B. Fougère^1,2, B. Vellas^1,2, 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.fougere@gmail.com (B. Fougère)

J Prev Alz Dis 2015;2(3):199-211
Published online June 10, 2015, http://dx.doi.org/10.14283/jpad.2015.73

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Abstract

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.

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Background 

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.

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).

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).

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).

Nutrition

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).

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.

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.

Conclusion

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.

References

1. Larson EB, Yaffe K, Langa KM. New insights into the dementia epidemic. N Engl J Med. 2013 Dec 12;369(24):2275–7. 

2. Plassman BL, Langa KM, Fisher GG, Heeringa SG, Weir DR, Ofstedal MB, et al. Prevalence of dementia in the United States: the aging, demographics, and memory study. Neuroepidemiology. 2007;29(1-2):125–32. 

3. Duthey B. Alzheimer Disease and other Dementias. Priority Medicines for Europe and the World “A Public Health Approach to Innovation.” 2013; 

4. Callahan CM, Hendrie HC, Tierney WM. Documentation and evaluation of cognitive impairment in elderly primary care patients. Ann Intern Med. 1995 Mar 15;122(6):422–9. 

5. Lopez OL, Jagust WJ, DeKosky ST, Becker JT, Fitzpatrick A, Dulberg C, et al. Prevalence and classification of mild cognitive impairment in the Cardiovascular Health Study Cognition Study: part 1. Arch Neurol. 2003 Oct;60(10):1385–9. 

6. Jonker C, Geerlings MI, Schmand B. Are memory complaints predictive for dementia? A review of clinical and population-based studies. Int J Geriatr Psychiatry. 2000 Nov;15(11):983–91. 

7. Geerlings MI, Jonker C, Bouter LM, Adèr HJ, Schmand B. Association between memory complaints and incident Alzheimer’s disease in elderly people with normal baseline cognition. Am J Psychiatry. 1999 Apr;156(4):531–7. 

8. Jessen F, Wiese B, Bachmann C, Eifflaender-Gorfer S, Haller F, Kölsch H, et al. Prediction of dementia by subjective memory impairment: effects of severity and temporal association with cognitive impairment. Arch Gen Psychiatry. 2010 Apr;67(4):414–22. 

9. Jessen F, Wolfsgruber S, Wiese B, Bickel H, Mösch E, Kaduszkiewicz H, et al. AD dementia risk in late MCI, in early MCI, and in subjective memory impairment. Alzheimers Dement J Alzheimers Assoc. 2014 Jan;10(1):76–83. 

10. Reisberg B, Shulman MB, Torossian C, Leng L, Zhu W. Outcome over seven years of healthy adults with and without subjective cognitive impairment. Alzheimers Dement J Alzheimers Assoc. 2010 Jan;6(1):11–24. 

11. Lyketsos CG, Toone L, Tschanz J, Rabins PV, Steinberg M, Onyike CU, et al. Population-based study of medical comorbidity in early dementia and “cognitive impairment, no dementia (CIND)”: association with functional and cognitive impairment: The Cache County Study. Am J Geriatr Psychiatry Off J Am Assoc Geriatr Psychiatry. 2005 Aug;13(8):656–64. 

12. Monastero R, Palmer K, Qiu C, Winblad B, Fratiglioni L. Heterogeneity in risk factors for cognitive impairment, no dementia: population-based longitudinal study from the Kungsholmen Project. Am J Geriatr Psychiatry Off J Am Assoc Geriatr Psychiatry. 2007 Jan;15(1):60–9. 

13. Fischer P, Jungwirth S, Zehetmayer S, Weissgram S, Hoenigschnabl S, Gelpi E, et al. Conversion from subtypes of mild cognitive impairment to Alzheimer dementia. Neurology. 2007 Jan 23;68(4):288–91. 

14. Hampel H, Schneider LS, Giacobini E, Kivipelto M, Sindi S, Dubois B, et al. Advances in the therapy of Alzheimer’s disease: targeting amyloid beta and tau and perspectives for the future. Expert Rev Neurother. 2015 Jan;15(1):83–105. 

