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C. Takeda1, S. Guyonnet2, Y. Sumi3, B. Vellas2, I. Araujo de Carvalho3


1. Gérontopôle, Department of Geriatrics, CHU Toulouse, Toulouse, France; 2. Inserm UMR 1027, Toulouse, France; University of Toulouse III, Toulouse, France; Gérontopôle, Department of Geriatrics, CHU Toulouse, Toulouse, France; 3. Department of Ageing and Life Course, World Health Organization, avenue Appia 20, 1211 Geneva 27, Switzerland

Corresponding Author: C. Takeda, Gérontopôle, CHU Toulouse, Cité de la Santé, Hôpital La Grave, Place Lange, 31059 Toulouse cedex 9, France, Tel : +33.(0), Fax +33.(0), E-mail:

J Prev Alz Dis 2020;
Published online March 2, 2020,



Backgrounds: The World Health Organization has published the Integrated Care for Older People, ICOPE handbook Guidance on person-centred assessment and pathways in primary care. This is an integrated individual care tool focused on the individual and healthy ageing. The ICOPE tool proposes step by step, a screening, a fine assessment, the development of a personalized care plan, its implementation and follow up and finally the consideration of the caregivers and community. The new Geroscience field is focusing on preventing age-related diseases, and should now investigate with the ICOPE tool the optimal maintenance of intrinsic capacity (IC) through mobility, cognition, psychology, vitality, hearing and vision. This article aims to present this new tool and to presents its innovative implementation at the Toulouse University Hospital through the INSPIRE study. We believe that the ICOPE integrated care program will also be a pragmatic way to maintain cognitive functions and detect early Alzheimer.
Objectives: The main objective of the INSPIRE study is to build a Bio-resource Research Platform for Healthy Ageing gathering biological, clinical and digital resources in order to identify markers of ageing, age-related diseases and IC evolution. The study will be also testing the implementation and follow up of the ICOPE tool.
Methods: The Inspire Platform will gather clinical data and bio-specimens from 1000 subjects in the Occitania Region, of different ages (from 30 years and over) over 10 years. Data will be collected annually. Using the ICOPE tool IC domains will be monitored every 4 months. Once IC decline is identified, participants will have a thorough clinical assessment and blood sampling to investigate the response of markers of ageing at the time of decline. The French ethic committee approved the study.
Results: The Inspire platform aims to develop an integrative approach to promote novel new technologies for the assessment and monitoring of functional capacities.

Key words: Integrated care, person-centred assessment, intrinsic capacity, primary care.


On October 1st 2019, for the International day of Older Persons, the World Health Organization (WHO) published the Integrated Care for Older People (ICOPE) handbook Guidance on person-centred assessment and pathways in primary care (1) and launched its digital app «ICOPE Handbook app» for health and social care workers (2). This article aims to present these new ICOPE tools and to show its innovative implementation at the Toulouse University Hospital through the INSPIRE study.
Currently there is an unprecedented rapid change in global demographic, so far the number of young children was higher than older people but within a few years this balance will be reversed. The number of people aged 65 and over will be greater than the number of children under 5 years old (3). This is due to the rapid increase in the proportion of older people linked in particular to longer life expectancy and decreased fertility. In 2017, there were about 962 million people aged 60 and over, comprising 13% of the global population. One in five person will be 60 years of age or older by 2050 (1). These ICOPE tools are the continuity of a work begun in 2014 by WHO, in response to the global ageing of the population, following the United Nations Sustainable Development Goals of universal coverage of care (SDG3) and in particular for older people (4). In 2015, WHO introduces «healthy ageing» defined by the development and maintenance of functional ability enabling the well-being of older people (5). Functional ability allow healthy aging through i) the response to basic needs, (ii) learning, continuing to improve and making decisions, iii) to be mobile, iv) to be able to build and maintain social relations, (v) to be able to contribute within one’s family, friends and community (1). In 2017, WHO guidelines on community-level interventions to manage declines in intrinsic capacity in older people, lay the groundwork for integrated care for older people (6) based on evidence-based interventions offering 13 recommendations for health professionals. WHO defines intrinsic capacity as the composite of all physical and mental capacities and functional ability as the combination and interaction of intrinsic capacity with the person’s environment (1). Trajectory of intrinsic and functional ability over the life course can be divided into three periods: a relatively stable and high capacity period, a period of capacity decline and a period of significant loss of capacity characterized by care dependency. WHO targets six domains of intrinsic capacity: cognition, mobility, vitality represented by nutrition, mood, vision and hearing (1). The challenge of intrinsic capacity is to identify conditions associated with declines in intrinsic capacity even before the older person becomes frail in order to delay or even reverse this decline. The conventional approach to medicine, the curative model (clinical signs, diagnosis and treatment) needs to integrate this person-centred approach to maintain the well-being of older people. Implementing the ICOPE approach and maintaining it over the life-course is a challenge for our health and social care system. WHO proposes an ICOPE approach by setting person-centred goals, supporting self-management, screening for loss in intrinsic capacity, assessing health and social care needs, supporting caregivers and developing a personalized care plan (1). There are five steps in the ICOPE approach: Step 1 is a screening in search of decline in intrinsic capacity; Step 2 is person-centered assessment in primary care. Step 3 develops a personalized care plan with a multidisciplinary team. Step 4 is the implementation of the care pathway with regular monitoring in link to specialized geriatric care. Finally, Step 5 is the integration of the caregivers and the community.
The ICOPE screening tool (1) in Step 1, proposed by WHO is a simple tool, which can be used in the community and primary care settings, after training, by health and social care workers who are not necessarily medical doctors. This tool can also be used for the follow-up.
The screening tool comes in the form of questions or tests to screen declines of intrinsic capacity (figure 1 ICOPE screening tool (1)). The examiner must fill in the screening tool by checking the corresponding boxes. Conducting the screening test takes about 8 minutes. These are simple and reproducible tests over time. In case of signs of decline during screening, a more detailed assessment is necessary by switching to Step 2.

Figure 1. WHO ICOPE screening tool

Figure 1. WHO ICOPE screening tool


Step 2 is a more detailed, person-centred assessment. This assessment is carried out by a trained staff, but not necessarily by a medical doctor. First, you need to understand the person’s life, his or her values, priorities and preferences. Assess for decline of intrinsic capacity, look for underlying diseases and assess the person’s environment. This will help create personalized care plan in Step3.
Step 3 sets a goal and develops a personalized care plan in partnership with the individual, the caregivers and social workers. The objective is optimizing intrinsic capacity and functional ability in the integration of care. It is also an opportunity to monitor the progress and impact of interventions for the person. It is essential that the older person and caregiver(s) participate in the development of the goals. The personalized care plan includes self-management, advices, ICOPE interventions, management of chronic diseases and the consideration of the environment.
The Step 4 is the implementation and monitoring of the personalized care plan with referral to the specialist(s) if needed. Regular monitoring allows monitoring progress and adapting supports as needed. Addressing specialists, through defined care pathways, is essential for prompt management during acute events but also in palliative care situations. WHO stresses the importance of geriatric involvement at this level, due to the expertise in geriatric syndromes, polypharmacy and specific pathologies such as dementia. They must be intertwined with the care of the patient by assisting the primary care team.
The goal of Step 5 is to enlist the community and support caregivers. Indeed, the work of caregiver can be hard and sometimes requires the integration of interventions for the caregiver. This must be taken into account when developing the personalized care plan (training, advice and information resources).
The ICOPE approach is based in community and primary care settings, with the aim of ensuring that it is accessible to as many people as possible and emphasizes on strong links with specialists. For each domain of intrinsic capacity, the guide offers a care pathway (1) (figure 2). The ICOPE app offers a detailed assessment of decline and a person-centred care pathway (figure 3) (2).

Figure 2. WHO ICOPE Pathways

Figure 2. WHO ICOPE Pathways

Figure 3. WHO ICOPE app

Figure 3. WHO ICOPE app


In the final part of the guide, WHO briefly addresses the issue of the implementation and long-term maintenance of the integrated approach of older people. WHO provides ICOPE implementation framework Guidance for systems and services (7). Multiple studies have attempted to implement an integrated approach to older adults, but to date there is no consensus. The project will not be viable without national support. Upstream studies are needed, to determine the feasibility of the project (financial and organizational support) and the sustainability of the action (efficiency and workforce capacity). To support healthy ageing, there needs to be consistency and integration of all stakeholders, health system and social services.
At the same time, the Toulouse University Hospital is launching the INStitute for Prevention healthy agIng and medicine REjuvenative (INSPIRE) study, in align with the implementation of ICOPE in primary care in the Occitania region, by systematically applying the ICOPE screening tool every 4 months over 10 years.
The main objective of the INSPIRE study is to create an innovative research platform combining biological, clinical (including imaging data) and digital data from patient in primary care. These data will help identify biomarkers of ageing, and track the evolution of markers of the trajectory of intrinsic capacity (mobility, memory, mood, nutritional status, vision and hearing), from adulthood (30 years) to the most advanced ages (no upper age limit) and thus defining strategies for maintaining autonomy and preventing dependency.
The secondary objectives of the study are multiple:
– To create a web platform to track subjects remotely with collection of lifestyle and clinical data (especially on intrinsic capacity).
– To test the feasibility and acceptability of a smartphone and tablet application to remotely evaluate and monitor intrinsic capacity.
– Identify, using clinical, biological and digital data, markers of biological ageing that characterize systemic morphological and functional changes in the body, capable of predicting the temporal trajectory of domains of intrinsic capacity.
– To study the trajectory of different domains of intrinsic capacity over time (natural history), their interactions, predictors and the causes of their decline.
– To analyze data on the loss of intrinsic capacity, pejorative events and consumption in care, in order to define a better approach to care management.
– To study the rate of acceptability and adherence to screening, evaluation and monitoring of areas of intrinsic capacity (i.e. WHO’s ICOPE program) in different clinical settings, in order to contribute to the development of health and social care pathways focused on functional status by developing a clinical cohort.
– Discover markers that could be outcomes for clinical trials in the field of Geroscience.
– Exploring the development of digital markers of ageing through the ICOPE app.

