jpad journal

AND option

OR option

TARGETING LIFESTYLE BEHAVIOR TO IMPROVE BRAIN HEALTH: USER-EXPERIENCES OF AN ONLINE PROGRAM FOR INDIVIDUALS WITH SUBJECTIVE COGNITIVE DECLINE

 

L.M.P. Wesselman1, A.K. Schild2, A.M. Hooghiemstra1,3, D. Meiberth2, A.J. Drijver4, M.v. Leeuwenstijn-Koopman1, N.D. Prins1, S. Brennan5, P. Scheltens1, F. Jessen2,6, W.M. van der Flier1,7, S.A.M. Sikkes1,8

 

1. Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands; 2. Department of Psychiatry, University Hospital Cologne, Medical Faculty, Cologne, Germany; 3. Department of Medical Humanities, Amsterdam Public Health Research Institute, Amsterdam UMC, Vrije Universiteit Amsterdam, De Boelelaan 1089a, 1081 HV Amsterdam, The Netherlands; 4. Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Neurology, The Netherlands; 5. The Adapt Centre, & The Institute of Neuroscience, Trinity College Dublin; 6. German Center for Neurodegenerative Disorders (DZNE), Bonn-Cologne, Germany; 7. Department of Epidemiology and Biostatistics, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands; 8. Clinical Developmental Psychology & Clinical Neuropsychology, Faculty of Behavioural and Movement Sciences (FGB), Vrije University Amsterdam, Amsterdam, the Netherlands.

Corresponding Author: Linda M.P. Wesselman, Alzheimer Center Amsterdam and Department of Neurology, Amsterdam Neuroscience, Amsterdam UMC, P.O. Box 7057, 1007 MB Amsterdam, the Netherlands, Telephone: +31-204440816; Fax: +31-204448529; E-mail: l.wesselman@amsterdamumc.nl

J Prev Alz Dis 2020;3(7):184-194
Published online March 2, 2020, http://dx.doi.org/10.14283/jpad.2020.9

 


Abstract

Background: Online programs targeting lifestyle have the potential to benefit brain health. We aimed to develop such a program for individuals with subjective cognitive decline (SCD). These individuals were reported to be at increased risk for dementia, and report both an intrinsic need for brain health information and motivation to participate in prevention strategies. Co-creation and user-evaluation benefits the adherence to and acceptance of online programs. Previously, we developed a prototype of the online program in co-creation with the users .
Objectives: We now aimed to evaluate the user-experiences of our online lifestyle program for brain health.
Design: 30-day user test; multi-method.
Setting: Participants were recruited in a memory clinic and (online) research registries in the Netherlands (Alzheimer Center Amsterdam) and Germany (Center for memory disorders, Cologne).
Participants: Individuals with SCD (N=137, 65±9y, 57% female).
Measurements: We assessed user-experiences quantitatively with rating daily advices and usefulness, satisfaction and ease of use questionnaires as well as qualitatively using telephone interviews.
Results: Quantitative data showed that daily advices were rated moderately useful (3.5 ±1.5, range 1-5 points). Participants (n=101, 78%) gave moderate ratings on the programs’ usability (3.7±1.3, max 7), ease of learning (3.6±1.9) and satisfaction (4.0±1.5), and marginal ratings on the overall usability (63.7±19.0, max 100). Qualitative data collected during telephone interviews showed that participants highly appreciated the content of the program. They elaborated that lower ratings of the program were mainly due to technical issues that hindered a smooth walk through. Participants reported that the program increased awareness of lifestyle factors related to brain health.
Conclusions: Overall user-experience of the online lifestyle program was moderate to positive. Qualitative data showed that content was appreciated and that flawless, easy access technique is essential. The heterogeneity in ratings of program content and in program use highlights the need for personalization. These findings support the use of online self-applied lifestyle programs when aiming to reach large groups of motivated at-risk individuals for brain health promotion.

Key words: Lifestyle, dementia, subjective cognitive decline, eHealth, prevention.

Abbreviations: SCD: subjective cognitive decline; MCI: mild cognitive impairment; SUS: System Usability Scale; USE: User Satisfaction and Ease of use.


 

Introduction

The World Health Organization (WHO) Global Action Plan on Dementia emphasized the need for campaigns to increase public awareness and understanding of dementia (1). Recent studies found that knowledge about prevention and treatment of dementia remains poor and that there is a need for adequate dementia prevention education (2, 3).
The body of evidence on the association between a healthy lifestyle and brain health keeps growing (4). Risk factors for dementia due to Alzheimer’s disease (AD), such as lifestyle factors, are suggested to be partly modifiable (5). A healthy lifestyle may therefore decrease the risk for AD dementia. Since the etiology of AD is complex and multifactorial, recommendations are made to target several risk factors simultaneously (6, 7). Indeed, a multifactorial intervention has been found to improve or maintain cognitive functioning in people at risk for dementia (8). However, this intervention was offered face-to-face, which is beneficial for program use because of personal contact, but is relatively expensive and limits possibilities to reach a larger group of individuals. Offering intervention programs online has an important advantage because it offers the opportunity to reach many users, in particular in remote areas (9).
Our international EuroSCD-project aimed to develop an online lifestyle program for brain health. Individuals with subjective cognitive decline (SCD) experience cognitive decline in absence of objective cognitive impairments. SCD has previously been reported to be a risk factor for dementia and AD (10, 11). Therefore, individuals with SCD might be an ideal target group for online interventions. This at-risk group might present at memory clinics, their GP or research registries, and was found to be motivated to participate in prevention strategies (12). Individuals at-risk might benefit most from prevention strategies aimed at optimizing brain health or preventing cognitive decline (13, 14).
Our recent review and meta-analysis on online lifestyle programs for brain health suggested that these programs could indeed benefit brain health (15). However, the programs that we reviewed were heterogeneous in content and set-up. Further, characteristics and the methods and results of evaluations of the programs were often not described consistently. More specifically, it was often unclear how user-participation was operationalized and thus how users were involved during the development of the programs (15). This is an important aspect during the development of online programs, because it is essential to involve future users during development. With the users’ input, a program will better fit the users’ needs, which benefits acceptance and adherence, and thereby the implementation of sustainable innovations (16). Previously, we investigated barriers and facilitators for the use of an online lifestyle program in individuals with SCD (12). We found that both program characteristics and personal factors need to be considered, with trustworthiness, user-friendliness, and personalization being important facilitators. We implemented these results during the development of an online lifestyle program for brain health. In co-creation with the users, we developed and adapted the program in multiple iterations. We now aimed to evaluate user-experiences of our online lifestyle program in Dutch and German individuals with SCD, using both quantitative and qualitative methods.

 

Methods

Project and study design

This study is part of the European ‘Subjective cognitive decline in preclinical Alzheimer’s Disease: European initiative on harmonization and on a lifestyle-based prevention strategy’ project (Euro-SCD; JPND_PS_FP-689-019), which aims to develop an online lifestyle program for individuals with SCD. The Euro-SCD project is a collaboration between the Alzheimer Center Amsterdam, the Netherlands (17), Hospital Clinic Barcelona, Spain, and the Center for memory disorders, University Hospital Cologne, Germany. The study was conducted in accordance with Good Clinical Practice (GCP) Guidelines, applicable national guidelines, and to the Declaration of Helsinki. The local ethical committees approved this study and all participants provided informed consent.
The current study was conducted in the Netherlands and Germany (Figure 1: study overview). First, we conducted a feasibility study in the Netherlands to evaluate practicalities and study procedures. This allowed us to improve the online program and optimize the planned study procedures. Subsequently, we performed a 30-day online user test in both the Netherlands and Germany to evaluate user-experiences.

Figure 1. Study overview

Figure 1. Study overview

NOTE: This Figure illustrates the study overview. During the feasibility study, using an iterative process, the program was adapted and study procedures were optimized. The 30-day online user test was quantitatively evaluated with questionnaires, rating of daily advices and data log, and qualitatively by follow-up telephone interviews in a subsample of participants. USE: User Satisfaction and Ease of use questionnaire; SUS: System Usability Scale. a: conducted in the Netherlands, b: recruited via Dutch Brain Health Registry, c: recruited via Cologne Alzheimer dementia prevention registry.

 

Participants

Individuals with SCD were recruited through either a memory clinic or research registry:
1) memory clinic: we included individuals that visited the Alzheimer Center Amsterdam because of cognitive complaints. They underwent clinical work-up including clinical evaluation, neuropsychological assessment, and MRI scan. Although not mandatory, an informant was present in most cases during consults and assessments. When all clinical investigations were normal, and no cognitive disorder could be objectified, patients were labelled as having SCD ((17) i.e. clinical criteria for MCI, dementia or psychiatric disorder not fulfilled, no neurological diseases known to cause memory complaints (e.g. Parkinson’s disease, epilepsy), HIV, abuse of alcohol or other substances). Individuals were invited for study participation based on the following criteria: I) diagnosis of SCD II) age 50 years or older, and III) owning a smartphone, tablet or computer.
2) research registries: we included individuals that signed up for research registries, a) the Dutch Brain Health Registry (online register; www.hersenonderzoek.nl) which facilitates participant recruitment for neuroscience studies and is open for individuals of any age; b) the Cologne Alzheimer dementia prevention registry [Kölner Alzheimer Präventionsregister (KAP)], which is open for individuals of any age interested in the field of dementia. Through newsletters individuals receive information on research and are asked to participate in scientific studies. Individuals were invited for study participation based on the following criteria: I) self-reported experience of memory loss as assessed by either the question “Do you have memory complaints?” (Dutch registry) or the SCD interview (18) (German registry), II) age 50 years or older, III) no diagnosis of Alzheimer’s disease, another type of dementia or mild cognitive impairment, as assessed through self-report, and VI) owning a smartphone, tablet or computer to access the online lifestyle program. No informant information was available for the participants from the research registries.

