring that all have access to prevention programs, care, and supportive living environments.

Key words: Risk reduction strategies, risk factors, life course, public awareness, national plans.


 

Introduction

This statement has been prepared by an international committee set up through the InterAcademy Partnership for Health (IAP-H), which is a component of the The InterAcademy Partnership (IAP). The InterAcademy Partnership (IAP) was launched in 2016, and currently has a membership of 135 academies of science, medicine and engineering from around the world. These include both national academies/institutions as well as regional/global groupings of scientists. This statement is modified from a position paper that was initially commissioned by the Canadian Academy of Health Sciences, and written, approved and submitted by the Research Executive Committee (REC) of the Canadian Consortium on Neurodegeneration in Aging (CCNA). Members of the Research Executive Committee of the CCNA and the International IAP committee on Dementia also appear at the end of the statement.
The proportion of the world’s population that is 65 years of age or greater has grown over the last number of decades, and this trend will continue. Advancing age is the greatest known risk factor for dementia (1, 2). If there is no change in age-standardized prevalence, societal aging is predicted to nearly triple the number of individuals living with dementia worldwide by 2050 (3, 4). It is estimated by that year the number of individuals with dementia will rise from 47.5 million people to an estimated 135.5 million with most of this increase occurring among people living in low- and middle income countries (2). Aside from the personal cost of dementia, these rising numbers will be associated with an economic burden. The 2015 global estimated cost of dementia was US $818 billion and is expected to be a trillion dollars by 2018 (5).
The World Health Organization (WHO) now recognizes dementia as a public health priority (6, 7). To respond to this challenge, a global series of actions initiated during the UK G8-Presidency in 2013 were undertaken by bodies such as the Organisation for Economic Co-operation and Development (OECD; (8)), Alzheimer’s Disease International (ADI) and by the World Dementia Council (WDC; (9)).

 

Dementia Overview

Dementia is an acquired, persisting and typically progressive decline in cognitive abilities, affecting learning and memory, language, and/or reasoning that is severe enough to interfere with independence in everyday activities. It becomes more common with increasing age during adulthood. Besides cognitive impairment, dementia is often associated with debilitating neuropsychiatric symptoms, such as agitation, psychosis, sleep disturbance, depression, anxiety and apathy (10). Dementia can arise from numerous conditions acting alone or in combination (11, 12). For many it is due to a neurodegenerative process, an umbrella term for a number of debilitating conditions that result in the progressive degeneration and/or death of neurons (5). Alzheimer disease is the most common neurodegenerative cause of dementia and is currently incurable. A mixture of brain diseases often underlies dementia, with many people showing changes consistent with both Alzheimer and cerebrovascular disease (13, 14). Dementia is usually a slowly progressive illness where the diagnosis is made after the process has been present for years (15).
Risk factors and conditions (such as smoking, or diabetes) commonly associated with vascular conditions (stroke, heart disease) are also known to be associated with dementia (16, 17). Frailty itself is a considerable risk factor for dementia (18). Parkinson’s disease is closely associated with the development of dementia (19). The majority of older individuals with dementia have mixed pathology in their brain (11, 12, 20, 21).
While young onset (under 60 years) dementia is seen infrequently in many countries, this may not be the case in countries with high HIV prevalence. The HIV epidemic is concentrated in younger people of low-income countries, particularly in Sub-Saharan Africa, where young people may subsequently bear a disproportionately greater burden of dementia (22).
Women are at both greater risk of developing dementia and then living longer with the condition after its onset (23). Women also provide most of the informal (unpaid) care for people living with dementia.
While there are currently no cures for the neurodegenerative conditions that lead to dementia, emerging research suggests that some life-style factors (e.g., engaging in physical activity, managing blood pressure, selected forms of cognitive training) may have the potential to delay, if not prevent, its onset (24-27). Population studies have suggested additional associated risk and protective factors, which require research to evaluate their potential as primary prevention intervention targets (28, 29). The progress to date in developing effective pharmacological treatment options has been disappointing (30-32), underscoring the need to understand better what contributes to the dementia syndrome in different generational cohorts as well as in different populations (33).
A key area for research and support is the development and dissemination of improvements for the care provided to people living with dementia including compassionate and appropriate end-of-life care (34-37). Greater acceptance and inclusion of people living with dementia within communities is increasingly seen as an important factor in improving their quality of life and minimizing disability (7, 38). The needs of patients and their families change along the course of dementing illnesses and it is necessary to gear support and therapy for the different stages of the disease.