The main study focuses on biomarker research with the study of two cohorts, a human cohort called a translational cohort and an animal cohort. Biomarkers can better predict health events, better track and treat patients. The biomarkers of ageing should differentiate people of different ages, but also those with faster ageing than others. They should also be associated with changes in function or morphological changes observed during aging. Finally, these biomarkers will have to predict serious acute events, sometimes observed during ageing such as chronic diseases, cancers or addiction.
In addition to these two main study cohorts, a third cohort (care cohort) is added, enabling an epidemiological study in primary care in the Occitania region of the implementation of the ICOPE screening tool through the systematic implementation of STEP 1 every 4 months, which will be monitored by the Toulouse regional team for ageing and prevention (Equipe régionale vieillissement et prevention de la dépendance). A final digital cohort will only be followed by the digital ICOPE application tailored to the study’s needs.

Expected outcome forward

In the event of a good response in Occitania, the Toulouse University Hospital hopes to be able to deploy this ICOPE approach at the national level. This approach is a real challenge for doctors in the context of the ageing population and the lack of a doctors in France (8). Screening for the decline of intrinsic capacity, systematic, short, achievable by all, in self-management every 4 months, would anticipate functional decline. This approach facilitates the work of the general practitioner and identifies health problems in common practice ahead of the acute event.

Acknowledgements and fundings: The Inspire Plateform is supported by grants from the Occitania Region and the European Regional Development Fund (ERDF), and co-funding by the APOC, the CTAD, and the Edenis, Korian, Pfizer, and Pierre Fabre groups. The promotion of this study is supported by the University Hospital Center of Toulouse

Conflicts of interest: The author declares no conflict of interest.

Open Access: This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, 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.


1. WHO-Handbook-ICOPE.pdf [Internet]. [cité 1 oct 2019]. Disponible sur:;jsessionid=31CB3214293723D1D9 A7D2B822B92D0E?sequence=1
2. WHO ICOPE Handbook App- Apps on Google Play. Accessed 10 November 2019. -Apps on Apple Store. Accessed 10 December 2019.
3. global_health.pdf [Internet]. Accessed 1 October 2019.
4. SDGs .:. Sustainable Development Knowledge Platform [Internet]. Accessed 1 October 2019.
5. Rapport mondial sur le vieillissement et la santé.pdf [Internet]. Accessed 1 October 2019.
6. World Health Organization, Department of Ageing and Life Course. Integrated care for older people: guidelines on community-level interventions to manage declines in intrinsic capacity. [Internet]. 2017 Accessed 1 October 2019.
7. Implentation framework.pdf [Internet]. Accessed 2 October 2019.
8. Santé M des S et de la. Lutter contre les déserts médicaux [Internet]. Ministère des Solidarités et de la Santé. 2019 Accessed 2 October 2019.


B. Fougère1,2, B. Vellas1,2, J. Delrieu1, A.J. Sinclair3, A. Wimo4, C.J. Herman5, H. Fillit6, S. Gauthier7, S. Oustric2

1. Gérontopôle, Centre Hospitalier Universitaire de Toulouse, Toulouse, France; 2. Inserm UMR1027, Université de Toulouse III Paul Sabatier, Toulouse, France; 3. Foundation for Diabetes Research in Older People, Diabetes Frail Ltd, Hampton Lovett, Worcestershire, UK; 4. Department of Neurobiology, Care Sciences and Society, Alzheimer’s Disease Research Center, Karolinska Institutet, Stockholm, Sweden; 5. University of New Mexico Center on Aging, 1720 Louisiana NE, Suite 300, Albuquerque, NM 87110, USA; 6. Alzheimer’s Drug Discovery Foundation, New York, New York, USA; 7. Alzheimer Disease Research Unit, Memory Clinic, McGill Centre for Studies in Aging, McGill University, Verdun, QC, Canada; 8. Department of Primary Care, University of Toulouse, Toulouse, France.

Corresponding Author: B. Fougère, Institut du Vieillissement, Gérontopôle, Université Toulouse III Paul Sabatier, 37 Allées Jules Guesde, 31000 Toulouse, France; Tel: +33561145657 ; Fax: +33561145640; E-mail address: (B. Fougère)

J Prev Alz Dis 2015;2(3):199-211
Published online June 10, 2015,


Most old adults receive their health care from their primary care practitioner; as a consequence, as the population ages, the manifestations and complications of cognitive impairment and dementia impose a growing burden on providers of primary care. Current guidelines do not recommend routine cognitive screening for older persons by primary care physicians, although the vast majority recommend a cognitive status assessment and neurological examination for subjects with a cognitive complaint. Also, no clinical practice guidelines recommend interventions in older adults with cognitive impairment in primary care settings. However, primary care physicians need to conduct a review of risks and protective factors associated with cognitive decline and organize interventions to improve or maintain cognitive function. Recent epidemiological studies have indicated numerous associations between lifestyle-related risk factors and incidental cognitive impairment. The development of biomarkers could also help in diagnosis, prognosis, selection for clinical trials, and objective assessment of therapeutic responses. Interventions aimed at cognitive impairment prevention should be pragmatic and easy to implement on a large scale in different health care systems, without generating high additional costs or burden on participants, medical and social care teams. Key words: Biomarker, cognitive impairment, elderly, multidomain intervention, prevention, primary care.

Key words: Biomarker, cognitive impairment, elderly, multidomain intervention, prevention, primary care.


Recent reports, generally based on population-based community studies or survey data, point out that despite declining incidence rates, the number of dementia patients will grow dramatically as the older  population increases (1). In a nationwide population-based study, approximately 14% of older adults aged 70 and older had dementia (2). The total number of people with dementia is projected to almost double every 20 years, to 65.7 million in 2030 and 115.4 million in 2050 (3). In primary care, between 10% and 15% of older adults have evidence of cognitive impairment (4,5). The prevalence of memory impairment with normal cognitive performance subjective (subjective memory complaint; SMC) in older adults ranges from 25 to 50% (6). SMC is an at-risk condition of developing AD (7–10). It has been shown that subjective memory complaints with self-reported worries is associated with a two-fold risk of AD dementia in comparison with subjective memory complaints without concerns (8,9). Prevalence of mild cognitive impairment (MCI) varies according to definition, but community prevalence rates of MCI in older adults have been reported to be 6.9% to 22% (5, 11, 12). Individuals with MCI develop dementia at a greater rate than those with normal cognition; conversion rates from MCI to dementia are approximately 12% per year (2, 13). When implementing preventive and therapeutic strategies for cognitive impairment, two options are possible: interventions on lifestyle and risk factors in large populations or a much more focused strategy offering targeted drug trials to participants selected on specific criteria and based on biomarkers (14, 15). Indeed, the high prevalence of vascular and lifestyle related risk factors are readily available, efficient and relatively cheap pharmacological and non-pharmacological interventions have raised the question of whether cognitive impairment could be prevented or postponed by a better risk factor management (16–19). It was estimated recently that up to 50% of the cognitive impairment cases worldwide are attributable to vascular risk factors and physical and cognitive inactivity, rendering these factors an extremely useful target for prevention (20). In this context, it is necessary to propose effective interventions in primary care to delay onset and/or modify the progression of cognitive impairment in older adults.     

This paper aims to propose some recommendations for the future management of older adults with memory complaints in primary care settings. Primary care physicians (often termed General Practitioners (GPs)) are often best placed to offer an intervention service as they frequently encounter patients who are potentially at risk of dementia and are able to implement risk factor modification approaches such life style advice, exercise management, alcohol and smoking advice, nutritional guidance; these are provided as part of a regular health monitoring environment in primary care. In fact we must be ready to:  (a) benefit from general intervention and promote participation in targeted drug trials; and (b) adapt our clinical practice to new drugs developed for dementia prevention. We propose to follow an algorithm based on the results of cognitive functions monitoring made by the primary care physician and on the existing frailty phenotype, if any. For patients with subjective memory impairment, the primary care physician must propose the management of the established modifiable risk factors for AD. If the patient has an objective memory complaint and is reported to be in good health, specific biomarkers can be realized. However, if the patient is frail, we need to identify multiple domains/causes of frailty and recommend a multidomain intervention strategy.