15. Ousset PJ, Delrieu J, Vellas B. Should interventions to treat or prevent Alzheimer’s disease be tested in a population or as targeted treatment of highly selected study participants? Alzheimers Res Ther. 2013;5(6):62. 

16. Alagiakrishnan K, McCracken P, Feldman H. Treating vascular risk factors and maintaining vascular health: is this the way towards successful cognitive ageing and preventing cognitive decline? Postgrad Med J. 2006 Feb;82(964):101–5. 

17. Fratiglioni L, Paillard-Borg S, Winblad B. An active and socially integrated lifestyle in late life might protect against dementia. Lancet Neurol. 2004 Jun;3(6):343–53. 

18. Hachinski V. Preventable senility: a call for action against the vascular dementias. Lancet. 1992 Sep 12;340(8820):645–8. 

19. Middleton LE, Yaffe K. Promising strategies for the prevention of dementia. Arch Neurol. 2009 Oct;66(10):1210–5. 

20. Barnes DE, Yaffe K. The projected effect of risk factor reduction on Alzheimer’s disease prevalence. Lancet Neurol. 2011 Sep;10(9):819–28. 

21. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology. 1984 Jul;34(7):939–44. 

22. Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol. 1999 Mar;56(3):303–8. 

23. Petersen RC, Doody R, Kurz A, Mohs RC, Morris JC, Rabins PV, et al. Current concepts in mild cognitive impairment. Arch Neurol. 2001 Dec;58(12):1985–92. 

24. Petersen RC. Mild cognitive impairment as a diagnostic entity. J Intern Med. 2004 Sep;256(3):183–94. 

25. Clarnette RM, Almeida OP, Forstl H, Paton A, Martins RN. Clinical characteristics of individuals with subjective memory loss in Western Australia: results from a cross-sectional survey. Int J Geriatr Psychiatry. 2001 Feb;16(2):168–74. 

26. Derouesné C, Alperovitch A, Arvay N, Migeon P, Moulin F, Vollant M, et al. Memory complaints in the elderly: a study of 367 community-dwelling individuals from 50 to 80 years old. Arch Gerontol Geriatr Suppl. 1989;1:151–63. 

27. Commissaris CJ, Ponds RW, Jolles J. Subjective forgetfulness in a normal Dutch population: possibilities for health education and other interventions. Patient Educ Couns. 1998 May;34(1):25–32. 

28. Hänninen T, Reinikainen KJ, Helkala EL, Koivisto K, Mykkänen L, Laakso M, et al. Subjective memory complaints and personality traits in normal elderly subjects. J Am Geriatr Soc. 1994 Jan;42(1):1–4. 

29. Pearman A, Storandt M. Predictors of subjective memory in older adults. J Gerontol B Psychol Sci Soc Sci. 2004 Jan;59(1):P4–6. 

30. Jungwirth S, Fischer P, Weissgram S, Kirchmeyr W, Bauer P, Tragl K-H. Subjective memory complaints and objective memory impairment in the Vienna-Transdanube aging community. J Am Geriatr Soc. 2004 Feb;52(2):263–8. 

31. Blazer DG, Hays JC, Fillenbaum GG, Gold DT. Memory complaint as a predictor of cognitive decline: a comparison of African American and White elders. J Aging Health. 1997 May;9(2):171–84. 

32. Flicker C, Ferris SH, Reisberg B. A longitudinal study of cognitive function in elderly persons with subjective memory complaints. J Am Geriatr Soc. 1993 Oct;41(10):1029–32. 

33. Schofield PW, Marder K, Dooneief G, Jacobs DM, Sano M, Stern Y. Association of subjective memory complaints with subsequent cognitive decline in community-dwelling elderly individuals with baseline cognitive impairment. Am J Psychiatry. 1997 May;154(5):609–15. 

34. Jorm AF, Christensen H, Korten AE, Jacomb PA, Henderson AS. Memory complaints as a precursor of memory impairment in older people: a longitudinal analysis over 7-8 years. Psychol Med. 2001 Apr;31(3):441–9. 

35. Schmand B, Jonker C, Geerlings MI, Lindeboom J. Subjective memory complaints in the elderly: depressive symptoms and future dementia. Br J Psychiatry J Ment Sci. 1997 Oct;171:373–6. 