Online lifestyle program

Hello Brain is a European Project (FP7 grant no 304867) led by Trinity College Dublin. Hello Brain comprises a website and app which are available in English French and German. The website www.hellobrain.eu shares information and videos about the brain, brain health and brain research. The App aims to support users to live a brain healthy life by giving daily suggestions called ‘brain buffs’. There are five brain buff categories: physical activity, social activity, mental activity, lifestyle (nutrition, smoking, alcohol) and attitude (referring to stress management and positive thinking; 30 brain buffs per category). Participants are instructed to read the brain buff and are encouraged to engage in the described activity. If the user cannot or does not want to conduct a specific brain buff, a new brain buff can be requested.
For the current project, a collaboration was started between the EuroSCD team and Trinity College Dublin. We first investigated the preferences and wishes for an online lifestyle program in an international group of users (12). Then, in collaboration with users and a technical party, we adapted the program HelloBrain (Dutch: HalloHersenen, German: HalloGehirn; Appendix 1: details and screenshots). The scientific content was translated and the modules were adapted in order for the interactive module to become the main module. Additional brain buffs were created by a team of brain researchers and added to the program (15 per category) in order to allow tailoring based on a personal profile. The overall lay-out of HelloBrain was changed to a calmer look-and-feel by applying the grey background, that was included in some of the original HelloBrain screens, to all screens while keeping the colorful details.

Feasibility study

After the above mentioned adaptations, we performed a feasibility study to evaluate accessibility and the study procedures, to collect qualitative feedback and optimize study procedures for the online user test. We used 4 iterations of user input and adaptations to create a version of the program that was ready to evaluate user-experiences in a 30-day user test.

Focus groups

In 4 focus groups (memory clinic + Dutch Brain Health Registry, total N=17: 67±6y, 65% female) the language and structure of the program was evaluated. Specific topics were hierarchy of screens (wireframe), language, lay-out, and the wording of reminders and instructions. Feedback was translated into technical and content-related adaptations, and passed on to the developers. We used an iterative process, meaning that after each focus group the program was adapted. In the next focus group the adapted version of the program was evaluated.

Technical pilot

We conducted a technical pilot to evaluate accessibility of the program. Accessibility was defined as the ability to log in to the website or the app independently, with devices at home. Participants (memory clinic, N=5: 61±8y, 80% female) received access to the program through the website or the app for 2 weeks. All technical issues raised by the participants were collected and adaptations were made.

Pilot test phase

To evaluate feasibility of the planned study procedures, we conducted a pilot test phase in which we included 43 SCD subjects (Dutch Brain Health Registry, 65±8y, 66% female). Participants received account information by email and were instructed to use the program for 30 days. Users were able to email the researchers and if necessary, we initiated contact by telephone. At the end of the test-period, participants received digital questionnaires by email to evaluate the procedure of sending online questionnaires, having participants filling out the questionnaires and adequate data collection.

30-day user test: user-experiences

Participants

Finally, we conducted a 30-day user test to evaluate user-experiences. Individuals from the Dutch Brain Health Registry and the Cologne Alzheimer dementia prevention registry were approached. These individuals were not involved in previous phases of the program development.

Procedures

Participants received account information and could access the program for 30 days. Participants were instructed to use the program on a daily basis and complete one brain buff each day. Besides the daily brain buff, participants could access the information on brain health as they liked. After the 30-day user test the participants received self-report questionnaires to evaluate the program. In addition, participants were asked whether they were willing to share their experiences during a telephone interview. Study procedures slightly differed between centers, because of characteristics of the research registers (online in the Netherlands, on paper after an in-person information session in Germany) and requirements of the Cologne ethical committee to send information via post instead of email.

Measures

Data log

During the online user test, log data regarding the usage of the program were collected. Log data entailed number of log ins, log outs, brain buffs completed, brain buffs passed, and page visits during the test period.

Usefulness of daily advices

After indicating that a brain buff was completed, participants were asked to provide a rating of the usefulness of the brain buff. This rating was illustrated with 1 to 5 stars. Participants were invited to leave a comment.

Usability, ease of learning and satisfaction

We used the User Satisfaction and Ease of use (USE) (19) and the System Usability Scale (SUS) questionnaire (20) to assess perceived user-experiences of the online program. The USE questionnaire includes items on usefulness (e.g. is the program perceived as useful, does it have value to the user), ease of learning (e.g. is it easy to learn how the program works) and satisfaction (e.g. does it fulfill the wishes and expectations of the user), with scores ranging from 1 to 7. We used the domain scores for usefulness, ease of learning and satisfaction, by averaging the scores of items per domain. The SUS questionnaire includes 10 items on usability (scores ranging from 1-5; e.g. degree of convenience when using the program). The SUS questionnaire includes both positive and negative items. Total SUS score (range 0-100) was calculated by subtracting 1 from positive items and inversing negative items (5 – item score), summing these scores and multiplying with 2.5 (20). For both questionnaires higher scores indicate better ratings.

Qualitative exploration of user-experiences

We held semi-structured telephone interviews to gain more insight in the questionnaire results and to discuss additional topics. We chose a random sample (N=30) from participants that indicated to be willing to participate in the telephone interview. Aspects that were deemed most important to improve, good and useful aspects of the program and communication during the user test were discussed. In case the questionnaire results needed clarification, the interviewer posed specific questions.

Frequency of Internet use

In the Dutch subsample, a question regarding frequency of internet use was included in the usability questionnaire. In a German subsample frequency of internet use was discussed during the in-depth interview.

Data analysis

Analyses of quantitative data were conducted using SPSS version 22. Descriptive methods were used to describe demographics, average ratings of daily advices per category, use of the program (data log) and user-experience scores (questionnaires) in means and standard deviation, or percentages. Analysis of variance was used to compare questionnaire scores of Dutch and German participants, and to compare the ratings between brain buff categories. P-values of ≤0.05 were considered significant. Qualitative data was collected during the telephone interviews. Every interview was summarized in a short report. All comments were summarized independently by two researchers (LW, AKS). Data was then structured by these researchers upon consensus, in order to identify themes that were of importance to the participants when using the program of when participating in this study.

 

Results

Feasibility study

Focus groups

We let the participants discuss terminology within the program. At first, we kept some English terms in the program. The participants proposed to use Dutch language only. We discussed which terms should be incorporated to replace the English terms. ‘Brain buff’ became ‘Oppepper’ (Dutch for ‘Boost’), and although the category name ‘Attitude’ also translates to the Dutch ‘Attitude’, participants preferred a different wording (‘Houding’; Dutch synonym for ‘Attitude’). Participants agreed with the order and hierarchy of the screens (the wireframe). Upon their input the button for instructions was enlarged and placed more prominently, and we added ‘Uitleg’ (Dutch for ‘Explanation’) underneath this circled question mark symbol. Participants mentioned that back-and-forth buttons needed to be more prominent, which we adapted accordingly, and the hierarchy of the current location should be visible. Therefore, so called ‘Breadcrumbs’ were added to the page. Breadcrumbs are a simple display of the current location in the program, and easy way to click to a location with higher hierarchy (e.g. Start page / Brain Health / Neuroplasticity). Participants mentioned that they would prefer more instructions when entering the main screen. Together with the technical party and participants we came up with the solution to add a highlighting instruction, which highlights and explains all parts of the screen one by one.

Technical pilot

Of the 5 participants that evaluated the accessibility of the program, nearly all (4/5) reported a smooth download and log in without any assistance. One participant was not able to log in, as a result of a problem with the internet browser. Together with the technical party, the issue was resolved. After log in, 2 participants reported several technical bugs, such as wrong linking between pages or not enough variation in the daily advices, which was caused by an algorithm error. These issues were solved by the technical party.

Pilot test phase

Sending and receiving the questionnaires digitally went well. Participants did not report problems filling out the digital questionnaires. Almost all communication was done via email and online questionnaires. Some participants liked the efficient communication and felt that they were skilled enough to work online, while others would have preferred personal contact throughout the test-phase and provide feedback by telephone. Some participants mentioned that they would have liked an ‘emergency hotline’ in order to have personal contact by telephone in case they would have needed help when using in the program. Based on participants’ suggestions, we made the instructions for the online user test more detailed.

30-day user test: user-experiences

Participants

In total, 137 SCD subjects (55 Netherlands, 82 Germany) were included in the online user test. Participants were on average 65.1±8.6 years of age, 57% female and participants completed 11.3±1.9 years of education. German participants had on average more years of education (12.6±1.4) compared to Dutch participants (10.2±1.9, p<.01). The majority of the participants reported to use the internet on a daily basis (>90% of a subsample; Dutch N=55, German N=15).

Data log

In total, 120 (88%) participants used the online lifestyle program during the 30-day test period, whereas 17 (12%) participants did not log in. On average, participants reported to have completed 31±31 daily advices and requested a different brain buff 23±40times during these 30 days. Participants switched between pages on average 117 times (from brain buff screen to informative module and back, or within the informative module).

Usefulness of brain buffs

In total, participants rated 3266 brain buffs with a mean score of 3.5 (±1.5, max 5). The mean ratings differed between categories (F(4,3261)=5,725, p=.000). In general, buffs in the Attitude (3.6±1.4) and Physical activity (3.6±1.4) categories were higher appreciated than Lifestyle advices (3.3±1.6, resp. p<.001 and p=.001). Brain buffs of all categories received scores ranging from 1 to 5 stars and rankings were accompanied by both positive and negative comments. While some participants really liked a brain buff (“It would be very easy and fun to do this every day”) others disliked the same brain buffs (“I have never liked this and I will not do this today”). This diversity in appreciation of the categories, is presented in Figure 2.