Older adults with subjective memory complaints and risk of dementia 

Primary care physicians are confronted frequently with older patients complaining about memory problems. Memory loss is an essential criterion  in the diagnosis of dementia and belongs to the first clinical signs of AD (21). Thus, SMC has become a key element in diagnostic concepts of pre-dementia in memory clinics (22–24). Studies in community-based settings have shown that a prevalence of SMC ranges between 25 to 50% (6) depending upon age and many other factors. SMC is not specific to Alzheimer’s disease. It is also found to be associated with depression (7, 25, 26), anxiety (25–27), certain personality traits (28, 29), higher level of general education (7) and level of knowledge about memory (27). While some studies show that the existence of SMC in healthy individuals is not correlated with objective measures of cognitive functions (26,30) or future cognitive decline (31–33), other studies have found that these complaints are indeed predictive of an unfavorable cognitive outcome (7, 34, 35). Naturally, SMC is more consistently associated with depression than cognitive impairment but evidence supports that depression is also a risk factor for dementia (36, 37). Therefore, the identification of memory complaints and advanced signs of cognitive deterioration are essential in the diagnostic process of suspected dementia and becoming a crucial issue with regards to the hopes of early intervention and in prevention trials. A study has also shown that healthy behaviors are associated with better self-sensed memory abilities throughout adult life, suggesting that lifestyle behavior habits may protect brain health and possibly delay the onset of memory symptoms as people age (38).


Cognitive screening instruments in primary care

The primary care physician has a central role in the management of older subjects with cognitive impairment. Assessments of potential cognitive impairment are often initiated and carried out in primary care.  Until now primary care physicians may not recognize cognitive impairment when using routine history and physical examination (39, 40) in as many as 76% of patients with dementia or probable dementia (41–43), and most of these patients are not diagnosed until they are at moderate to severe stages of the disease (44).  This can and must be improved. Early identification of mild dementia would ideally allow patients and their families to also receive specialist care at an earlier stage in the disease process, which could lead to a better prognosis and decreased morbidity (45). In fact, in primary care there are two ways to approach cognitive impairment. The first is clinical: someone (the patient, a family member, staff in social services or health care) has noticed or have a suspicion of a cognitive impairment and thus the question whether it is dementia is highlighted. Many patients themselves or family members experience memory problems or other slight cognitive symptoms and ask their primary care physicians “if it is Alzheimer´s disease” and such a question needs an answer. The second approach is a screening or case finding approach irrespective whether there is a suspicion of cognitive impairment or dementia or not, difficult in primary care.

Primary care physicians have indicated that they would like to know more about the diagnosis of dementia and would like to be responsible for initiating cognitive evaluations in their patients needing them but require tools to screen for cognitive impairment (43, 46, 47). Crucial for any diagnostic process of cognitive impairment is a good case history, which can be done in a structured way (48), aiming at describing the development of different domains of cognitive impairment. The primary barrier to the primary care physician involvement, is time and expertise particularly in cognitive assessments to distinguish age-related changes in memory from MCI. Ideally, a good cognitive test for use in primary care practice would be: brief, easily administered without props, easily memorized and scored, with high sensitivity and specificity for identifying impairment.

The aim is firstly to detect any episodic memory failure in a quick and simple manner. The family must be questioned about a recent event that the patient should remember (in family life or in the news). The patient is then questioned about this event. The primary care physician must also examine the patient’s ability to state his age, or give his date of birth. The family must also be questioned about memory problems such as repeated questions and forgetfulness of recent events. Next the MMSE (49) can be used, as it remains the reference tool, and in particular its three-word recall test, an important way to detect memory impairment simply. However, some consider that the MMSE takes too much time to be administered in general practice. For this reason, other tools have been developed such as the 7- minute screen (50), the MIS (Memory Impairment Screen) (51) the Mini-Cognitive Assessment Instrument (Mini-Cog) (52) and the GPCOG (General Practitioner of Assessment of Cognition) (53). Although memory impairment is the first sign to be looked for, evaluation of other cognitive functions and instrumental functions is also very important. Other useful tests are “the clock drawing test” (54) and “the five-words” (55), a test of verbal anterograde memory using free and cued recall, both immediate and delayed, which can be administered in standard clinical practice. As for the assessment of other cognitive domains, this can be done by a specialist. However, a verbal fluency test may be given together with qualitative evaluation of language (search for use of stereotyped speech, poor in content, conveying little information when questioned, with repetitive elements). In 2006, Brodaty et al reviewed the best tools for dementia detection and validation in general practice. Criteria used were: an administration time of less than 5 minutes and a negative predictive value at least equal to that of the MMSE. The MMSE, the clock-drawing test and the GPCOG seem to be the most useful, practical and validated tools for the detection of dementia in primary care (56) (Table 1). However, an active seeking or screening for all older patients in primary care in primary care cannot be recommended today (57). Applied on large populations, any screening can be unfavorable and may overloaded with false positive cases primary care physicians (and specialized clinical services). Thus, the solution is to increase the expected prevalence in the target population by a clinical “filter”, which today should be a patient who come in consultation for memory complaints (motive of consultation). Obviously, if effective disease modifying treatment will be available, the situation will have to change.

Table 1. Examination, biomarker, and application

Abbreviations: MRI, magnetic resonance imaging; FDG, fluorodeoxyglucose; PET, positron emission tomography; CSF, cerebrospinal fluid; ApoE ε4, Apolipoprotein E gene ε4 allele; AD7c-NTP, Alu sequence-containing cDNA neuronal thread proteins.

Based on the initial cognitive testing, primary care physicians often observe three categories of older adults with cognitive impairment (Figure 1):

– subjects in good health with normal cognitive performance (SMC; Subjective Memory Complaints),

– people in good health  with abnormal cognitive performance and,

– frail older adults with abnormal cognitive performance (cognitive frailty).

Figure 1. Older adults with memory complaints in primary care: decision algorithm

Abbreviations: CRP, C-reactive protein; GPCOG, General Practitioner of Assessment of Cognition; IL-6, Interleukin 6; MMSE, Mini Mental State Examination; MIS, Memory Impairment Screen; Mini-Cog, Mini-Cognitive Assessment Instrument; MRI, magnetic resonance imaging; CSF, cerebrospinal fluid; FDG, fluorodeoxyglucose; PET, positron emission tomography.


For each, we propose specific recommendations to optimize the management of these situations in patients in primary care. Other staff categories than primary care physicians, such as nurses, physiotherapists, occupational therapists may be also involved. Sometimes resources outside the primary care organization (such as volunteer organizations) may provide activities under the guidance of primary care.

Subjects in good health with normal cognitive performance (subjective memory complaints) 

For these subjects in good health and with normal cognitive function, the primary care physician’s focus should be on identifying and managing any established modifiable risk factors for AD and other dementias. The modifiable part of cognitive impairment includes lifestyle and vascular related risk factors such as education and social interactions, physical activity, cognitive training, smoking and alcohol intake and nutrition. This approach is already today part of the daily work in primary care for the prevention of cardiovascular disorders, obesity, diabetes etc. and thus it is not an increased burden of the work in primary care. In this context, to delay onset and/or modify progression of cognitive impairment, primary care physicians should to be able to provide lifestyle advice to their patients (Table 2).

Table 2. Studies on the effects of physical activity, social interactions and cognitive training, smoking and alcohol, and nutrition on cognition and or dementia risk

Abbreviations: AD, Alzheimer’s disease; APOE ε4 allele, ε4 allele of the apolipoprotein E gene; MCI, mild cognitive impairment; MMSE, mini mental scale examination; RCT, randomized controlled trial.

Education and social interactions

Education is a marker of cognitive reserve, along with professional occupation. It has been associated with a reduction in the risk of incident dementia (58,59). Better education provides protection against the clinical manifestation of dementia/AD, even in individuals with an unfavorable genetic background i.e. APOE ε4 carriers (60, 61). A study of the impact of white matter lesions (WML) on the risk of MCI and dementia was conducted on a cohort of 500 older subjects, over a 7-year period. It was reported that subjects with higher education were resistant to the harmful effects of WML on cognition (62). Another trial concluded that high cognitive reserve protected against the progression from normal cognition to the onset of clinical symptoms independent of amyloid levels in CSF, but was associated with low levels of t-tau and p-tau (63). A study in three  population cohorts reported that higher education reduced the risk of dementia; not due to any reduction in dementia-related neuropathology, but rather because of an increase in the threshold at which these pathological changes would manifest themselves clinically (64). Structural MRI analysis for cortical thickness and brain volume in a multicenter longitudinal study cohort, determined that more years of education was able to increase the threshold before which brain atrophy became manifest clinically among patients with AD, a phenomenon explained by increased cognitive reserve.

Social characteristics refer to a wide range of attributes. For example, high social networking, purpose in life, high education and socioeconomic position, involvement in cognitively challenging tasks and being in a relationship, are all claimed to be protective against AD (64–68).