 

A Call to Action

Because of these issues, developing a comprehensive strategy internationally to address the challenges of dementia will require wide consultation followed by the long term implementation of a comprehensive, integrated and responsive series of actions. Most initiatives will be nationally based, but additional international collaborations to address dementia will also be advantageous. The nationally based initiatives will generally share similar high-level goals and principles to address this global health problem. We call for countries within regions that have resources, to establish a network that can support other countries similar to them in their approach to dementia. The goals and principles of a call to action would include addressing the following broad areas: (a) Increasing public awareness – educating the general population about dementia, how to maintain brain health, and on the importance of addressing this health challenge, accepting people with dementia as they are, and accommodating to their remaining abilities; (b) supporting fundamental research to find and implement effective approaches (both pharmacological and non-pharmacological) to delay, prevent, slow down, treat, ameliorate, and eventually cure the common causes of dementia; (c) investing in national health care systems – this would entail both training a sufficient number and mix of providers as well as building the necessary infrastructure to ensure timely, competent person-centered care is available to those living with dementia and their caregivers through all stages of the illness.
Our Call to Action is one which aims at developing an evidence-based and a public health orientated approach. Ultimately, this should include a clear assessment for each population of the potential for primary prevention (upstream prevention), secondary prevention (early detection followed by effective treatment, considered to be likely more effective at that stage than later) and tertiary prevention (mitigation of dementia and its ramifications through various therapies and end-of-life care for those with dementia).

 

Elements of an Action Plan to Face the Challenge of Dementia

An action plan to face the challenge of dementia in its global context must include a concerted and coordinated series of actions from policies, to research, to care, to social  inclusion. Here are seven key elements of such an action plan.

National dementia plans must be established

National plans to combat dementia have been initiated in 29 countries/states since 2005. There is a global plan on dementia being developed by the WHO (6, 7) and the first regional plan on dementia in the Americas, published by the Pan American Health Organization (PAHO) in October 2015 (See the website of ADI https://www.alz.co.uk/dementia-plans/ for a list of national plans currently underway as well as countries currently lacking national plans). Canada is the only G7 country without a national dementia plan (39).
Each country should develop a national plan coherent with its health care goals which could coordinate activities, harmonize where appropriate with international efforts, promote the sharing of successful local initiatives, address identified gaps, ensure efficient use of resources, and mobilize further investment in all aspects of dementia including care and research. A national plan would acknowledge dementia as a public health priority and heighten awareness of this daunting health challenge.
As a first step, towards such plans, we propose that a national dementia status report should be carried out in as many countries with resources as possible. Such a status report for each region would be wide-ranging, including burden of all dementia types, comorbid disorders, risk factors, therapeutic approaches and care systems.
More research is necessary to establish the strength and interaction of lifecourse risk and protective factors relevant to dementia. Nevertheless, assessment of the “exposome”, potential risk and protective factors for each population, would be an important part of this report (40, 41). These should establish, for key lifestages, the balance in those populations of positive and negative features for brain health (42, 43). This would encompass a broad range of environmental factors such as maternal health, early life health, infections, education, vaccination, as well as adverse exposures such as poor housing, smoking, poor diet, and exposure to noxious substances.
A 5-year follow-up report should be planned to document the impact of national policies (public awareness, risk factors, care systems, etc.) and the creation of a national dementia strategy.