Figure 2. Variety in reported usefulness of brain buffs

Figure 2. Variety in reported usefulness of brain buffs

NOTE: This figure illustrates the percentages of brain buffs that received 1 to 5 stars ratings per category, and presents a negative (1 star, left) and a positive (5 stars, right) quotes for each category for illustrative purposes

 

Usability, ease of learning and satisfaction

The questionnaire was completed by 101 participants (response rate 74%; 37 Netherlands, 64 Germany). Participants gave on average moderate scores on items of the USE questionnaire (max 7): usefulness 3.7±1.3, ease of learning 3.6±1.9 and satisfaction 4.0±1.5 points. Dutch participants rated the program higher on these 3 domains compared to German participants (Dutch: 4.1±1.3, 4.8±1.5, 4.4±1.4 vs. German: 3.4±1.3, 2.4±1.5, 3.7±1.6; p<.05). The average score for usability on the SUS questionnaire was 63.7±19 out of 100, which translates to ‘OK to good’ (21) and did not differ between Dutch and German participants. Figure 3 presents the heterogeneity of user-experience scores within the total group.

Figure 3. Heterogeneity in user-experiences

Figure 3. Heterogeneity in user-experiences

 

Qualitative exploration of user-experiences

Table 1 gives a summary of the qualitative feedback illustrated by quotes. Participants mentioned that they would prefer a personalized program, meaning that it would fit their specific preferences. For example, with content based on their current lifestyle and preferred lifestyle category. Some of the participants used the program mainly for information, while others mainly liked the interactive part. When asked what was most important to improve, participants mostly mentioned to optimize technical aspects of the program to ensure a smooth walk-through.
Most participants mentioned to highly appreciate the content of the program. They liked to have a platform available to read about the brain and brain health, and to have access to a trustworthy source of information. When specifically asked what they liked most about the program, participants reported that the program induced awareness of lifestyle factors that are related to brain health. While most participants knew that physical exercise is related to brain health, they were often not aware of the relation between nutrition or social activities and brain health. Some participants mentioned that the program was positive and induced motivation to live healthier. Others were stimulated to look at their current lifestyle, felt confirmation that they have a healthy lifestyle or were motivated to continue with current lifestyle changes.

Table 1. Summary of in-depth exploration of user-experiences, collected during telephone interviews

Table 1. Summary of in-depth exploration of user-experiences, collected during telephone interviews

NOTE: This Table presents qualitative feedback, which was provided by 30 participants during the telephone interviews.

 

Discussion

We developed an online lifestyle program for brain health and found that its’ overall user-experience was moderate to positive. Qualitatively, participants reported to appreciate the content of the program and having a trustworthy source of information on lifestyle and brain health. Quantitative scores on usefulness and ease of learning showed room for improvement. We observed high heterogeneity in the preference of specific lifestyle topics, which emphasizes the need for personalization.
Content on the brain and brain health of the online program, as offered in the brain buffs and the information pages, was highly appreciated by the participants. Both the brain buffs and the information pages were reported to be interesting and useful. Many participants reported to have learned new things. Often they were not aware that all the lifestyle factors that were included in the program were associated to brain health. Previous studies into the attitudes towards prevention of AD and related dementias highlighted the need to improve the beliefs and attitudes towards dementia prevention (1, 3, 22). Our study showed that a tool with information on lifestyle and brain health can contribute to the awareness on modifiable risk factors of dementia.
Involving the users throughout the process of development of an online program is expected to benefit usability and thereby adherence to the program. Our recent review, however, showed that for online lifestyle programs aimed at brain health it was often unclear whether and how users were involved during development and evaluation of the program (15). For example, a study on adherence to lifestyle interventions for dementia prevention found that adherence was lowest for the unsupervised computer-based cognitive training compared to other supervised trainings (23). However, user-involvement during development and evaluation was not described and therefore it remains unclear whether this could have benefitted adherence rates. In this study we aimed to evaluate and optimize user-experiences. When a program will be implemented internationally, it is important to explore cultural differences. Our multinational participatory research design increases the quality of output and sustainability, but also ensures culturally appropriate research, which is of importance when developing an international application (24). As a next step, additional options to increase the impact of the program should be explored. It might be worthwhile to evaluate integration of persuasive technologies that aim to influence behavior and attitudes. If such technologies are used the right way, it is more likely that users reach health-related goals (25).
The heterogeneity in the ratings of brain buffs, the frequent requests for different brain buffs and the qualitative feedback emphasize the need for personalization. Personalization has also been identified as one of the principles to increase appreciation and overall adherence to an online intervention (26, 27). In the current version of the program, part of the content was personalized, since users could request a different brain buff and could access information as they wished. Participants mentioned that they would prefer to receive brain buffs based on their current lifestyle behavior. Further evaluation and integration of personalization options, such as adapting lifestyle advices based on current lifestyle habits, could improve user-experience and thereby adherence to the program.
Lessons learned from the qualitative input of the users, mainly entail the preference for tailoring based on current lifestyle behavior. In addition, participants mentioned different possible effects of the program. Therefore, it might be interesting to rethink the most appropriate outcome measures of future lifestyle-based interventions in SCD. While changes in lifestyle or brain health might seem obvious, effects on psychological well-being or fear for dementia could also be worth consideration.
The quantitative ratings evaluating user-experience were moderate, which was lower than we expected. We identified room for improvement, particularly in ease of learning. Meaning that additional adaptations are necessary to improve instructions and clarity within the program. Differences in ratings could have several reasons, such as education, cultural differences, differences in reporting and differences in digital skills – which we did not assess systematically. Regarding the 30-day user test, German participants reported difficulties when learning to use the program. Some of the technical difficulties occurred only in the German back-end. Although we fixed these technical issues and thoroughly tested the program, we could not rule out remaining minor issues, possibly contributing to the differences in these scores. In our previous study (12), we found that German individuals with SCD used the Internet less often compared to the Dutch participants. However, information on the current Dutch sample and a subset of the German sample showed that over 90% of the participants uses the internet on a daily basis and therefore frequency of internet use is unlikely to influence perceived difficulties. Further, we did not match participants from the feasibility study and 30-day user test. Therefore, we cannot rule out the influence of demographical differences on perceived usability and satisfaction during development and the actual test phase.
In summary, qualitative feedback on the programs’ content was positive, while quantitative feedback on program characteristics showed room for improvement. This discrepancy between the positive qualitative feedback and the moderate quantitative ratings emphasizes the importance of combining methods when evaluation usability of eHealth applications, which was also emphasized in a recent scoping review on methods of usability testing in the development of eHealth applications (28).
This study had some limitations. First, the development and feasibility study took place in the Netherlands, and not in Germany. However, we believe it is promising that participants with different nationalities appreciated the same program, strengthening feasibility to offer one program in multiple countries. Second, a selection bias might have occurred, a study on an online program could have attracted individuals with better digital skills. However, the digital literacy of the participants varied from limited to very skilled, which was also reflected in the variety of feedback regarding ‘ease-of-learning’. Since an online program will only be used by those able and willing to access a program online, the current participants seem representative for the actual target group. Third, we did not have detailed information on drop-outs and therefore cannot describe their characteristics. We did however encourage all individuals to complete the questionnaires and we interviewed individuals independent of their attitude towards the program. Fourth, the participants were recruited based on different SCD criteria between the memory clinic and the research registries. However, we deem the population representative for the heterogeneous populations that can be recruited via memory clinics and brain health registries, and results are generalizable as such. Finally, based on the data log we cannot make a distinction between merely clicking through the program and attentively reading pages. Therefore, we could not take frequency or duration of active participation into account. In the future, this information could be considered when evaluating user-experiences and lifestyle effects of the program.
The strengths of the study include the study design. This was a multicenter study conducted in Germany and the Netherlands. This international character contributes to the generalizability of the findings to other European populations. Results also suggest that although some differences were found, one online tool for multiple European countries would be feasible. Second, we involved the target population throughout the process of development and evaluation. Co-creation is expected to increase the extent to which the tool fits the users’ preferences and digital skills and thereby acceptation and impact of the innovation in further stages (29, 30). Therefore, the users’ input was crucial and resulted in an online lifestyle program fitting the needs and preferences of individuals with SCD. Third, we combined methods to assess user-experiences of the online lifestyle program. The quantitative and qualitative methods were found to complement each other. Finally, we focused on individuals with SCD, who do not show cognitive deficits but at group level are at increased risk for cognitive decline. Therefore, this group is of clinical relevance in the context of dementia prevention. Individuals with SCD also report a need for brain health information, which has not yet been fulfilled since trustworthy sources are still lacking. This group is willing to participate in prevention strategies, which was also observed during recruitment and led to a higher inclusion number than planned.
In conclusion, in this study we developed and evaluated an online lifestyle program for brain health in individuals with SCD. We found that the overall user-experience of our program was moderate to positive. Participants appreciated content on lifestyle and brain health. The variety in preferences for different categories highlighted the need for personalization. It was feasible to offer this online lifestyle program in an at-risk population with SCD. Online self-applied lifestyle programs seem useful when aiming to reach large groups of motivated at-risk individuals for brain health promotion.

 

Conflicts of interest: The authors state no conflicts of interest. Ms. Wesselman reports grants from JPND/ZonMw, grants from Stichting Equilibrio, during the conduct of the study; Dr. Schild reports grants from Bundesministerium für Bildung und Forschung, during the conduct of the study; Dr. Hooghiemstra has nothing to disclose; Mr. Meiberth reports grants from Bundesministerium für Bildung und Forschung, during the conduct of the study; Ms. Drijver has nothing to disclose; Ms. v Leeuwenstijn-Koopman has nothing to disclose; Dr. Prins has nothing to disclose; Dr. Brennan has nothing to disclose; Dr. Scheltens has nothing to disclose; Dr. Jessen reports grants from Bundesministerium für Bildung und Forschung, during the conduct of the study; Dr. van der Flier reports grants from JPND/ZonMw, during the conduct of the study; Dr. Sikkes reports grants from JPND/ZonMw, grants from Stichting Equilibrio, during the conduct of the study.

Funding: The project is supported through the following funding organizations under the aegis of JPND (www.jpnd.eu; JPND_PS_FP-689-019): Germany, Bundesministerium für Bildung und Forschung (BMBF grant number: 01ED1508), the Netherlands, ZonMw grant no. 733051043. It was additionally supported by a research grant from Stichting Equilibrio. W.M. van der Flier is recipient of a grant by Gieskes-Strijbis fonds. S. Sikkes is recipient of a ZonMw Off Road grant (grant no. 451001010).