Physical activity 

Physical activity in midlife has been shown to decreases the risk of dementia 26 years later (69). This can be explained by the decline in the cardiovascular risk profile and a reduction in brain tissue loss (69). Physical activity of high and moderate intensity decreased the risk of cognitive decline in healthy individuals by up to 38 and 35% respectively (70). Aerobic exercise reduced the risk of cognitive impairment and dementia. This can be attributed to either a direct neurotrophic effect of exercise or to an improvement in the cerebrovascular and cardiovascular risk profiles (71). In a prospective study with healthy participants, a Mediterranean diet and a higher level of physical activity seemed to protect against AD (72). In the Cardiovascular Aging and Dementia study cohort (CAIDE), leisure time physical activity, but not work related physical activity, measured at midlife was related to a 50% reduced risk of late life AD and dementia (73, 74). The association between leisure time physical activity and the reduced AD risk was more pronounced among APOE ε4 carriers than in non-carriers (73). With respect to the leisure time activities, cognitively stimulating exercises but not physical activities were associated with a decrease in vascular cognitive impairment (75).

Primary care physicians can recommend some physical exercises to their patients. Physical activity is generally grouped into four categories. Because each of these different kinds of exercise focuses on improving particular body performances, increased benefit will be obtained by regularly engaging in some of each kind.

• Aerobic or endurance exercise is a physical activity that increases breathing and heart rate. Performed regularly it improves physical endurance and the health and fitness of the lungs, heart and blood vessels. It includes moderate-to-high intensity activities like walking, jogging, swimming, cycling and even energetic housework. Guidelines recommend that individuals should try to  do at least 30 minutes of moderate-intensity aerobic activity on most days of the week, preferably every day (76–78).

• Strength or resistance training is a physical activity that uses weights or resistance, including body weight, to work muscles. Performed regularly, it improves muscle strength and tone, as well as the health and fitness of tendons, bones and joints. Guidelines recommend strength exercises for each major muscle group at least twice a week (77, 78).

• Flexibility exercises are those that stretch the muscles. Performed regularly they help the joints and muscles to stay limber and flexible. There are numerous types of stretching exercises, and activities like yoga, Pilates and tai-chi, that include controlled stretching often in conjunction with strength and balance. Flexibility exercises can be done as often as possible and are an important component of aerobic and strength training programs.

• Balance exercises help to improve balance and coordination and reduce the risk of falls. They include movements that test your balance and activities like tai-chi. Lower-body strength exercises, yoga and Pilates can also help improve the balance. Guidelines recommend that older adults carry out  balance exercises at least 3 times a week (77).

Of course, many physical activities combine elements of more than one of these types of exercise. Experts classify four types because it is important to include each of them in the activities chosen to be done by the patient. It is also very important to select activities that the patient will enjoy and will be able to sustain for long-term benefits.

Cognitive training

Cognitive impairment is prevalent in older adults and is associated with decline in the performance of instrumental activities of daily living (IADLs). Cognitive training has demonstrated its utility in reducing cognitive decline in normal aging (79, 80).

Cognitive training interventions seems to hold promising results for improving cognitive function (e.g., memory, working memory, psychomotor speed, reasoning, and executive function) and for lowering healthcare resource used among older adults, including those with chronic conditions such as HF. In the Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) trial,  of face-to-face cognitive training interventions (10 sessions over 5-6 weeks) among 2832 healthy older adults (81), 87% of participants who received the interventions had improved psychomotor speed, 74% had improved reasoning, and 26% had improved memory immediately after the interventions and improvements were sustained for two and 5 years (82). Results at 10 years demonstrate that cognitive training has beneficial effects on cognitive abilities and on self-reported IADL functions (83). In a computerized memory training intervention tested among 182 persons aged 60 and more (84), adults who completed the intervention had improved memory compared with the adults of the attention and no-contact control groups (84). In a multisite randomized controlled double-blind trial, the computerized intervention Brain Fitness (PositScience) was tested among 487 community-dwelling older adults without cognitive impairment (85). Improved memory and attention were significantly greater in the group who received memory training (3.9 points) than in the active control group (1.8 points). The magnitude of the effect sizes suggests that results were clinically meaningful (85).

In primary care, cognitive training can focus on memory, reasoning, and speed-of-processing, as prior research indicates that these abilities show early age-related decline and are relevant to ADLs.

• Memory training focuses on verbal episodic memory (86–88). Primary care can introduce mnemonic strategies for remembering word lists and sequences of items or details of stories. For example, patients can be instructed how to organize word lists into meaningful categories and to form visual images and mental associations to recall words and texts (eg, recall a list of names, a paragraph, a shopping list, details of a prescription label).

• Reasoning training focuses on the ability to solve problems that follow a serial pattern (89, 90). Such problems involve identifying the pattern in a letter or number series or understanding the pattern in an everyday activity such as prescription drug dosing or travel schedules. Primary care can teach strategies to reasoning tasks (e.g. letter series) or reasoning problems related to activities of daily living.

• Speed-of-processing training focuses on visual search and ability to process increasingly more-complex information presented in successively shorter inspection times (91, 92). Patients can practice increasingly complex speed tasks on a computer. Task difficulty is manipulated by decreasing the duration of the stimuli, adding either visual or auditory distraction, increasing the number of tasks to be performed concurrently, or presenting targets over a wider spatial expanse.

Smoking and Alcohol

Studies on the association of smoking and alcohol intake with cognition have yielded inconsistent results. Previous research has claimed nicotine to be a neuroprotective agent and thus the harmful association of heavy smoking on increased risk of AD might be attributable to the other 4000 substances present in cigarette smoke which are known to trigger oxidative stress, neuronal degeneration and plaque formation (93). Heavy midlife smoking in a large multi-ethnic cohort predicted dementia, AD and vascular dementia in a dose dependent manner more than two decades later. This association was not affected even after controlling for stroke, a disease for which smoking is a well-established risk factor. Instead, it pointed to an independent association between smoking and vascular dementia and AD, not restricted to the cerebrovascular insults (94). In another large cohort of CAIDE, midlife smoking increased the risk of dementia and AD among APOE ε4 allele carriers, but not among non-APOE ε4 carriers. This indicates that there is a complicated gene environment interplay between smoking and dementia risk (95). Data about another indulgence – alcohol – depicts that mild-moderate alcohol intake is protective against dementia while excessive consumption increases the risk of cognitive decline and dementia (58, 96–99).


Epidemiological analysis of the relations between nutrient consumption and cognitive decline is complex and it is highly unlikely that a single component plays a major role. A paper based on the findings of the French Three Cities study, suggested that a diet with little variety may increase the risk of dementia (100). In this work, daily consumption of fruits and vegetables was associated with reduced risk of dementia. Weekly consumption of fish was associated with reduced risk of AD and dementia only in non-APOE ε4. Regular consumption of oil or fish rich in omega-3 fatty acids was associated with reduced risk of dementia, whereas regular consumption of oils rich in omega-6 fatty acids increased this risk. Another study has shown decreased risk of AD in subjects with a diet similar to the Mediterranean diet (101). Finally, others studies have also shown that saturated fats were reported to increase the risk of AD, while healthy dietary patterns such as diets rich in fruits and vegetables, adherence to a Mediterranean diet, intake of antioxidants and omega 3 fatty acids have been found to decrease the dementia risk (100–103). The impact of classic social determinants of diet, such as regional cultures, social status and educational level, must of course be taken into account. Communication and nutritional advice will benefit from being adapted to dietary habits and to the patient’s place in the cycle of ageing (104–106).

Primary care can supply these nutritional advices to their patients. Based on the dietary guidelines established by the French National Nutrition and Health Program for older subjects, these indications are now considered as the official reference in France (107).

For older adults in good health with normal cognitive performance, the primary care physician can organize the recommendations as part of a multidomain intervention (see below). It will also be essential to follow the patient regularly and to assess his/her cognitive functions with a simple cognitive screening test every 6 months.

The cognitive impairment risk scores have provided practical tools to estimate the risk of cognitive impairment and target interventions for those at highest risk. A major asset of the single risk factor approach is that it highlights the potential for individual risk factors, but is limited as it considers each risk factor as independent. However, these factors are often interconnected. For example, three of the risk factors (diabetes, hypertension, and obesity) constitute the metabolic syndrome and this syndrome is related to physical inactivity, all of which are related to educational level. In this context, the multidomain intervention studies (e.g. FINGER, MAPT,) provide healthy lifestyle recommendations for preventing cognitive impairment and disability, and information on how adherence to lifestyle changes can be improved.

Subjects in good health with abnormal cognitive performance 

If a cognitive impairment is verified by testing in primary care, such persons can either fulfill criteria for dementia (according to for example ICD or DSM) or not (then it is MCI or similar concepts). Furthermore, in many cases it may be problematic in primary care to distinguish between dementia and MCI. Then, if the patient is in a good health, further diagnostic work up including subtyping is the specialist’s role in specialized clinical services. We can also propose to patients testing for specific biomarkers.