Increase investment in national research programs on dementia

The investment in medical research varies widely across countries. In 2016 the American investment in dementia research was US $936 million, which translates to US$2.93 per capita (23). In contrast, the Canadian investment in research on dementia was smaller (less than a quarter per capita of what is invested in the USA) (44). Overall, developed countries do not adequately invest in dementia research when compared to the funding of research on other conditions such as cancer and heart disease even though the cost of caring for persons with dementia is estimated to be greater than that for dealing with either of the other two conditions (45, 46). It has been stated that a goal of 1% of the national annual cost of dementia should be steered into dementia research programs (Dementia in Canada: A National Strategy for Dementia-friendly Communities, Report from Canadian Senate, 2016 (6)). This additional investment in each country will have to be thoughtfully allocated and managed. Broad coordination within each country should be organized for best use of research funds. Governance and prioritization of dispersal of these funds must also involve individuals living with dementia and their caregivers, the research community, and practitioners.

This investment must span all aspects of dementia research

Allocated research funds should support a broad range of activity from biomedical investigation to inquiries dealing with clinical aspects, health systems and services research. There must be fundamental research to unveil the mechanisms involved in the onset of neurodegenerative diseases and hopefully pave the way to a specific and effective pharmacological treatment. In addition, research to gain better insight into understanding the social cultural and environmental factors that affect the health of populations is essential. Investments should target national research capacity, supporting knowledge transfer, addressing the needs of unique populations (for example, indigenous people and those living in rural and remote communities (47-49)), investigating sex and gender differences in dementing conditions, and embracing ethical and social dimensions (50, 51).
There is now considerable potential for earlier diagnosis of various forms of dementia using clinical, imaging, and biomarker support (52). The advantages and potential of early diagnosis is a critical focus of research in Western countries (53-57). Attention must now be paid to delineating the optimal approaches to early diagnosis and establishing the risks and benefits of translating this knowledge into health care policy.
The neuropsychiatric (behavioral and psychological) symptoms of dementia need more attention given their strong impact on quality of life, caregiver burden and rate of institutionalization (10, 58, 59 60). Future research into the prevalence, etiology and therapy (including randomized controlled trials) of neuropsychiatric symptoms of dementia is needed.
There must be research investment into understanding what combinations of modifiable lifestyle factors across the lifecourse increase and decrease the risk, of developing dementia with aging (26, 61). This is not a one-size-fits-all syndrome across the globe. The combinations of relevant risk factors may vary in different cultures and communities. The most effective preventative and public health strategy for dementia will only emerge when the fullest understanding of these factors is achieved.
Specific attention should be devoted to the support of social research aimed at identifying the actual needs of subjects with dementia and their caregivers (62-64). The general purpose of such investigations would be the planning of multifaceted interventions encompassing environmental, psychological, medical and social support.

Risk reduction strategies should be instituted

While there is still a considerable amount to learn about the full interplay of risks, governments must support national risk reduction and empowerment strategies for the public and support the efforts of health professionals to promote healthy brain aging. Current evidence can be used to empower the public and health professionals to act in ways that will reduce the risks of all dementia types developing, postponing the appearance of their clinical manifestations, and optimizing everyday functioning in meaningful social activities and roles. The focus of such risk reduction would include treatment and prevention of vascular risk factors – hypertension, obesity, diabetes, smoking, and high-calorie diets, and treatment of HIV to prevent HIV-related dementia. It would also include risk reduction to address sleep problems, illiteracy, head trauma, malnutrition, and physical inactivity in addition to other region-specific risk factors (5).
Risk reduction at the individual level must be supplemented by evidence-based structural and legislative alterations that support these reductions. Smoking legislation, strategies for excessive alcohol risk reduction, reduction of dietary salt, legislation to reduce head injuries are only a few of the risk reduction strategies that can be undertaken by governments to affect the occurrence of dementia in the population. Such governmental interventions will lead to less inequality because they benefit the disadvantaged as well. The  WHO Global Noncommunicable  Diseases Action Plan 2013-2020 focuses on many of these elements (6).