Acknowledgements: We thank all participants for their contribution to this research project. We thank Roxelane BV. and specifically Rudolf Wolterbeek, Brian Fa Si Oen and Max Hasenaar for their contribution to this project representing the technical party within the collaboration. We thank Mark Dubbelman for data visualization. We thank the founders of HelloBrain.eu (Trinity College Dublin, supported by European Union’s Seventh Framework Program for research, grant no. 304867) for the fruitful collaboration. The website www.hellobrain.eu shares easy-to-understand information and animations about the brain, brain health and brain research. The freely available interactive app, Hello Brain Health, aims to support users to live a brain healthy life by giving daily suggestions called ‘brain buffs’. The app is available on the project website, the App Store and Google Play. The Alzheimer Center Amsterdam is supported by Alzheimer Nederland and Stichting VUmc fonds. Research of the Alzheimer Center Amsterdam is part of the neurodegeneration research program of Neuroscience Amsterdam. Wiesje van der Flier holds the Pasman chair. Hersenonderzoek.nl is funded by ZonMw-Memorabel (project no 73305095003), a project in the context of the Dutch Deltaplan Dementie, the Alzheimer’s Society in the Netherlands and the Brain Foundation Netherlands.

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.

 

SUPPLEMENTARY MATERIAL

 

References

1. Petersen R C, Smith GE, Waring SC, et al. Mild cognitive impairment: clinical characterization and outcome. Archives of Neurology 1999;56:303-308.
2. Winblad B, Palmer K, Kivipelto M, et al. Mild cognitive impairment–beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment. Journal of Internal Medicine 2004;256:240-246.
3. Baumgart M, Snyder HM, Carrillo MC, et al. Summary of the evidence on modifiable risk factors for cognitive decline and dementia: a population-based perspective. Alzheimer’s & Dementia 2015;11:718-726.
4. Bourre J & Paquotte P. Seafood (wild and farmed) for the elderly: Contribution to the dietary intakes of iodine, selenium, DHA and vitamins B12 and D. The Journal of Nutrition, Health & Aging 2008;12:186-192.
5. Dangour A, Allen E, Elbourne D, et al. Fish consumption and cognitive function among older people in the UK: Baseline data from the opal study. The Journal of Nutrition, Health & Aging 2009;13:198-202.
6. Morris MC, Evans DA, Tangney CC, et al. Fish consumption and cognitive decline with age in a large community study. Archives of Neurology 2005;62:1849-1853.
7. Innis SM. Dietary (n-3) fatty acids and brain development. The Journal of Nutrition 2007;137:855-859.
8. Valenzuela A. Docosahexaenoic acid (DHA), an essential fatty acid for the proper functioning of neuronal cells: their role in mood disorders. International Journal of Fats and Oils 2009;60:203-212.
9. van de Rest O, Geleijnse JM, Kok FJ, et al. Effect of fish oil on cognitive performance in older subjects: a randomized, controlled trial. Neurology 2008;71:430-438.
10. Dangour AD, Allen E, Elbourne D, et al. Effect of 2-y n−3 long-chain polyunsaturated fatty acid supplementation on cognitive function in older people: a randomized, double-blind, controlled trial. The American Journal of Clinical Nutrition 2010;91:1725-1732.
11. Danthiir V, Hosking DE, Nettelbeck T, et al. An 18-mo randomized, double-blind, placebo-controlled trial of DHA-rich fish oil to prevent age-related cognitive decline in cognitively normal older adults. The American Journal of Clinical Nutrition 2018;107:754-762.
12. Moran C, di Palumbo AS, Bramham J, et al. Effects of a Six-Month Multi-Ingredient Nutrition Supplement Intervention of Omega-3 Polyunsaturated Fatty Acids, vitamin D, Resveratrol, and Whey Protein on Cognitive Function in Older Adults: A Randomised, Double-Blind, Controlled Trial. The Journal of Prevention of Alzheimer’s disease 2018;5:175-183.
13. Nilsson A, Radeborg K, Salo I, et al. Effects of supplementation with n-3 polyunsaturated fatty acids on cognitive performance and cardiometabolic risk markers in healthy 51 to 72 years old subjects: a randomized controlled cross-over study. Nutrition Journal 2012;11:99.
14. Witte AV, Kerti L, Hermannstädter HM, et al. Long-chain omega-3 fatty acids improve brain function and structure in older adults. Cerebral Cortex 2013;24:3059-3068.
15. Külzow N, Witte AV, Kerti L, et al. Impact of Omega-3 Fatty Acid Supplementation on Memory Functions in Healthy Older Adults. Journal of Alzheimer’s Disease 2016;51:713-725.
16. Quinn JF, Raman R, Thomas RG, et al. Docosahexaenoic acid supplementation and cognitive decline in Alzheimer disease: a randomized trial. JAMA 2010;304:1903-1911.
17. Freund-Levi Y, Eriksdotter-Jönhagen M, Cederholm T, et al. ω-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: OmegAD study: a randomized double-blind trial. Archives of Neurology 2006;63:1402-1408.
18. Kotani S, Sakaguchi E, Warashina S, et al. Dietary supplementation of arachidonic and docosahexaenoic acids improves cognitive dysfunction. Neuroscience Research 2006;56:159-164.
19. Chiu C-C, Su K-P, Cheng T-C, et al. The effects of omega-3 fatty acids monotherapy in Alzheimer’s disease and mild cognitive impairment: a preliminary randomized double-blind placebo-controlled study. Progress in Neuropsychopharmacology and Biological Psychiatry 2008;32:1538-1544.
20. Yurko-Mauro K, McCarthy D, Rom D, et al. Beneficial effects of docosahexaenoic acid on cognition in age-related cognitive decline. Alzheimer’s & Dementia 2010;6:456-464.
21. Vakhapova V, Cohen T, Richter Y, et al. Phosphatidylserine containing ω–3 fatty acids may improve memory abilities in non-demented elderly with memory complaints: A double-blind placebo-controlled trial. Dementia and Geriatric Cognitive Disorders 2010;29:467-474.
22. Mazereeuw G, Lanctot K, Chau S, et al. Effects of omega-3 fatty acids on cognitive performance: a meta-analysis. Neurobiology of Aging 2012;33:1482.e17-1482.e29.
23. Sinn N, Milte CM, Street SJ, et al. Effects of n-3 fatty acids, EPA v. DHA, on depressive symptoms, quality of life, memory and executive function in older adults with mild cognitive impairment: a 6-month randomised controlled trial. The British Journal of Nutrition 2012;107:1682-1693.
24. Lee L, Shahar S, Chin AV, et al. Docosahexaenoic acid-concentrated fish oil supplementation in subjects with mild cognitive impairment (MCI): a 12-month randomised, double-blind, placebo-controlled trial. Psychopharmacology 2013;225:605-612.
25. Rondanelli M, Opizzi A, Faliva M, et al. Effects of a diet integration with an oily emulsion of DHA-phospholipids containing melatonin and tryptophan in elderly patients suffering from mild cognitive impairment. Nutritional Neuroscience 2012;15:46-54.
26. Yacong B, Xueyuan Z, Youli W, et al. The n-3 Polyunsaturated Fatty Acids Supplementation Improved the Cognitive Function in the Chinese Elderly with Mild Cognitive Impairment: A Double-Blind Randomized Controlled Trial. Nutrients 2017;9:54.
27. Barberger-Gateau P, Samieri C, Feart C, et al. Dietary omega 3 polyunsaturated fatty acids and Alzheimer’s disease: interaction with Apolipoprotein E genotype. Current Alzheimer Research 2011;8:479-491.
28. Fjell AM & Walhovd KB. Structural brain changes in aging: courses, causes and cognitive consequences. Reviews in the Neurosciences 2010;21:187-222.
29. Chhetri JK, de Souto Barreto P, Cantet C, et al. Trajectory of the MAPT-PACC-preclinical Alzheimer cognitive composite in the Placebo Group of a Randomized Control Trial: results from the MAPT Study: lessons for Further Trials. The Journal of Prevention of Alzheimer’s disease 2018;5:31-35.
30. Berlau DJ, Corrada MM, Head E, et al. APOE ε2 is associated with intact cognition but increased Alzheimer pathology in the oldest old. Neurology 2009;72:829-834.
31. Randolph C. Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). San Antonio: Psychological Corporation, 1998;.
32. Nelson H. The Nelson adult reading test (NART) manual. Windsor, England. NFER-Nelson 1982;530:531.
33. Mendoza JE, Apostolos GT, Humphreys JD, et al. Coin rotation task (CRT): a new test of motor dexterity. Archives of Clinical Neuropsychology 2009;24:287-292.
34. Pachana NA, Thompson, LW, Marcopulos BA, et al. California older adult Stroop test (COAST) development of a Stroop test adapted for geriatric populations. Clinical Gerontologist 2004;27:3-22.
35. Army US. Army individual test battery. Manual of directions and scoring. Washington, DC: War Department, Adjutant General’s Office, 1944.
36. Wechsler D. Wechsler Adult Intelligence Scale, 3rd ed. San Antonio, TX: Psychological Corporation, 1997.
37. Thornton A & Leathem, JM. Coin rotation task. The development of norms for New Zealand and the United States. Presented at 6th International and 11th National Congress of Clinical Psychology. Santiago De Compostela, Spain, (2013, June).
38. Sheikh JI & Yesavage JA. Geriatric Depression Scale (GDS): Recent evidence and development of a shorter version. Clinical Gerontologist: The Journal of Aging and Mental Health 1986;5:165-173.
39. Pachana NA, Byrne GJ, Siddle H, et al. Development and validation of the Geriatric Anxiety Inventory. International Psychogeriatrics 2007;19:103-114.
40. Ware Jr JE & Gandek B. The SF-36 Health Survey: Development and use in mental health research and the IQOLA Project. International Journal of Mental Health 1994;23:49-73.
41. Bartels C, Wegrzyn M, Wiedl A, et al. Practice effects in healthy adults: a longitudinal study on frequent repetitive cognitive testing. BMC Neuroscience 2010;11:118.
42. Ahl RE, Beiser A, Seshadri S, et al. Defining MCI in the Framingham Heart Study Offspring: Education vs. WRAT-based norms. Alzheimer Disease and Associated Disorders 2013;27:1-15.
43. Das UN. Nutritional factors in the pathobiology of human essential hypertension. Nutrition 2001;17:337-346.
44. Morris MC, Sacks F & Rosner B. Does fish oil lower blood pressure? A meta-analysis of controlled trials. Circulation 1993;88:523-533.
45. Sullivan PF, Neale MC & Kendler KS. Genetic epidemiology of major depression: review and meta-analysis. American Journal of Psychiatry 2000;157:1552-1562.
46. Deckers K, Boxtel MP, Schiepers OJ, et al. Target risk factors for dementia prevention: a systematic review and Delphi consensus study on the evidence from observational studies. International Journal of Geriatric Psychiatry 2015;30:234-246.