In recent years, significant advances have been made to reveal early stages of dementia through biomarkers. A biomarker can be used to view the pathogenesis of dementia and helps predict or evaluate the disease risk to identify a clinical diagnosis or therapeutic intervention monitoring that may alter or stop the disease (108, 109). Ideally, the biomarker should detect the neuropathological processes even before a clinical diagnosis and should help identify people who are at risk of developing dementia. The International Working Group (110, 111) and the National Institute on Aging–Alzheimer’s Association criteria (112–114) recognize the importance of imaging and cerebrospinal fluid (CSF) markers for the early diagnosis of AD at the stage of MCI. The proposed criteria states that positivity on one or more biomarkers of brain amyloidosis (decreased levels of amyloid beta 42 (Aβ42) in the CSF and increased binding of amyloid imaging ligands on positron emission tomography [PET]) and neuronal injury (medial temporal atrophy [MTA] on magnetic resonance imaging (MRI), increased total tau or phospho-tau in the CSF, and cortical temporoparietal, and posterior cingulate cortex hypometabolism on fluorodeoxyglucose positron emission tomography [FDG-PET] or if FDG-PET is unavailable, hypoperfusion on single positron emission computed tomography [SPECT]), is associated with a high probability that the patient’s cognitive impairment is due to AD pathology. These criteria should be regarded as “research” criteria predominantly, although they may be applicable in some specialized clinical services with appropriate knowledge and facilities (115) (Table 3). Thus, there are no really clinically useful biomarkers, but in future clinical practice they would be very valuable in making early diagnosis more cost effective especially if they could obviate the need for more formal cognitive testing. Other biomarkers were also developed but are only experimental. For example, Alu sequence-containing cDNA neuronal thread proteins (AD7c-NTP), increases in cortical neurons, brain-tissue extracts, cerebrospinal fluid, and urine in the early course of AD, and its level is positively correlated with the severity of dementia, which make it a potential biomarker for AD (116). Urine AD7c-NTP test is non-invasive, and the development of a urine AD7c-NTP diagnostic kit makes it more convenient to implement. When combined with other biomarkers, such as tau, it will provide a higher diagnostic accuracy (117). Non invasive detection of tau protein deposits in the brain would be useful to diagnose AD as well as to track and predict disease progression. Recently, several PET tracers, developed for imaging Paired Helical Filaments-tau (PHF-tau) have shown promising results in humans (118). These tracers are reported to be selective for PHF-tau in vitro. PET tau imaging would be useful for early detection of disease-related pathology, for pharmacological evaluation of drug efficacy and for understanding the pathophysiology in AD. Additional studies are required to assess their reliability and quantitative performance, and to validate the in vivo binding selectivity of these tracers to tau pathology. Finally, gene expression profile is considered to be a promising approach for the early detection of dementia. Several studies have been conducted through the genetic analysis of related disorders, such as AD, to evaluate the genetic risk factor that may lead to dementia. The ε4 allele of the apolipoprotein E gene is the major lipid carrier of protein to the brain, and its inheritance is associated with the onset of AD and vascular dementia (VaD). Accordingly, age and the inheritance of the ε4 allele have been used as a common risk factor and/or pathogenesis for both AD and VaD (109, 119–122) (Table 3).

Table 3. Examination, biomarker, and application

After testing for biomarkers, two outcomes are possible. If biomarkers are positive, specific target interventions can be offered to the patient. Indeed, disease-modifying drugs are likely to be most effective in the earlier stages of AD, before neurodegeneration is too severe and widespread, so trials for this type of drug will need to include AD cases in the pre dementia states (123). However, so far no disease modifying agents have reached the market although there are many compounds in pipeline. Biomarkers can be used in all stages of drug development including phase I, phase II and phase III. They can be used to enhance inclusion and exclusion criteria, for stratification or as baseline predictors to increase the statistical power of trials. Biomarkers can also be used as outcome markers to detect treatment effects. Particularly, if biomarkers are intended to be used as surrogate endpoints in pivotal studies, they must have been qualified to be a substitute for a clinical standard of truth and as such reasonably predict a clinical meaningful outcome. Finally, biomarkers can be used to identify adverse effects. Now, if biomarkers are negative, a multidomain intervention can be considered (see below).

Frail older adults with abnormal cognitive performance (cognitive frailty)

In many frail older adults, a cognitive impairment is just one of many domains that are affected. Other domains may be the musculoskeletal system, the cardiovascular system, renal, liver and endocrinological systems etc. In order to design effective interventions, we need to identify multiple domains/causes of frailty. We invite clinicians to specifically identify and target the dimensions of frailty specified in the Frailty Phenotype (weak grip strength, slow walking speed, exhaustion, weight loss, low activity). Once frailty is reported, management is guided by a multidisciplinary assessment using the principles of Comprehensive Geriatric Assessment (CGA) (124, 125), while  targeting the problems associated with frailty, in particular. Suggested principles of assessment in older people diagnosed as frail are: (a) comprehensive, interdisciplinary assessment of physical, emotional, psychological and social factors, and support mechanisms. This may be time consuming due to comorbidities, polypharmacy, pain and disability resulting from impaired vision, hearing, speech and cognition. (b) assessment of psychological and social factors that are potential barriers to implementation, uptake and adherence with the intervention. (c) regular re-evaluation, particularly following an illness or injury, to detect changes in needs and ensure timely modifications of care provision. Then, some of the biological markers may be able to capture correctly both the risk of future physical and cognitive declines, such as inflammatory biomarkers [e.g. C-reactive protein (CRP) and interleukin-6 (IL-6)] (28, 75, 76-78). However, biomarkers predictive of both types of decline (frailty and cognitive impairment) may not be particularly useful in differentiating whether a person is at a higher risk of future physical decline rather than  cognitive decline (and vice versa).

Usually frail older persons do not complaint about memory, but in the Gérontopôle Frailty clinics, almost 60% of older subjects who are referred to us for physical frailty, report symptoms of MCI. In Swedish population based studies it has been shown that MCI is associated with poor physical health, leading to the hypothesis of a causal relationship between physical diseases and MCI in older populations (126).

Besides considering treatment with symptomatic drugs (acetyl-cholinesterase inhibitors or memantine) if criteria for Alzheimer´s disease with dementia are fulfilled, a list of possible preventive interventions should be considered.  These may include promotion of physical activity, cognitive stimulation and training, healthy dietary habits, smoking cessation, promotion of emotional resilience, active and socially integrated lifestyles, optimal daily sleep, maintenance of optimal body weight, and metabolic control (127). Indeed, best evidence is available for treatment of hypertension, which was shown to be effective in prevention of dementia in one randomized controlled trial (RCT) and in a recent meta-analysis (107, 108). Two RCTs investigating the effect of statins reported no effect on cognition (109,110). The Accord-Mind study is the first and still ongoing RCT designed to assess the effects of glycemic control on cognition (111). Physical exercise training has shown to be modestly effective in one recent study in slowing cognitive decline in subjects with subjective or objective cognitive impairment (112). Concerning diet, several interventions focusing on single nutrients including B-vitamins and omega-3 fatty acid have shown equivocal results (113–116). Cognitive training in specific domains can positively influence daily functioning in non-demented older people and is persistent over time, but it is still unsure if this can prevent or delay dementia onset (93, 117). Given that cognitive impairment and dementia are multi-factorial disorders, interventions targeting several risk factors simultaneously are needed to obtain an optimal preventive effect. Multi-component interventions aimed at vascular risk factors and life-style changes in middle-aged and older people have been shown to be feasible and effective in preventing cardiovascular events and new onset diabetes mellitus (118–120). In this context, multi-component interventions aimed at vascular and lifestyle related risk factors could also prevent or delay the onset of dementia. Interventions on modifiable risk factors may prevent/postpone dementia onset, but the pharmacological and non-pharmacological intervention studies conducted so far have had somewhat disappointing results as pointed out in a report by the National Institutes of Health (121). There are several reasons for this. Previous trials have mostly used a single agent intervention and they have been conducted in older and/or already cognitively impaired populations, which may partly explain the modest results. Many of these trials were designed for other outcomes and cognitive outcomes were secondary. There are however some positive signs that antihypertensive drug treatment (108), vitamin B supplementation (122), physical activity (112) and cognitive training (93) may be beneficial, at least in certain population groups. Other important lessons learnt from previous studies include timing of the intervention (starting earlier may lead to better results), target populations (targeting at risk individuals may be the most effective approach), and the importance of long follow-up. In Europe, there are three large ongoing RCTs on dementia prevention: Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) (123), Multidomain Alzheimer Prevention study (MAPT) (124), and Prevention of dementia by intensive vascular care (preDIVA) (125) (Table 4). The common factor in these studies is the multidomain approach which aims to target simultaneously several proposed vascular and lifestyle related risk factors for dementia and targeting older ‘at risk’ adults. As an example, the FINGER study targets 60-77-year old individuals selected according to the CAIDE Dementia risk score (6 points or higher), and the CERAD neuropsychological test battery (cognitive performance at the mean level or slightly lower than expected for age according to Finnish population norms) (123). The 2-year multidomain intervention includes nutritional guidance, cognitive training, increased social activity, and monitoring and management of metabolic and vascular risk factors. The primary outcome is cognitive decline measured by a sensitive Neuropsychological Test Battery and the Stroop and Trail Making tests. The first outcomes of the FINGER study reported at the Alzheimer’s Association International Conference 2014 (AAIC 2014) showed that physical activity, nutritional guidance, cognitive training, social activities and management of heart health risk factors improved cognitive performance, both overall and in separate measures of executive function, such as planning abilities, and the relationship between cognitive functions and physical movement (128). These new data are very encouraging, and we look forward to the results of others studies (MAPT and preDIVA) to confirm and extend these findings.