The required workforce must be planned and trained

Workforce requirements to deal with the increasing number of persons with dementia must be determined and steps taken to ensure the required workforce is both trained and supported in their activities. A well trained and supported workforce of the right mix and number to deal with the needs of this emerging population is required. In each country, a national workforce plan will have to be created and implemented with the active involvement of local and regional authorities.
The full breadth of necessary trainees will only emerge after appropriate evidence-based strategies for risk reduction emerge. The workforce trained will initially be focused on the elderly, and the health care sector, but addressing modifiable risks (for example, limited education, early childhood nutrition) implies an investment in teachers, nutritionists, and a host of other professionals in the future.

We must ensure that it is possible to live well with dementia

When a diagnosis of dementia is made, an individual should not be constrained to abandon her/his social role and participation. Creating the conditions within a country where one can live well with dementia includes ensuring that the public is aware of dementia in all its complexity, that there are accommodations in the environment (including work) to compensate for changing abilities, that there is adequate protection against abuses of all kinds against individuals living with dementia, and legal that rights are not automatically withdrawn from people living with dementia. Cooperation between academies and local administration should be encouraged so that all the needs of persons living with dementia and of their caregivers can be assessed and met.

Access to prevention and care should be made available to all

To the extent possible, access to preventive programs, systems of care, and supportive living environments should be made available to all citizens with, or at risk of, dementia (49, 65-67)

 

The Future of the Dementia Challenge

Dementia will be part of the global landscapes for many decades, reaching levels that are at least twice the current 2016 values. Indeed, even if research could provide the means of eradicating brain diseases causing dementia tomorrow, numerous individuals would already be on the trajectory to dementia. Brain diseases causing dementia are now known to start many decades before any clinical signs. For these reasons, a total solution will not be available for some time to come. This is why the member Academies of IAP for Health are focusing attention on the necessity of engaging in an action plan for dementia which is balanced and designed to address all aspects of the challenge, especially the wellness of those living with dementia and their caregivers.

 

Conflict of interest: Dr. Chertkow reports grants from the Canadian Institutes of Health Research (Foundation grant) and the Weston Foundation (Canada). He also reports clinical trial conduct-related fees from TauRx, Hoffmann-Laroche, and Merck Inc. In addition, he reports indirect support from the Alzheimer Society of Canada (funding partner of the Canadian Consortium on Neurodegeneration in Aging). No other disclosures relevant to the manuscript.

Open Access: This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, duplication, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

 

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ALZHEIMER’S ASSOCIATION: INITIATIVES & PUBLIC HEALTH PERSPECTIVE

 

H.M. Snyder, M.C. Carrillo

 

Medical & Scientific Relations, Alzheimer’s Association, Chicago, IL, USA

Corresponding Author: Maria C. Carrillo, Ph.D., Alzheimer’s Association, Medical & Scientific Relations, 225 North Michigan Avenue, Suite 1700, Chicago, IL 60601, Phone: (312) 335-5722, Email: mcarrillo@alz.org

J Prev Alz Dis 2016;3(4):178-180
Published online August 23, 2016, http://dx.doi.org/10.14283/jpad.2016.111

 


 

Introduction

There are an estimated 47 million people worldwide living with dementia today (1) and without a way to stop or slow the progression, this number is expected to triple by mid-century (1).  A recent report by the Alzheimer’s Association suggests that if onset of the most common cause of dementia, Alzheimer’s disease (AD), was delayed by 5 years, there will be significant reduction in both the numbers of individuals affected and the cost of care for these individuals (2).  There is a clear urgency for therapies and interventions to slow, stop or prevent AD and related dementias.    
As the leading voluntary health organization dedicated to AD, the Alzheimer’s Association is an adamant supporter of all legitimate avenues of scientific investigation – from basic research into the causes of the disease through clinical trials (3).  There are over two-hundred clinical trials on-going today in the United States and an even greater number in the global landscape, examining potential pharmacological disease-modifying therapies to stop or slow the progression of disease (4). However, recent evidence suggests that strategies to reduce the risk of developing dementia may be of growing import for reducing the number of individuals affected by dementia.  Thus, there will be a need for the pipeline of pharmacological treatments to include intervention strategies that combine pharmacological and behavior modification approaches.  
A combined approach is consistent with public health messaging and intervention delivery seen in other non-communicable diseases, such as diabetes, cancer and heart disease (5).  As evidence continues to emerge for a similar approach in AD and related dementia, there is a need for on-going evaluation of the scientific data surrounding these strategies. This discussion explores the emerging pipeline of evidence surrounding lifestyle interventions and Alzheimer’s Association public health messaging and programs.  