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.

 

References

1.     Alzheimer’s Disease International. Alzheimer’s Disease International Annual Report 2016. London.
2.    Alzheimer’s Association. Changing the Trajectory of Alzheimer’s disease Report. 2015. http://www.alz.org/documents_custom/trajectory.pdf
3.    Alzheimer’s Association organizational description. http://www.alz.org – accessed March 13, 2016.
4.    Alzheimer’s disease clinical trials. http://www.clinicaltrials.gov. Accessed May 15, 2016.
5.    Baumgart M, Snyder HM, Carrillo MC, Fazio S, Kim H, Johns H. Alzheimers Dement. 2015 Jun;11(6):718-26.
6.    Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease 2013. Nat Genet 45(12):1452-8.
7.    National Institutes of Health. NIH Consensus Development Conference Statement on Preventing Alzheimer’s Disease and Cognitive Decline. Bethesda, MD: National Institutes of Health; April 26-28, 2010
8.    Satizabal CL, Beiser AS, Chouraki V, Chene G, Dufouil C, Seshadri S. Incidence of Dementia over Three Decades in the Framingham Heart Study. N Engl J Med 2016. 374(6):523-32.
9.    Matthews FE, Stephan BC, Robinson L, Jagger C, Barnes LE, Arthur A, Brayne C. A two decade dementia incidence comparison from the Cognitive Function and Ageing Studies I and II. Nat Commun 2016 19;7:11398.
10.    Doblhammer G, Fink A, Zylla S, Fritze T, Willekens F. Short-term Trends in German Dementia Prevalence, Incidence, and Mortality. 2014 Alzheimer’s Association International Conference. Abstract number 44259.
11.    Schrijvers EMC, Verhaaren BFJ, Koudstaal PJ, Hofman A, Ikram MA, Breteler MMB. Is dementia incidence declining? Trends in dementia incidence since 1990 in the Rotterdam Study. Neurology.2012;78:1456–1463.
12.    Larson EB, Yaffe K, Langa KM. New insights into the dementia epidemic. N Engl J Med 2013. 369(24): 2275-7.
13.    Ngandu T, Lehtisalo J, Solomon A, Levalahti E, Ahtiluoto S, Antikainen R, et al. A 2 year multidomain intervention of diet, exercise, cognitive training and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomized controlled trial. 2016. Lancet 385(9984): 2255-63.
14.    Institute of Medicine report on Cognitive Aging. 2015. Chaired by Dr. Daniel Blazer.  http://iom.nationalacademies.org/Reports/2015/Cognitive-Aging, accessed August 5, 2016.
15.    Vellas B, Carrier I, Gillett-Guyonne S, Touchon J, Dantoine T, Dartigues JF et al. J Prev Alzheimers Dis. 2014; 1(1): 13-22.
16.    Vellas.B, Voisin T, Dufouil C, Carrie.I, Gillette-Guyonnet.S, Gabelle. A et al. 2015 Clinical Trials in Alzheimer’s Disease abstract MAPT (Multi-Domain Alzheimer’s Prevention Trial): Clinical, Biomarkers results and lessons for the future. Abstract number OC33.
17.    AlzForum discussion with authors.  http://www.alzforum.org/news/conference-coverage/health-interventions-boost-cognition-do-they-delay-dementia. Accessed August 4, 2016.
18.    Richard E et al. Prevention of Dementia By Intensive Vascular care (preDIVA) – A Cluster Randomized Trial. Oral Session, O4-05-01, 8599. Alzheimer’s Association International Conference 2016.
19.    Moll van Charante EP, Richard E, Eurelings LS, van Dalen JW, Ligthart SA, van Brussel EF et al. Effectiveness of a 6-year multidomain vascular care intervention to prevent dementia (preDIVA): a cluster-randomised controlled trial. Lancet. 2016.
20.    Edwards J et al. University of South Florida. The ACTIVE Study: What We Have Learned and What Is Next? Alzheimer’s Association International Conference, 2016.
21.    Shah H et al. From the WHO Research Priorities and Research Portfolio Analysis to the Identification of Research Gaps to Reduce the Global Burden of Dementia 2016 Alzheimer’s Association International Conference Abstract number 12426.  
22.    Alzheimer’s Association 10 Ways to Love Your Brain, http://alz.org/brain-health/10_ways-to-love-your-brain.asp Chicago, IL. Last accessed August 5, 2016.

INTERVENTIONS TO PREVENT COGNITIVE DECLINE AND DEMENTIA IN ADULTS WITHOUT COGNITIVE IMPAIRMENT: A SYSTEMATIC REVIEW

J.C. Barnett, A. Bahar-Fuchs, N. Cherbuin, P. Herath, K.J. Anstey

Centre for Research on Ageing, Health and Wellbeing and Dementia Collaborative Research Centre- Early Diagnosis and Prevention, The Australian National University, Canberra, Australia

 Corresponding Author: Professor Kaarin J. Anstey, Centre for Research on Ageing, Health and Wellbeing, The Australian National University, ACT 0200, Australia. Phone: +61 2 6125 8411. Fax: +61 2 6125 1558. E-mail: kaarin.anstey@anu.edu.au.

J Prev Alz Dis 2015;2(1):38-45
Published online Januay 15, 2015, http://dx.doi.org/10.14283/jpad.2015.36


Abstract

Without preventative strategies, the burden of dementia is likely to increase rapidly worldwide. Primary prevention approaches involve modifying risk factors before symptoms of cognitive impairment develop. This review systematically assesses Randomised Controlled Trials (RCTs) and reviews of RCTs for their effectiveness in primary prevention. We searched Medline, the Cochrane Library, Web of Science and Psych-Info for relevant studies using pre-determined keywords. Both non-pharmacological and pharmacological interventions were considered. Inclusion criteria were sample size greater or equal to 50, at least 6 months of follow-up, and participants with no cognitive impairment at baseline. Outcomes included dementia incidence, cognitive decline and cognitive function. Study quality was rated using the Jadad criteria. Thirty-nine studies, 17 non-pharmacological and 22 pharmacological, were included. Results were heterogeneous across interventions and studies, with few significant effects. Studies investigating physical activity and calcium channel blocker treatment demonstrated significant effects in preventing cognitive decline. There were no conclusive results demonstrating overall capacity of assessed interventions to reduce risk of dementia. The review provides an overview of the current literature, and identifies areas in need of further research.

 Key words: Prevention, Alzheimer’s disease, cognitive ageing, lifestyle.


Introduction 

With an ageing population, the global incidence and cost of dementia is predicted to intensify in future years (1, 2). Reducing the rate of dementia may alleviate the predicted financial and social costs associated with the syndrome. As yet, however, there is no cure for dementia. In randomised controlled trials (RCTs), progression has, at best, been marginally slowed down by interventions (3). Since very few clinical trials are currently under way and given the very long development time, our incomplete understanding of the disease process and the lack of success of previous approaches it is likely the number of people living with dementia will increase substantially into the future. Primary prevention strategies, which target patients before the onset of the disease, have currently more potential to reduce dementia incidence and burden in the short to medium term through early intervention and risk exposure reduction.    

Primary prevention approaches for dementia centre around reducing an individual’s risk before any symptomatic cognitive decline occurs. We acknowledge that the disease process leading to dementia is likely to occur decades prior to symptom onset but for the purpose of this review we focus our definition on disease manifestation i.e.  prevention of symptom onset as this reflects the main focus of the literature as an outcome measure. While variables such as older age, female gender, traumatic brain injury and lower education are associated with increased dementia risk and are not generally open to modification, many risk factors are modifiable (4). In addition, dementia risk factors are shared with other health conditions and any reduction is likely to provide additional health benefits. In particular, cardiovascular disease shares modifiable risk factors with Alzheimer’s disease and vascular dementia. These include smoking, excessive alcohol consumption, poor diet, obesity, depression and sedentary lifestyle. Further, certain lifestyle factors such as social engagement and cognitive activity appear to have protective effects against dementia.

Many of these risk and protective factors have been carefully investigated in past research and have been well documented in systematic reviews (4, 5). Moreover, a number of RCTs have begun to evaluate the impact of treating risk factors on brain health, cognitive decline and dementia. These studies most often focus on manipulating one single risk or protective factor, and relatively few comparisons have been made between interventions. To our knowledge, there has been no comprehensive review of the effectiveness of interventions across risk and protective factors in primary prevention.

The aim of the present review is to assess the evidence regarding efficacy of pharmacological and non-pharmacological interventions aimed at reducing risk exposure in the primary prevention of dementia. Given the paucity of studies with dementia as an outcome, the review extends to studies where cognitive decline was an outcome measure as these studies are likely to be strongly relevant to dementia prevention.