Table 4. Characteristics of RCTs with Multidomain interventions for prevention of cognitive impairment, dementia and Alzheimer’s disease

Recent studies have indicated a decline in dementia incidence (129–131). As an example, recent data from the Medical Research Council Cognitive Function and Aging Study (MRC CFAC) in three areas of England has identified that there has been a decline in the prevalence of dementia taking place during the past two decades among individuals 65 years and older. This 1.8% decline in prevalence of dementia in this older population would be observed in future generations if putative efforts are employed in effective primary prevention of risk factors for cognitive impairment in conjunction with an improvement in protective factors such as better levels of education and more physical activity (132). Efficacy of preventive strategies to prevent or postpone cognitive impairment onset have a major impact on patients, caregivers, public health and health economics.


In summary, prevention is now increasingly highlighted as the main therapeutic goal to tackle dementia. Primary care physicians will have to play a role to better focus those who can benefit from multi-domain interventions or targeted therapies (Figure 1). Presently, we must target those with memory complaints, monitor cognitive functions and increase the participation of older adults in drug trials and other intervention studies. As important is the need to implement preventative strategies for Alzheimer’s disease into everyday clinical practice.

Authors’ contributions: BF and BV have made substantial contributions to conception and design. BF wrote the manuscript. BF and BV have made substantial contributions to the final manuscript. All authors read and approved the final manuscript.

Conflict of interests: The authors declare that there is no conflict of interests regarding the publication of this paper.


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B. Vellas

UMR INSERM 1027, Gerontopole, CHU Toulouse, University Paul Sabatier, France

Corresponding Author: Bruno Vellas, M.D., PhD,

J Prev Alz Dis 2014;1(3):168-175

Published online November 25, 2014,


An evolving consensus about the need to treat AD in the presymptomatic phase has emerged following the disappointing results of several trials that enrolled subjects with mild to moderate disease, as well as accumulating research demonstrating that AD pathologic process begins decades before the appearance of symptoms. Several lessons can be learned from past prevention trials. The targeted populations were too diverse, the interventions probably not strong enough, and the time of exposure was most likely too short. We have learned from these trials that future prevention trials must be targeted, use strong interventions with known biological activity, and must be sustained with a long-term intervention. In this paper, we focus on three prevention trial approaches:

A. Targeted therapy: Preventing AD by targeting a specific population with a specific intervention. Such preventive approaches and trials must be based on biomarkers and imaging to select a study population in accordance with the mechanism of the specific intervention;

B. Multi-domain interventions targeting a larger, more diverse population over a longer time period with long-term exposure to non-specific, multi-domain intervention. The rationale for this approach stems from studies showing that several environmental factors are associated with the risk of developing dementia. These factors may include educational level, vascular and metabolic risk factors, physical activity, cognitive stimulation, and nutritional status. It may also be possible to identify healthy adults at high risk of AD and likely to benefit from intervention based on subjective memory complaint, ApoEε4 carriage, family history of AD, or the presence of frailty; and use multidomain interventions to compensate for low specificity;

C. What will be probably the future of clinical practice: A preventive approach, integrated into primary care settings that begins with longitudinal monitoring of memory function in a general population to identify decliners, followed by a specific intervention based on biomarkers and imaging discussed case by case. Finally, preventing AD will require new and improved infrastructure.

Key words: Alzheimer, primary care, drug trials, intervention trials, prevention.



In worldwide efforts to address the oncoming public health and economic crisis resulting from the rising prevalence of Alzheimer’s disease (AD), prevention has been recognized as a key goal (1, 2). Primary prevention by targeting modifiable risk factors could potentially reduce disease incidence by millions of cases by 2050 (3). Meanwhile, the field has coalesced around the idea of secondary prevention, which involves diagnosing and treating the disease before symptoms become apparent (4). An evolving consensus about the need to treat AD in the presymptomatic phase has emerged following the disappointing results of several trials that enrolled subjects with mild to moderate disease (e.g., (5-7)), as well as accumulating research demonstrating that AD pathologic process begins decades before the appearance of symptoms (e.g., (8)).

Several lessons can be learned from past prevention trials. For example, the GuidAge clinical trial — the largest preventive trial conducted in the EU — tested whether long-term use of a Ginkgo biloba extract could reduce the risk of progression to AD among subjects over age 70 who spontaneously subjective memory complaints reported to their primary-care physician (9). This randomized, placebo-controlled trial enrolled 2840 individuals and followed them for five years. At the end of the study, there were no statistically significant differences in AD incidence between the two groups. Three reasons were cited as contributing to these disappointing results: the targeted population was too diverse, the intervention with Gingko biloba was probably not strong enough, and the time of exposure was most likely too short. The population of individuals with subjective memory complaints is highly variable, with the overall incidence of dementia quite small, making it difficult to achieve statistical significance. In addition, progression to dementia is slow, so in order to demonstrate a slowing of progression, one would likely need either an intervention with a very robust effect or exposure for a very long time, taking into account that the impact of exposure may not be proportional but may increase over time. Taken together, these factors suggest that future preventive trials will need to consider novel statistical approaches with pre-defined endpoints that take into consideration the fact that the impact of intervention could depends on the time of exposure.

Phase 3 trials of solanezumab and bapineuzumab, both monoclonal antibodies directed against beta-amyloid (Aβ), provide additional lessons (6, 7). Despite the fact that both trials enrolled subjects who met criteria for mild-to-moderate AD, biomarker studies revealed that a substantial number of subjects (nearly 30% of those with mild dementia) had no amyloid in the brain (10). Moreover, amyloid-negative subjects receiving placebo showed almost no disease progression during the 18- month study period, suggesting that they did not have AD. After this trial, the sponsor Eli Lilly launched a third, targeted solanezumab trial (Expedition III), which enrolled only individuals with biomarker evidence of brain amyloid. Interestingly, the practice of conducting targeted trials in other disease areas such as oncology is credited with much of the progress achieved in developing effective drugs.

We have learned from these trials that future prevention trials must be targeted, must use strong interventions with known biological activity, and must be sustained with a long-term intervention. Here, we propose three prevention trial approaches:

  • Targeting a specific population with a specific intervention
  • Multi-domain interventions on a large, more diverse population over a longer time period.
  • What will be probably the future of clinical practice: A preventive approach, integrated in primary care setting that begins with longitudinal monitoring of memory function in a general population to identify decliners, followed by a specific intervention based on biomarkers and imaging if the disease progress


Targeted therapy: Preventing AD by targeting a specific population with a specific intervention

One approach to the development of an effective disease-slowing therapy is to select a study population in accordance with the mechanism of a specific intervention (11). Targeting therapies in this way depends on identification of biomarkers or genetic markers that provide evidence of the stage or type of disease, as hypothesized by Jack and colleagues (12) and demonstrated in subsequent studies (8, 13). For example, trials of anti-amyloid therapies would enroll subjects at early disease stages when deposition of amyloid is underway, but not so far along that neurodegeneration has ensued.

In 2011, the National Institute on Aging and the Alzheimer’s Association (NIA-AA) proposed modifications to the diagnostic criteria for AD, which included a category called “preclinical AD,” subdivided into three stages based on biomarker findings (Figure 1): stage 1 is defined by the presence of amyloid, evidenced using PET imaging or a CSF analysis; stage 2 by the presence of amyloid plus markers of neurodegeneration, indicated by hypometabolism on fluorodeoxyglucose positron emission tomography (FDG-PET), elevated CSF tau or phospho-tau, or structural MRI findings of hippocampal atrophy or cortical thinning; or stage 3, where in addition to amyloidosis and neurodegeneration, there is evidence of subtle cognitive decline (14). Subsequent refinement of the criteria added two additional preclinical stages: stage 0, where all biomarkers are normal and there is no cognitive impairment; and suspected non-Alzheimer’s pathophysiology, i.e., markers of neurodegeneration but not amyloidosis (SNAP) (15).

Figure 1. N.I.A classification (adapted from Sperling)

Vos et al. used these criteria to classify 311 cognitively normal (CDR 0) subjects living in the community. They found that 41% were classed as stage 0, 15% as stage 1, 12% as stage 2, 4% as stage 3, 23% as SNAP, and 5% remained unclassified. They also determined the 5-year progression rate to symptomatic AD (CDR ≥ 0.5). Only 2% of stage 0 subjects progressed, whereas, 11% of stage 1 subjects, 26% of stage 2 subjects, 56% of stage 3 subjects, and 5% of SNAP subjects progressed (16). These data support the temporal order of biomarkers proposed Jack et al, and its relevance for clinical progression (12, 13), in particular that amyloid accumulation begins in the preclinical stage of the disease and that this could be the appropriate time to intervene with anti-amyloid therapies.