 

Impact of Lifestyle Factors on Cognitive Decline & Dementia   

Age is the greatest risk factor for AD.  However, family history and heritability also play a significant role in later life risk for disease. To date, approximately thirty or more genetic risk factors have been found to be associated with increased prevalence of late-onset AD (LOAD) (6).  The exact function of many of these genes is still being investigated, including the potential interaction of environment and epigenetics; neither of these areas is well understood. Although it is known age and genetics play a role in risk, these are factors that today cannot be modified by behavior.  The 2010 National Institutes of Health (NIH) convened State of the Science conference found insufficient evidence to support association between modifiable factors and AD risk (7). Since 2010, there are numerous studies providing strong evidence for behavioral modifications that may impact overall brain health.   
One example, data from the Framingham Heart Study (FHS) suggests there may be a progressive, decades long decline in dementia incidence among older people in this specific population.  The research team examined possible contributing factors; key among these may be the rising levels of education and reductions in vascular risk factors (8). Data from the United Kingdom, the Netherlands, and Germany suggest similar trends in their population-based studies (9-11). Langa et al observed the broader landscape of these decreased incidence trends, while prevalence continues to rise, that there are a number of factors, especially rising educational levels and more aggressive treatment of cardiovascular risk factors such as hypertension and high cholesterol that may lead to improved brain health and the subsequent decline of dementia in certain geographical areas of the world. However, it is unclear if this trend will continue in the context of rising levels of obesity and diabetes and how the low and middle income countries may also be impacted (12).
In further, the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) examined the idea of a multimodal approach to reducing risk for cognitive decline in a cognitively healthy aging population in Finland.  FINGER was the first randomized control trial on multivariate risk factors and cognitive decline, and suggested that participants with higher cardiovascular risk profiles benefited on overall cognitive performance and executive function with a multi-component lifestyle intervention. This specific intervention involved physical activity, management of cardiovascular risk factors, nutritional guidance, cognitive training and social activities (13).
Building off both the growing number of population and intervention studies like FINGER, the Alzheimer’s Association undertook an evaluation of the existing body of published evidence to draw conclusions and summarize the state of the science from a population based perspective. In June 2015, the Alzheimer’s Association published a summary of data regarding modifiable risk factors related to cognitive decline in aging and dementia. As a result of this review, the Alzheimer’s Association issued the following recommendations for the global community based on the level of evidence for modifiable risk factors (5). The Association’s public statement, from a population based perspective, is:  

(1)    Regular physical activity and management of cardiovascular risk factors (e.g. diabetes, obesity, smoking and hypertension) have been shown to reduce the risk of cognitive decline and may reduce the risk of dementia;
(2)    A healthy diet and lifelong learning/cognitive training may also reduce the risk of cognitive decline.