Methods

Inclusion and Exclusion Criteria

RCTs and review articles with minimum samples of 50 participants and for which follow-up data were available at least six months after the end of the intervention were eligible for inclusion. These parameters were chosen to be inclusive of a range of studies in order to identify what research had been completed in the field. Trials were only included if the sample was described as cognitively unimpaired at baseline. Samples were eligible for inclusion irrespective of whether the presence of dementia risk factors was established. RCTs describing single or multi-domain interventions, pharmacological or non-pharmacological, were eligible for inclusion if dementia (of any aetiology) and/or cognitive decline were explicitly included as outcomes. Intervention trials had to target at least one established modifiable risk factor including sedentary lifestyle (physical, mental or social inactivity), inadequate nutrition, smoking, or the management of chronic health condition(s) including hypertension, diabetes, and overweight/obesity. Risk factor interventions included those that used pharmacological treatment to decrease exposure to risk factors rather than treating the developing pathology itself. No restrictions were imposed regarding the duration and intensity of interventions. Trials had to include at least one control condition, and this could include treatment as usual, waitlist, crossover, or active (placebo) control. We excluded retrospective case-control or cohort studies, as well as studies published in languages other than English.

Search Strategy

Potential trials were identified through searches in several databases including Medline, the Cochrane Library, Web of Science and Psych-Info. The following search terms were used to identify potential studies: (Dementia OR Alzheimer’s disease OR Mild cognitive impairment, Cognitive decline) AND (Primary prevention OR Omega 3 OR Fish consumption OR Physical activity OR Exercise OR Cognitive training OR Brain training OR Diet OR Mediterranean diet OR Fruit and vegetable intake OR Statin OR anti-hypertensive OR hypertension OR Hormone Replacement Therapy OR Oestrogen OR Progesterone OR NSAIDS OR Cholinesterase inhibitors OR Vitamins OR Nutritional supplements OR DocosaHexAenoic acid OR Homocysteine OR Aspirin). The census date for the search was November 2012. Search results were reviewed for inclusion independently by two reviewers, and unresolved questions were solved in consultation with other reviewers. All authors were involved in consensus decisions.

Rating of methodological quality

The methodological quality of included studies was rated between 0 and 5 independently by two reviewers using Jadad criteria (6), which score RCTs on randomization, blinding, and description of discontinuation rates. Inconsistencies were resolved by a consensus decision by the authors (see Supplementary Table 1, which shows Jadad scores for included studies).

Results

Results of the search strategy are shown in Figure 1. Thirty-nine studies met the inclusion criteria, of which 17 were non-pharmacological and 22 were pharmacological interventions. Non-pharmacological interventions are described first (see Supplementary Table 2, which summarises non-pharmacological studies included in this review). One multi-domain intervention was identified. Single-domain interventions included 12 nutrition and supplementation treatments, 2 cognitive and 2 physical activity interventions.

Figure 1. Search results

Pharmacological interventions are summarised next, and only single-domain treatments were identified (see Supplementary Table 3, which summarises pharmacological studies included in this review). Included in this review are 7 hormone replacement therapy, 9 anti-hypertensive, 2 statin, 1 non-steroidal anti-inflammatory drugs (NSAIDs) and 2 aspirin studies.

Table 1. Effectiveness of Interventions

While primary outcome measures are the foci of interventions in this review, we also discuss secondary analyses for completeness. Post hoc analytic results should be given less weight when weighing up the evidence.

Non-Pharmacological Interventions

Multi-domain 

One single-blind cluster-randomised trial of 498 patients was included (7). Intervention involved lifestyle advice as well as regulation of metabolic parameters, including treatment of chronic conditions where applicable. Participants had Type 2 diabetes and were free from disorders affecting cognition. The primary outcome was a cognitive function composite score that included measures of memory, information-processing speed, attention and executive function. The study had a mean duration of 6.8 years. Between-group differences were not observed in primary or secondary analyses at first or second follow-up, and cognitive scores in both groups declined.

Nutrition and Supplementation

Long chain polyunsaturated n-3 fatty acids.  Three placebo-controlled double-blind RCTs were included. Primary outcomes were cognitive function or cognitive performance. All studies used eicosapentaenoic acid and docosahexaenoic acid (EPA-DHA) 400mg to 1800mg as treatment. One study also included alpha-linolenic acid (ALA) 2g (8). There were 4080 participants aged 65+ of which 4044 were cognitively healthy. Study size ranged from 302 (9) to 2911 (8). Geleijnse et al.(8) included only coronary patients. Study duration varied from 26 weeks (9) to 40 months (8). There were no overall effects of EPA-DHA on cognitive performance (9, 10); however, van de Rest et al. (9) observed benefits of treatment on attention in carriers of the APOE-ε4 allele and in men in the low dose group after 26 weeks. In the study of coronary patients, there was a borderline benefit to men taking ALA treatment. In the same treatment group, risk of cognitive decline was reduced in the following subgroups: subjects with myocardial infarction in the 4 years prior to the study, those aged younger than 70, and those with a fish intake of more than 20g per day.

Homocysteine-lowering treatment. Two placebo-controlled double-blind RCTs were reviewed. There were 2024 participants and four treatment groups in total. Study sizes were 1748 (11) and 276 (12). In both studies treatment involved folate, vitamin B-12 and vitamin B-6. Andreeva et al. (11) also included EDA-DHA treatment alone and combined with B vitamins. Dosage was once daily for a duration of two (12) and four years (11). Primary outcome for both studies was cognitive function. In both studies, individuals aged over 65 who received B vitamins had poorer overall scores compared to placebo or EDA-DHA groups. Andreeva et al. (11) found no treatment effect on younger individuals but observed that cardiovascular disease was associated with lower temporal orientation and semantic memory sub scores. McMahon et al. (12) observed longer reaction times on the Trail-Making test, measuring attention and task switching, in the treatment group.

Antioxidant supplementation. Three placebo-controlled double blind RCTs were reviewed. There were 9386 participants in total, 95 of whom were male. Study size ranged from 185 (13) to 6377 (14). The two largest RCTs included only women (14, 15). Antioxidant treatment consisted of vitamin E taken orally. Two studies included additional vitamin C and beta carotene treatments (13, 14). Cognitive function was the primary outcome. Duration of studies ranged from 12 months (13) to 5.6 years (14). None of these studies reported dementia incidence as an outcome. Overall, no main effects were found for vitamin E or beta carotene on cognitive function. In the vitamin C treatment groups, Kang et al. (14) reported better cognitive composite and subtest scores at final follow up compared to controls. In secondary analyses, one study observed beneficial effects of vitamin E treatment in women with diabetes, those with low dietary intake of vitamin E, and in those reporting engaging in physical activity less than once per week (15). Similarly, Kang et al. (14) reported cognitive benefits of ß-carotene in women with low dietary intake of carotenoids. This study also reported a positive modifying effect of new cardiovascular events for women receiving vitamin C.

Multivitamin supplementation. One double-blind RCT of 910 adults was reviewed (16). Primary outcome was cognitive function, based on verbal fluency and digit span forward, a test of verbal working memory. After 12 months, there were no between group differences.

Subgroup analyses showed a weak positive effect of treatment on verbal fluency in subjects aged 75 or older, and in those at higher risk of nutritional deficiency.

Gingko biloba. Two double blind placebo-controlled RCTs and one large pilot study were included. In total, 6041 older adults were allocated to three treatment and three placebo groups. Study size ranged from 118 (17) in the pilot study to 3069 (18). In two studies, treatment was 120mg of gingko biloba extract (18, 19). The pilot study administered 240mg of gingko biloba as well as a daily multivitamin (17). Duration of studies varied from 42 months (17) to 6.1 years (18). Primary outcomes were cognitive decline (17) and dementia incidence (18, 19). Where dementia was the outcome measure, subjects with mild cognitive impairment were not excluded. Results reported here reflect only those of cognitively healthy individuals.

No overall between group differences were found where dementia incidence was the outcome. In subgroup analyses Vellas et al. (19) observed treatment effects by sex, alcohol consumption and duration of treatment. Snitz et al. (18) found no effect of covariates.

Outcome measures for cognitive decline were a Clinical Dementia Rating (CDR) scale score of 0.5, interpreted as presence of mild cognitive impairment (MCI), and a delayed recall test to assess decline in memory function. No treatment effect was observed over 24 months.

Secondary analyses showed a protective effect of gingko biloba on CDR and, when adherence was controlled for, on decline in memory function. Depression was found to predict progression of cognitive decline. Results were not retained when controlling for other covariates.

Cognitive Training 

Two single-blind RCTs were included. Participants totalled 3045, and included older adults.One study included only women with a study size of 259 (20). The second RCT included 2786 participants (21). Duration and frequency of cognitive training differed between studies, and included sessions of 60 to 90 minutes up to three times per week for a period of 6 months (20) or 5 years (21). Primary outcomes were cognitive function (20) and incident dementia (21). Where dementia was an outcome, group allocation was unrelated to dementia incidence. Age, gender, race, physical functioning, mini-mental state examination (MMSE) score and diabetes predicted incident dementia; however, the effect of these covariates were not modified by cognitive training.

Where cognitive function was an outcome, the treatment group showed improved scores on one measure of episodic memory. The treatment group also maintained scores on another measure of episodic memory and an executive function task while the control group’s performance declined. There were no between group differences on other measures.

Physical Activity

Two single blind RCTs were reviewed. In total there were 414 participants, all of whom were female (20, 22). Study sizes were 155 (22) and 259 (20). Interventions varied in frequency and type of physical activity, with study durations of 6 months (20) and 52 weeks (22). The primary outcome was cognitive function. For this intervention there were no studies where dementia was an outcome.

At six months, one study observed beneficial between group effects of treatment over time (20). Liu-Ambrose et al. (22) found no effect at the six-month midpoint of the trial, but observed improved cognitive performance in the treatment group at final follow up.

Pharmacological Interventions

Hormone Replacement Therapy (HRT) 

Six double blind placebo-controlled RCTs and one systematic review were included. Participants numbered 13229 in total. Study size ranged from 87 (23) to 4532 (24). One study included  men (25). Studies differed in the type of HRT used and included didehydroepiandrosterone (DHEA), conjugated equine estrogen plus medroxyprogesterone acetate (CEE +MPA), raloxifene, raloxifene + calcium + vitamin D and estradiol. Duration of studies ranged from 8 months (23) to 5.21 years (24). Primary outcomes were effects of treatment on cognitive function (23, 25-27) and incidence of MCI  or dementia (24, 28).