Johnson et al used florbetapir PET imaging to assess amyloid load in healthy controls, demonstrating that the mean SUVR increases with age even among cognitively normal subjects, from 5.3% positive in those aged 50 to 59, 10.5% in those 60-69, 15.0% in those 70-79, and 33 % in those 80 years or older (17). These results suggest that it may be possible to enroll subjects based on the presence of brain amyloid (by CSF or amyloid PET), with no objective cognitive decline, possible subjective memory complaints, and preserved activities of daily living. The advantages of such a trial targeting amyloid are its specificity and the ability to treat at a very early stage before non-reversible lesions have developed. The drawbacks are the difficulty of demonstrating a slowing of cognitive decline in an already slowly-declining population and the low conversion rate to dementia. These drawbacks result in long and costly trials.

Nonetheless, a trial based on this strategy already started this year. The Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4 trial) will be the first prevention trial in subjects determined to be at risk based on brain amyloid demonstrated with PET imaging (18). This placebo-controlled trial will use solanezumab as the treatment and a composite of well-validate neuropsychological tests known to be sensitive in the early stages of cognitive decline as the primary outcome.

The A4 trial aims to exclude older persons without cognitive impairment who, based on the absence of brain amyloid, are much less likely to develop AD. Overall, in our point of view, amyloid PET or CSF seems to be best for selecting trial participants. As tau PET imaging continues to develop, it may be useful for assessing disease-stage and perhaps response to treatment.

We must underline, however, that such trials are expensive and raise cost effectiveness issues. It will be hard to use such treatment for very long period of time, e.g., decades. There are also ethical concerns raised by treating individuals who may never develop AD with drugs that have unknown long-term safety profiles, particularly in people who may develop other chronic diseases. Moreover initiating treatment based on biomarker findings has the potential to affect the life and well-being of subjects. For example, when we detect amyloid and propose treatment in still-normal older adults, we will likely induce stress and other life-altering decisions, which must be taken into consideration. While we hope to prevent the development of AD in some older people, we must realize that not all would have gone on to develop AD and that many other diseases can also occurs at this age.

Other trials targeting the preclinical stages of AD have also begun enrolling subjects. These trials – conducted by the Alzheimer’s Prevention Initiative (API) (19) and the Dominantly Inherited Alzheimer’s Network Trials Unit (DIAN-TU) (20) are targeting individuals with autosomal dominant mutations that make them almost certain to develop early-onset AD (EOAD). A third trial, also by API, will target ApoEε4 carriers, who are at elevated risk of developing late onset AD (LOAD). All of these trials will test the efficacy of active immunotherapeutic agents.

Another possible target population for preventive trials is late MCI due to AD. Individuals at this stage have objective decline in memory, for instance evidenced by low scores in logical memory testing, and a positive amyloid signature (CSF or amyloid-PET), but generally preserved activities of daily living. The advantage of targeting this population is the fact that they have a higher likelihood of converting to AD and, because they are already symptomatic, are more likely to comply with the study protocol. However, they are difficult to screen due to the low prevalence and the high cost of screening with imaging, CSF biomarkers, or extensive cognitive testing. Moreover the cut-off at which cognitive impairment represents MCI is still unclear, and is impacted by education, sleep, general health, life events, and other factors. Finally the learning effect must be taken into consideration in this population when a repetitive test is used as a screening tool. In the GuidAge trial, for example, the learning effect with the free and cued selective reminding test (FCSRT) was observed over 2 years both in subjects with CDR 0 and CDR 0.5 (personal data). CDR-SB may be a reasonable end point in late MCI, (ADNI and MAPT personal analysis), while in those with early MCI, a composite score appears to be more appropriate. Recently a composite score composed of tests for Word Recall, Delayed Word Recall, Orientation, the CDR-SB, and the FAQ was proposed (21).

Several drugs with varying mechanisms of action have been, or plan to be, used in preclinical, MCI, and AD trials. A phase 3 trial of the gamma-secretase inhibitor semagacestat was tested in patients with mild-to- moderate AD but did not improve cognition and, in fact, was associated with a worsening of functional abilities among those receiving a high dose of the drug. There were also more adverse side effects among those receiving drug compared to placebo (5). Beta-secretase inhibitors may be more efficacious (22). Despite evidence of hepatic toxicity with some of these compounds, at least one (MK-8931) is recruiting subjects for a phase 3 study. Other approaches include monoclonal antibodies such as solanezumab and gantenerumab, which are also in phase 3 studies. Less advanced molecules targeting alpha secretase or tau protein, as well as neuroprotective compounds still in early development. Some studies have been terminated, for example a study of the microtubule stabilizer epothilone D.

Table 1 summarizes prevention trials in MCI due to AD and prodromal AD currently underway. However, questions remain about whether treating at these stages is too late. While it makes sense to treat before neurodegeneration begins, the progression of the disease is still slow in prodromal AD and MCI, suggesting that there may be some benefit to treating at these stages.

Table 1. Drug trials


Alzheimer Prevention Trials: Larger Target, Non Specific but Multi-Domain Intervention, Long-Term Exposure

An alternative approach for prevention trials is to have a larger more diverse population group with long-term exposure to non-specific, multi-domain intervention. The rationale for this approach stems from studies showing that several environmental factors are associated with the risk of developing dementia. These factors may include educational level, vascular and metabolic risk factors, physical activity, cognitive stimulation, and nutritional status. In addition, recent studies suggest a declining incidence and prevalence of AD over the last ten years, thought to be due to improvements in overall health and educational levels (23, 24). Finally, a recent autopsy study of 1599 older people compared amyloid deposition in subjects 65 yrs. and older who died between 1972 and 2006. Lower amyloid deposition was seen in the 2006 cohort and was particularly marked in the oldest age groups, providing preclinical evidence supporting recently described decreases in AD incidence (25). These accumulating data recently led the U.S. National Institute on Aging (NIA) to encourage all adults to exercise regularly, eat a healthy diet rich in fruits and vegetables, engage in social and intellectual activities, control type 2 diabetes, lower high blood pressure, lower cholesterol levels, maintain a healthy weight, stop smoking, and get treatment for depression.

Targeting the general population for interventional AD prevention trials may not be feasible or even desirable, although there is the potential to promote more informed decision-making by the general public on low-risk approaches that could improve brain health and reduce the risk of dementia (26). In addition, it may be possible to identify healthy adults at high risk of AD and likely to benefit from intervention based on subjective memory complaints (SMC, also called subjective memory impairment [SMI] or subjective cognitive impairment [SCI]), ApoEε4 carriage, family history of AD, or the presence of frailty. Multidomain interventions may compensate for low specificity in these populations.

We would like to propose two specific approaches, targeting 1) those with subjective memory complaints, and 2) physically and cognitively frail older adults.

Individuals with SMC have, by definition, no objective cognitive decline and preserved activities of daily living (ADL). The prevalence has been estimated at between 11% in 65-85 year olds (27) to over 88% in those over age 85 (28), and some studies have suggested that the presence of SMC may predict subsequent dementia (29). Progression to dementia among those with SMC is elevated in individuals with a family history of dementia, expressed concern about memory, onset over the previous 5 years, and when the concern is severe enough to motivate consultation with a primary care provider (PCP)

The advantages of targeting individuals with SMC are that there are large numbers of potential subjects who are relatively easy to identify through PCPs, and that engaging PCPs in the process may increase compliance. Disadvantages of this approach include very high heterogeneity, slow decline, and minimal conversion to MCI or AD. The endpoint for a trial in this population could be a composite score including measures of logical memory or the FCSRT and measures of executive function.

Another large population that could be targeted for non-specific multi-domain trials are older persons with physical and/or cognitive frailty. In the longitudinal Rush Memory and Aging study, frailty was shown to be associated with both cognitive decline and incident AD (30). Indeed, the definition of frailty — increased vulnerability resulting from decline across multiple physiologic systems (31) — has recently been expanded to include cognitive decline (32). In 2013, a consensus group organized by the International Academy on Nutrition and Aging (IANA) and the International Association of Gerontology and Geriatrics (IAGG) proposed a definition of cognitive frailty that includes both physical frailty and cognitive impairment (e.g., CDR 0.5) in the absence of dementia (33). Individuals meeting this definition are typically 80 yrs. or older with preserved basic ADLs, but some decline in instrumental ADL (IADLs), due mostly to physical frailty.

The advantages of targeting frail older adults for multi- domain prevention trials include the importance of intervening and potentially slowing or reversing the frailty syndrome, the large numbers of persons affected, and the ability to target these individuals through PCPs. Disadvantages include the broad heterogeneity and presence of multiple morbidities within this population and the likelihood of poor compliance to intervention. In addition the neurobiology of frailty has yet to be defined. Endpoints of a study in this population could include both physical (e.g. gait speed) and cognitive functions (memory plus executive functions)

Multi-domain prevention trials in these two populations should include both pharmacological and non-pharmacologic therapies. Possible pharmacotherapies include anti-diabetic drugs such as pioglitazone. This drug is used in the oncoming TOMMORROW trial (34), which will enroll subjects based on their APOE and TOMM40 genotype. Other agents that could be considered for prevention trials include insulin (35), selective serotonin receptor agonists (SSRIs) (36), and a variety of nutrients such as resveratrol (37), the Ginkgo biloba extract EGB 761 (38), Vitamin D (39), B vitamins, including folate (40), and omega-3 fatty acids (41).