In further support of the Association’s recommendations (5), the Institute of Medicine (IOM) report discussing cognitive aging and cognitive decline reached a virtually identical conclusion (14).
Since 2015, two additional European-led multimodal lifestyle intervention trials have published initial results, the Multidomain Alzheimer’s Prevention Trial (MAPT study) and the Prevention of Dementia by Intensive Vascular Care (preDIVA) study.  The MAPT study, led by Vellas and colleagues in France, was designed to assess the efficacy of isolated omega-3 fatty acid supplementation, a multi-domain intervention (including nutritional counseling, physical exercise and cognitive stimulation), or a combination of the two interventions on cognitive functions in 1,680 individuals aged 70 years and older for a period of three years (15).   The original three year intervention was completed in March of 2014 and was reported at the 8th Clinical Trials in Alzheimer’s Disease conference in Barcelona, Spain this past November (2015). The results suggest that omega 3 fatty acid (DHA) plus multi-domain intervention group resulted in a statistically significant improvement in subgroup analysis of individuals with low DHA (16, 17).  Vellas and colleagues are currently considering a revised multimodal intervention study similar to MAPT with a focus on the low DHA population for evaluation.
Most recently, the Netherlands led Prevention of Dementia by Intensive Vascular Care (preDIVA) trial reported their six year results (18, 19).  The preDIVA study was a nurse-led vascular care intervention to determine effect on all-cause dementia in a cognitively healthy population. The preDIVA Study did not meet its primary outcomes for all cause dementia within their study population, however, fewer cases of non-AD dementia were observed in the intervention group compared to the control group.  In addition, there were fewer cases of incident dementia in the subgroup of people in the study with untreated hypertension who were adherent to the intervention (18, 19).  Multi-domain interventions continue to be of significant importance to the field, and further work will enable the field to more closely define optimal interventions or target populations.
As evidence continues to develop, the Alzheimer’s Association evaluation of our public health statements will also evolve.  For instance, during the Alzheimer’s Association International Conference (AAIC) 2016 in Toronto, Canada, Edwards et al presented 10-year results from the Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) study, which examined the impact of several types of brain training on 2.785 cognitively health older adults (average age 73.6).  After 10 years, only the speed of processing training group showed a statistically significant impact on cognitive, with a 33 percent reduction (p=0.012) in new cases of cognitive impairment or dementia.  This was further enhanced in participants who participated in booster sessions of the cognitive training – 11 or more sessions of the computerized training (48 percent reduction) (20).  The authors suggest there may be specific cognitive training interventions benefit long term brain health and possibly also dementia.  

 

New Directions for Public Health Messaging 

The World Health Organization (WHO) led a year-long intensive research prioritization exercise, and identified prevention and risk reduction as a top research focus.  Further, during the WHO- hosted first Ministerial Conference on Global Action Against Dementia in March 2015, 160 delegates adopted a Call for Action to reduce the global burden with a discussed emphasis that by sharing a commitment among countries to put in place the necessary policies and resources for care of people with dementia, promote research agendas, and give adequate priority to action against dementia in national and global political agendas, there could be forward action (21).  
The existing and growing evidence underscores the need to communicate to the broader population what the science indicates and to do so with diverse stakeholders and consistent messaging.  Specifically, certain health behaviors known to be effective for diabetes, cardiovascular disease, and cancer are also good for brain health and for reducing the risk of cognitive decline.  Since the 2015 publication, the Association has led several large scale efforts to further and more broadly communicate these recommendations.  It has engaged in a nationwide (US-based) campaign on the “10 Ways to Love Your Brain” and a community based educational program “Healthier Habits for a Healthier You” that is offered throughout the entire Alzheimer’s Association network.  Both these efforts are designed to share the latest research and practical information on ways to maintain overall brain health as we age with consumers (22).  

 

Conclusions   

There is a growing level of evidence that lifestyle factors play a considerable role in risk associated with cognitive decline and dementia.  It is clear that there are still many unanswered questions and significant uncertainly with the respect to the relationship between individual risk factors and dementia (for example, to what degree there is a causal relationship).  Additionally, there is a need for more research on risk reduction, prevention and brain health – both in longitudinal, population-based cohort studies and randomized controlled trials that address modifiable risk factors.  
Continued efforts of the WHO, the World Dementia Council (a convening group of individuals from around the world with diverse expertise in dementia), the Alzheimer’s Association, the National Institutes of Health (US) and others must continue to drive and advance the overall public health discussion and necessary research in communities around the world. There has never been a better time to define and distribute global messaging on public health for dementia.

 

Conflict of Interest: HM Snyder and MC Carrillo are both full time employees of the Alzheimer’s Association.

 

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