Where primary outcome was incidence of MCI, dementia or Alzheimer’s disease, a study with raloxifene, calcium and vitamin D treatment reported reduced risk of MCI in subjects receiving the highest dose (28). The systematic review demonstrated a reduced risk of dementia with HRT; however, they reported great heterogeneity among studies and a number of methodological issues that may affect validity of results (29). In contrast, Shumaker et al. (24) found that CEE + MPA and CEE only treatment were associated with increased risk of dementia and MCI. Risk was greater in older subjects and those with lower MMSE scores at baseline.

Of RCTs concerned with cognitive function, most reported no between group differences or change over time. One study observed less decline in task performance in the treatment group, but only in women with average or above average baseline scores (27). Similarly, the systematic review found benefits of HRT to be specific to cognitive functions and only in women with menopausal symptoms (29).

Anti-hypertensives

Six double blind RCTs, two meta-analyses and one systematic review were included.  Participants totalled 85014 and were adults aged over 55 with hypertension or a vascular health condition such as recent cerebrovascular disease, type 2 diabetes or vascular disease. Study size varied from 1140 (30) to 25620 (31). Treatment differed between studies and included angiotensin-converting-enzyme (ACE) inhibitors, diuretics, calcium channel blockers, beta blockers, angiotensin receptor blockers (ARB) or a combination of medications. Duration of studies ranged from 2 years (32) to 5 years (33). Outcomes were dementia and cognitive function. Five studies measured both outcomes. Dementia was an outcome in nine RCTs, one meta-analysis and the review article. Results varied by treatment type, and anti-hypertensive treatment alone had no effect on dementia incidence (32, 34). In a meta-analysis, Staessen et al. (34) found no effect of ACE-inhibitors and ARB treatment on dementia incidence, but use of diuretics and calcium channel blockers reduced risk of dementia by 18%. The review article also observed benefits for calcium channel blockers but, in contrast with Staessen et al., a benefit was also found for ACE-inhibitors (32). In the present review, there were no overall between-group differences for ARB or diuretic treatment alone or combined with ACE-inhibitors (30, 31, 35-37). In secondary analyses, one RCT reported benefits of ARB treatment in participants with low cognitive function at baseline (37). Similarly, an RCT with diuretic plus ACE-inhibitor treatment found treatment to be effective only in subjects with recurrent stroke (35). When calcium channel blockers were used alone or combined with other treatments, dementia incidence was reduced (38).

Where cognitive function was an outcome, cognition was not affected by ACE-inhibitors, alone or combined with ARB treatment, or diuretic plus beta-blocker treatment (30, 31, 33). No other benefits or between-group differences were recorded.

Statins

Two double blind RCTs and one meta-analysis were reviewed. Participants numbered 22252 in total. Study size for RCTs were 2528 (39) and 5804 (40). The meta-analysis had a study size of 13920 (41). The type and dosage of statin differed between studies. Study duration varied from 6 months (39) to 8.4 years (40). Primary outcomes were cognitive function and incidence of Alzheimer’s disease or dementia. Where Alzheimer’s disease and dementia were outcomes, the RCT demonstrated a reduced risk of Alzheimer’s disease associated with ongoing use of lipid lowering statins (39). These results were similar for any lipid-lowering treatments regardless of whether they were statins. There was no effect of treatment on incidence of MCI or MMSE scores. Similarly, the meta-analysis found a protective effect of statins against dementia; however, these effects became non-significant after adjusting for other covariates (41).

Where cognitive function was an outcome, Shepherd et al. (40) observed no between-group differences in cognitive change across time. Cognitive function declined at the same rate in treatment and control groups.

NSAIDS

One double blind RCT from the Alzheimer’s disease Anti-Inflammatory Prevention Trial was included. Participants were 2071 (42) adults aged 70 or older with a family history of Alzheimer’s-like dementia. Study duration was 21 (42) months. Primary outcome was incidence of Alzheimer’s disease (42). Treatment was celecoxib or naproxen taken twice daily. Outcome measures included a battery of cognitive tests, modified mini-mental state examination (3MS-E), self-rated memory, the Geriatric Depression Scale (GDS) and informant-rated Dementia Severity Rating Scale (DSRS). Treatment was positively associated with diagnosis after baseline dementia was controlled for. Secondary analyses showed that increased risk disappeared after the first 2.5 years and was associated with cognitive impairment at baseline. Furthermore, naproxen had a late protective effect in participants with no cognitive decline.

Aspirin

Two double-blind RCTs were included. There were 9727 participants in total, and one study included only women (43). Study sizes were 3350 (44) and 6377 (43). Duration of studies ranged from 5 (44) to 9.6 years. (43) Cognitive function was the primary outcome in both studies and was measured by a battery of cognitive tests to form a general or composite score. For this intervention, no studies were found with dementia as an outcome.

In primary analyses, treatment had no effect on general cognitive scores. One study demonstrated benefit of treatment on a test of executive function (43). In the same study, secondary analyses found a positive association between treatment and cognition for current smokers and women with high cholesterol. There were no between-group differences in the second study (44).

Discussion

This review aimed to assess existing research on primary prevention of dementia and cognitive decline. The results, summarised in Table 1, demonstrated little evidence of effective interventions against dementia and cognitive decline in the current literature. Quality of studies appeared to have no effect on results. For example, when we isolated the highest and lowest rated studies, there were few differences in treatment effects.

Overall, the results of published trials yielded few significant effects, with those detected generally being eliminated after controlling for covariates, or only identifiable in sub-groups.

These observations were true across interventions, with some notable exceptions. Favourable results were identified in physical activity, anti-hypertensive and statin interventions.

Physical activity interventions showed benefits to cognitive function in the two studies included. Given the variability in type of exercise, study quality and design these results should be interpreted with caution. Consideration should also be given to the relatively small size of these studies. While results are encouraging, larger studies with similar types of physical activity interventions would allow for more meaningful comparisons.

In antihypertensive interventions, calcium channel blockers were associated with reduced risk of dementia. These results are compelling as no other antihypertensive treatment showed consistent benefits for cognitive decline or dementia risk reduction. In addition, Anderson et al. (31) found that lowering blood pressure alone had no effect on cognition, highlighting the need to focus on treatment types in future interventions.

Results for statins were inconsistent across studies. In their RCT, Sparks et al. (39) found reduced dementia risk for all lipid-lowering treatments rather than specifically for statins. In addition, significant effects identified in the meta-analysis disappeared when controlling for other variables.

Interventions using B vitamin treatment or NSAIDs appeared to increase risk of dementia and cognitive decline. In the case of B vitamin treatment, overall detrimental effects were limited to participants aged over 65, certain subtests or, in one study, cardiovascular conditions (11). It should be noted that McMahon et al.(12) included only participants aged over 65 and, in this study, the effect of treatment on younger individuals cannot be surmised. Furthermore, the general association between treatment and cognitive decline was weak with one study observing borderline significant benefits of B vitamin treatments on cognition (11).

The NSAIDs intervention showed an increased risk of Alzheimer’s disease in the first 2 to 3 years of treatment. The risk was greater for participants with cognitive impairment or dementia erroneously included at baseline, and one analysis found a possible late protective effect of naproxen treatment in those with no cognitive deficit at baseline (42).

The present review provides a valuable overview of the current literature; however, it has several limitations. By focusing solely on primary prevention, we excluded any studies failing to control for cognitive decline. It is possible that by restricting the review to cognitively healthy individuals, we may have excluded good quality studies with more meaningful results. Similarly, broader search terms may have yielded a wider range of meaningful interventions. For example, by excluding studies with a sample size less than 50 and short follow ups, we may have missed informative studies. Limiting our search to RCTs and systematic reviews may have also impacted our findings. In particular, time-limited RCTs may fail to capture long term effects of treatment given the gradual development of dementia and cognitive impairment. Inclusion  of observational studies, for example, may provide further insight into prevention strategies.

This research needs to be viewed in the context of the length of exposure of risk factors, and the length of time over which neuropathological changes leading to dementia take place. As dementia and cognitive decline occur primarily in old age, the time scale of effects occurs over many decades. Hence, it is possible that intervention studies, which are at an early stage of development in this field, are not adequately targeting critical periods in the life course when they may be most effective. Failure to administer interventions at critical time points may confound or dilute effects. Identifying optimum timing of dementia prevention strategies would not only reduce heterogeneity of participant age in current literature, but may yield more robust results. The issue of follow-up time is similarly important. Follow-up intervals in studies are typically short, whereas dementia pathology develops over decades (45). Consequently, studies with limited follow-up times, particularly those of less than 12 months, may fail to capture longer-term effects.

In addition, trials may not use adequate treatment doses. For example, we still do not know the optimal amount of physical activity, cognitive activity or nutritional components for reducing risk of Alzheimer’s or dementia. The lack of consensus regarding dosage may contribute to considerable variability between studies and mask any significant effects. Similarly, inconsistencies in outcome measures and quality of studies impede meaningful comparison between studies. It is also possible that control conditions act as effective interventions. Mere involvement in a trial is a form of social engagement and stimulation that may have some cognitive benefits for participants or lead to behaviour change and risk reduction.

To date very few interventions targeting modifiable risk factors for dementia and cognitive decline have been shown to be effective. This review presents existing evidence while identifying gaps in the literature, particularly for large-scale multidomain interventions. Primary prevention studies are an important component of current research that could ultimately lead to reduced incidence and impact of dementia. While the review presents mixed results, the few effects identified show potential in the area of primary prevention. In part, the lack of significant results is due to methodological reasons and future research should aim to improve our capacity to detect effective intervention by targeting more specific age-groups, implementing longer follow-up periods to best capture meaningful effects, using more consistent outcome measures, and ensuring treatment dosage is precisely measured even in non-pharmacological interventions.