Omega-3 fatty acids (ω-3) are poly-unsaturated fatty acids (PUFAs), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) that are found in cold- water fish and fish oil and have been associated, in a number of epidemiologic studies, with a reduced risk of dementia (42). Based on the results of a pilot study (43), the NIA has funded a study to test the potential of ω-3 PUFAs to prevent vascular cognitive impairment. This 3- year, randomized, placebo-controlled trial of ω-3 PUFA will enroll 150 subjects age 80 and older with a CDR ≤ 0.5 (non-demented), low plasma ω-3 PUFA, and white matter hyperintensities (WMH) on MRI scans. Outcome measures include progression of WMH, progression of blood-based markers of inflammation, and cognitive decline (executive function and processing speed.

Physical exercise has been studied extensively in recent trials and found to be related to improvement of cognitive function (44), decreased MRI hippocampal brain atrophy (45), improved brain metabolism and some in amyloid deposit (ref…). Cognitive stimulation has been largely shown to improve cognition (46) and lower amyloid burden (47) in older adults.

Multi-domain intervention aims to bring together the benefits of nutritional intervention, physical exercise, cognitive stimulation, social activities, and vascular and metabolic risk control to increase the effect of each intervention, reach a threshold, and achieve clinically significant effects. The first and largest trial to have been designed is the Multi-domain Alzheimer’s Prevention Trial (MAPT) (48), a randomized, placebo-controlled study of 1680 subjects, 70 years of age or older living in the community and presenting with SMC (99% of subjects). The cohort was enriched for frail subjects with slow walking speed (4 meters test) in 11.9% of the sample and limitation in one IADL in 11.2%. Demented patients as well as those dependent for basic ADL were excluded. Subjects were randomized into four treatment rms: Omega 3 alone, Placebo alone, Omega 3 plus multi- domain intervention, and Placebo plus multi-domain intervention. The multi-domain intervention included physical and cognitive exercises, dietary counseling and weight maintenance, increased social activities, control of vascular and metabolic risk factors, and correction of vision and hearing impairments. The length of the intervention was 3 years plus 2 years of observational follow-up. Outcome measures included cognitive decline using the FCRST, cerebral and hippocampal volumes (n=500), cerebral glucose metabolism using FDG-PET (n=68) and amyloid PET scanning with florbetapir (n= 271).

The MAPT multi-domain intervention was shown be feasible with good compliance demonstrated by only 22.5% drop outs over the 3-year study. The MAPT trial is now completed and results will be released shortly.

Other multi-domain trials include the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER Study), a 2-year interventional trial targeting 1200 subjects at risk for dementia (49), the Prevention of Dementia by Intensive Vascular Care (Pre- DIVA) trial, the Vitamin D3, Omega-3, Home Exercise Healthy Ageing and Longevity Trial (DO-HEALTH), and the Healthy Aging through Internet Counseling of the Elderly (HATICE) program (50). Results presented from the FINGER study at the 2014 Alzheimer’s Association International Conference (AAIC) indicate positive effects on cognitive function (51). The Pre-Diva, MAPT and FINGER trials have been brought together under the umbrella of the European Dementia Prevention Initiative in order to share data and collaborate on new studies.

The advantages of multi-domain trials with large population targets and non-specific but multi-domain intervention delivered over a long time period are that these interventions are likely to be less expensive, easier to implement in daily clinical practice or at the population level, and safe for long-term exposure; and may act on different therapeutic targets. The disadvantages are interventions themselves are non- specific, the cohorts are highly variable and with different risks of developing dementia, and the potential for low compliance with the study protocol. For example, with regard to the variability in risk of dementia, amyloid PET scans performed in 271 subjects enrolled in the MAPT trial showed that 38.0% had significant brain amyloid (cortical SUVR > 1.17). Moreover these individuals were found to have lower cognitive function at baseline and more cognitive decline over the trial period, similar to what has been seen in observational studies (48).

In fact, these two preventive approaches: targeting a specific population with a specific intervention or targeting a larger at risk population with a multi-domain intervention are complementary and may both be appropriate at different time-points over the life time of an older adult. Indeed, this may be what is required in future clinical practice.


The future of clinical practice: A preventive approach, integrated in primary care setting that begins with longitudinal monitoring of memory function in a general population to identify decliners, followed by a specific intervention based on biomarkers and discussed case by case if the disease progress (FIG 2)

A prevention approach could start by making general recommendations to a large, diverse population (e.g., those age 50 years or older with normal cognition) on diet, physical and cognitive exercise, and risk factor control; then identify decliners through longitudinal monitoring of biomarkers or cognitive markers; and finally test interventions targeted specifically. These preventive approaches must start in primary care settings and integrate the family practitioners.

Among those with SMC and/or a family history of dementia, a tailored multi-domain intervention might be proposed, including nutrition, physical and cognitive exercise, and risk factor control, such as was used in the MAPT or FINGER trials. Ideally, these interventions could be delivered by PCPs who, at the same time, could begin longitudinal monitoring of cognition as a way to identify decliners for the next level of prevention trials. Some web resources will be probably helpful in the near future, such as the Brain Health Registry (

If subjects with early MCI, biomarkers (e.g., CSF amyloid, tau, as well as PET scans) may be considered despite the fact that they are expensive and invasive. Plasma biomarkers would greatly enhance the ability to conduct large, longitudinal progression studies. A recent study identified 10 plasma proteins that are strongly associated with structural MRI findings and appear to be able to predict conversion from MCI to AD with an accuracy of 87%, sensitivity of 85%, and specificity of 88% (52). In another study, a set of ten peripheral plasma phospholipids were identified that predicted conversion to MCI or AD over a 2–3 year timeframe with over 90% accuracy (53). However these findings have to be replicated and their clinical utility validated. At that point, it should be possible to offer multi-domain interventions to those who are biomarker-negative and oral drugs such as anti-amyloid drugs to those who are biomarker positive or those who transition to biomarker positivity during the trial. However, as mentioned earlier, there are those who believe that the MCI stage is too late to begin treatment with anti-amyloid therapy and that what is needed is better characterization of the transition from amyloid negativity to amyloid positivity. Anti-amyloid monoclonal antibodies will be also probably useful if the ongoing clinical trials of these drugs are successful.

Figure 2. A preventive approach, integrated in primary care setting that begins with longitudinal monitoring of memory function in a general population to identify decliners, followed by a specific intervention based on biomarkers and discussed case by case if the disease progress

If the disease progress to late MCI/prodromal AD stages of the disease, new therapies are needed, such as those that target tau; or it may be necessary to use combination therapies that simultaneously act on multiple therapeutic targets (e.g., amyloid plus tau). Anti- amyloid monoclonal antibodies may also be useful in these patients, depending on the outcome of ongoing studies of these agents. However these results will have to be scrutinized closely to assess the real impact of such therapies (54).

Comments and Research Directions

To achieve our goal of preventing AD, changes are needed in the way clinical trials are designed and conducted:

  • Clinical trials must target specific populations according to the intervention.
  • The interventions need to be robust and appropriate for the targeted population, e.g., a multi-domain intervention for a large heterogeneous population vs. an intervention with a specific mechanism of action for targeted populations.
  • Trials must be of sufficient length to assess long-term exposure to intervention
  • Trials will need to be implemented in clinical settings, beginning with the involvement of general practitioners and other primary care providers. These providers are in an ideal position to monitor longitudinally the cognition of elderly patients and identify decliners who can then be referred for more intensive assessment of progression using biomarkers.
  • Trial designs are needed that will enable the testing of combined approaches, including multi-domain approaches as well as combined pharmacotherapy against multiple therapeutic targets.

Moreover, preventing AD will require new and improved infrastructure. In the war against AD we need not only new weapons (drugs) but also the fleet (infrastructures, clinical research facilities) and the network (international collaborations). We must also learn from our failures to obtain clinically relevant and innovative results


Acknowledgment: Aisen P (ADCS-UCSD, San Diego CA, USA), Andrieu S (INSERM U 1027, Toulouse, France) Bain L (Elverson PA, USA), Delrieu J (Inserm U 1027, CHU, Toulouse, France), Ousset. P.J (INSERM U 1027, CHU Toulouse, France), Weiner. M (UCSF, San Francisco CA, USA). This paper was presented as a key-note lecture at AAIC 2014 in Copenhagen.

Conflicts of Interest: Scientific Board Member: Lilly, MSD, Nestlé, Roche, Sanofi. Research Grants: Abbvie, Affiris, Avid, Eisai, Envivo, Exhonit, Genentech, GSK, Lilly, MSD, Nutricia, Otsuka, Pharnext, Pfizer, Pierre-Fabre, Régénéron, Roche, Sanofi, Servier, TauRx Therapeutics, Wyeth.




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