Acknowledgements & Funding: This study was partly funded by the Dementia Collaborative Centre, Early Detection and Prevention. ABF is funded by an Alzheimer’s Australia Fellowship. NC is funded by ARC Fellowship 12010227 and KJA by NHMRC Fellowship APP1002560. The authors declare that they have no competing interests 

Conflicts of Interest: The authors have no conflicts of interest

Ethical standards: This is a literature review and ethical approval was not required.

References

1. Lobo A, Launer L, Fratiglioni L, et al. Prevalence of dementia and major subtypes in Europe: a collaborative study of population-based cohorts. Neurology 2000; 54: S4-S9. 

2. Ziegler-Graham K, Brookmeyer R, Johnson E and Arrighi HM. Worldwide variation in the doubling time of Alzheimer’s disease incidence rates. Alzheimer’s & Dementia 2008; 4: 316-323. 

3. de la Torre JC. Alzheimer’s disease is incurable but preventable. Journal of Alzheimer’s Disease 2010; 20: 861-870. 

4. Patterson C, Feightner J, Garcia A and MacKnight C. General risk factors for dementia: A systematic evidence review. Alzheimer’s & dementia : the journal of the Alzheimer’s Association 2007; 3: 341-347. 

5. Plassman BL, Williams JW, Jr., Burke JR, Holsinger T and Benjamin S. Systematic review: factors associated with risk for and possible prevention of cognitive decline in later life. Ann Intern Med 2010; 153: 182-93. 

6. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Controlled Clinical Trials 1996; 17: 1-12. 

7. Koekkoek PS, Ruis C, van den Donk M, et al. Intensive multifactorial treatment and cognitive functioning in screen-detected type 2 diabetes—The ADDITION-Netherlands study: A cluster-randomized trial. Journal of the neurological sciences 2012; 

8. Geleijnse JM, Giltay EJ and Kromhout D. Effects of n-3 fatty acids on cognitive decline: A randomized, double-blind, placebo-controlled trial in stable myocardial infarction patients. Alzheimer’s & Dementia 2012; 8: 278-287. 

9. Van de Rest O, Geleijnse J, Kok F, et al. Effect of fish oil on cognitive performance in older subjects A randomized, controlled trial. Neurology 2008; 71: 430-438. 

10. Dangour AD, Allen E, Elbourne D, et al. Effect of 2-yn− 3 long-chain polyunsaturated fatty acid supplementation on cognitive function in older people: a randomized, double-blind, controlled trial. The American Journal of Clinical Nutrition 2010; 91: 1725-1732. 

11. Andreeva VA, Kesse-Guyot E, Barberger-Gateau P, et al. Cognitive function after supplementation with B vitamins and long-chain omega-3 fatty acids: ancillary findings from the SU. FOL. OM3 randomized trial. The American Journal of Clinical Nutrition 2011; 94: 278-286. 

12. McMahon JA, Green TJ, Skeaff CM, et al. A controlled trial of homocysteine lowering and cognitive performance. New England Journal of Medicine 2006; 354: 2764-2772. 

13. Smith A, Clark R, Nutt D, et al. Antioxidant vitamins and mental performance of the elderly. Human Psychopharmacology: Clinical and Experimental 1999; 14: 459-471. 

14. Kang JH, Cook NR, Manson JE, et al. Vitamin E, Vitamin C, Beta Carotene, and Cognitive Function Among Women With or at Risk of Cardiovascular Disease The Women’s Antioxidant and Cardiovascular Study. Circulation 2009; 119: 2772-2780. 

15. Kang JH, Cook N, Manson J, Buring JE and Grodstein F. A randomized trial of vitamin E supplementation and cognitive function in women. Archives of Internal Medicine 2006; 166: 2462. 

16. McNeill G, Avenell A, Campbell MK, et al. Effect of multivitamin and multimineral supplementation on cognitive function in men and women aged 65 years and over: a randomised controlled trial. Nutr J 2007; 6: 1-5. 

17. Dodge H, Zitzelberger T, Oken B, Howieson D and Kaye J. A randomized placebo-controlled trial of Ginkgo biloba for the prevention of cognitive decline. Neurology 2008; 70: 1809-1817. 

18. Snitz BE, O’Meara ES, Carlson MC, et al. Ginkgo biloba for preventing cognitive decline in older adults. JAMA: the journal of the American Medical Association 2009; 302: 2663-2670. 

19. Vellas B, Coley N, Ousset P-J, et al. Long-term use of standardised ginkgo biloba extract for the prevention of Alzheimer’s disease (GuidAge): a randomised placebo-controlled trial. The Lancet Neurology 2012; 

20. Klusmann V, Evers A, Schwarzer R, et al. Complex mental and physical activity in older women and cognitive performance: a 6-month randomized controlled trial. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 2010; 65: 680-688. 

21. Unverzagt FW, Guey LT, Jones RN, et al. ACTIVE Cognitive training and rates of incident dementia. Journal of the International Neuropsychological Society 2012; 18: 669. 

22. Liu-Ambrose T, Nagamatsu LS, Graf P, et al. Resistance training and executive functions: a 12-month randomized controlled trial. Archives of Internal Medicine 2010; 170: 170. 

23. Goebel JA, Birge SJ, Price SC, Hanson JM and Fishel DG. Estrogen replacement therapy and postural stability in the elderly. Otology & Neurotology 1995; 16: 470-474. 

24. Shumaker SA, Legault C, Kuller L, et al. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women. JAMA: the journal of the American Medical Association 2004; 291: 2947-2958. 

25. KritzSilverstein D, Von Mühlen D, Laughlin GA and Bettencourt R. Effects of Dehydroepiandrosterone Supplementation on Cognitive Function and Quality of Life: The DHEA and WellNess (DAWN) Trial. Journal of the American Geriatrics Society 2008; 56: 1292-1298. 

26. Nickelsen T, G Lufkin E, Lawrence Riggs B, A Cox D and H Crook T. Raloxifene hydrochloride, a selective estrogen receptor modulator: safety assessment of effects on cognitive function and mood in postmenopausal women. Psychoneuroendocrinology 1999; 24: 115-128. 

27. Tierney MC, Oh P, Moineddin R, et al. A randomized double-blind trial of the effects of hormone therapy on delayed verbal recall in older women. Psychoneuroendocrinology 2009; 34: 1065-1074. 

28. Yaffe K, Krueger K, Cummings SR, et al. Effect of raloxifene on prevention of dementia and cognitive impairment in older women: the Multiple Outcomes of Raloxifene Evaluation (MORE) randomized trial. American Journal of Psychiatry 2005; 162: 683-690. 

29. LeBlanc ES, Janowsky J, Chan BK and Nelson HD. Hormone replacement therapy and cognition. JAMA: the journal of the American Medical Association 2001; 285: 1489-1499. 

30. Patel A. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. The Lancet 2007; 370: 829-840. 

31. Anderson C, Teo K, Gao P, et al. Renin-angiotensin system blockade and cognitive function in patients at high risk of cardiovascular disease: analysis of data from the ONTARGET and TRANSCEND studies. The Lancet Neurology 2011; 10: 43-53. 

32. Hanon O and Forette F. Prevention of dementia: lessons from SYST-EUR and PROGRESS. Journal of the neurological sciences 2004; 226: 71-74. 

33. Applegate WB, Pressel S, Wittes J, et al. Impact of the treatment of isolated systolic hypertension on behavioral variables: results from the Systolic Hypertension in the Elderly Program. Archives of Internal Medicine 1994; 154: 2154. 

34. Staessen JA, Thijs L, Richart T, Odili AN and Birkenhäger WH. Placebo-Controlled Trials of Blood Pressure–Lowering Therapies for Primary Prevention of Dementia. Hypertension 2011; 57: e6-e7. 

35. Tzourio C, Anderson C, Chapman N, et al. Effects of blood pressure lowering with perindopril and indapamide therapy on dementia and cognitive decline in patients with cerebrovascular disease. Archives of Internal Medicine 2003; 163: 1069-1075. 

36. Peters R, Beckett N, Forette F, et al. Incident dementia and blood pressure lowering in the Hypertension in the Very Elderly Trial cognitive function assessment (HYVET-COG): a double-blind, placebo controlled trial. The Lancet Neurology 2008; 7: 683-689. 

37. Trenkwalder P. The Study on COgnition and Prognosis in the Elderly (SCOPE)-recent analyses. Journal of hypertension 2006; 24: S107-S114. 

38. Forette F, Seux M-L, Staessen JA, et al. The prevention of dementia with antihypertensive treatment: new evidence from the Systolic Hypertension in Europe (Syst-Eur) study. Archives of Internal Medicine 2002; 162: 2046. 

39. Sparks DL, Kryscio RJ, Sabbagh MN, et al. Reduced risk of incident AD with elective statin use in a clinical trial cohort. Current Alzheimer Research 2008; 5: 416-421. 

40. Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. The Lancet 2002; 360: 1623-1630. 

41. Zhou B, Teramukai S and Fukushima M. Prevention and treatment of dementia or Alzheimer’s disease by statins: a meta-analysis. Dement Geriatr Cogn Disord 2007; 23: 194-201. 

42. Breitner JC, Baker LD, Montine TJ, et al. Extended results of the Alzheimer’s disease anti-inflammatory prevention trial. Alzheimer’s & Dementia 2011; 7: 402-411. 

43. Hee Kang J, Cook N, Manson J, Buring JE and Grodstein F. Low dose aspirin and cognitive function in the women’s health study cognitive cohort. BMJ 2007; 334: 987. 

44. Price JF, Stewart MC, Deary IJ, et al. Low dose aspirin and cognitive function in middle aged to elderly adults: randomised controlled trial. BMJ: British Medical Journal 2008; 337: 

45. Jack Jr CR, Knopman DS, Jagust WJ, et al. Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. The Lancet Neurology 2010; 9: 119-128. 

Supplementary Table 1.

 

Supplementary Table 2.

Supplementary Table 3.