36. Devanand DP, Sano M, Tang MX, Taylor S, Gurland BJ, Wilder D, et al. Depressed mood and the incidence of Alzheimer’s disease in the elderly living in the community. Arch Gen Psychiatry. 1996 Feb;53(2):175–82. 

37. Modrego PJ, Ferrández J. Depression in patients with mild cognitive impairment increases the risk of developing dementia of Alzheimer type: a prospective cohort study. Arch Neurol. 2004 Aug;61(8):1290–3. 

38. Small GW, Siddarth P, Ercoli LM, Chen ST, Merrill DA, Torres-Gil F. Healthy behavior and memory self-reports in young, middle-aged, and older adults. Int Psychogeriatr IPA. 2013 Jun;25(6):981–9. 

39. Ganguli M, Rodriguez E, Mulsant B, Richards S, Pandav R, Bilt JV, et al. Detection and management of cognitive impairment in primary care: The Steel Valley Seniors Survey. J Am Geriatr Soc. 2004 Oct;52(10):1668–75. 

40. Holsinger T, Deveau J, Boustani M, Williams JW. Does this patient have dementia? JAMA. 2007 Jun 6;297(21):2391–404. 

41. Chodosh J, Petitti DB, Elliott M, Hays RD, Crooks VC, Reuben DB, et al. Physician recognition of cognitive impairment: evaluating the need for improvement. J Am Geriatr Soc. 2004 Jul;52(7):1051–9. 

42. Olafsdóttir M, Skoog I, Marcusson J. Detection of dementia in primary care: the Linköping study. Dement Geriatr Cogn Disord. 2000 Aug;11(4):223–9. 

43. Valcour VG, Masaki KH, Curb JD, Blanchette PL. The detection of dementia in the primary care setting. Arch Intern Med. 2000 Oct 23;160(19):2964–8. 

44. Mitchell AJ. The clinical significance of subjective memory complaints in the diagnosis of mild cognitive impairment and dementia: a meta-analysis. Int J Geriatr Psychiatry. 2008 Nov;23(11):1191–202. 

45. Plassman BL, Williams JW, Burke JR, Holsinger T, Benjamin S. Systematic review: factors associated with risk for and possible prevention of cognitive decline in later life. Ann Intern Med. 2010 Aug 3;153(3):182–93. 

46. Bradford A, Kunik ME, Schulz P, Williams SP, Singh H. Missed and delayed diagnosis of dementia in primary care: prevalence and contributing factors. Alzheimer Dis Assoc Disord. 2009 Dec;23(4):306–14. 

47. Van Hout H, Vernooij-Dassen M, Bakker K, Blom M, Grol R. General practitioners on dementia: tasks, practices and obstacles. Patient Educ Couns. 2000 Feb;39(2-3):219–25. 

48. Galvin JE, Sadowsky CH. Practical Guidelines for the Recognition and Diagnosis of Dementia. J Am Board Fam Med. 2012 May 1;25(3):367–82. 

49. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975 Nov;12(3):189–98. 

50. Solomon PR, Hirschoff A, Kelly B, Relin M, Brush M, DeVeaux RD, et al. A 7 minute neurocognitive screening battery highly sensitive to Alzheimer’s disease. Arch Neurol. 1998 Mar;55(3):349–55. 

51. Buschke H, Kuslansky G, Katz M, Stewart WF, Sliwinski MJ, Eckholdt HM, et al. Screening for dementia with the memory impairment screen. Neurology. 1999 Jan 15;52(2):231–8. 

52. Borson S, Scanlan J, Brush M, Vitaliano P, Dokmak A. The mini-cog: a cognitive “vital signs” measure for dementia screening in multi-lingual elderly. Int J Geriatr Psychiatry. 2000 Nov;15(11):1021–7. 

53. Brodaty H, Pond D, Kemp NM, Luscombe G, Harding L, Berman K, et al. The GPCOG: a new screening test for dementia designed for general practice. J Am Geriatr Soc. 2002 Mar;50(3):530–4. 

54. Borson S, Brush M, Gil E, Scanlan J, Vitaliano P, Chen J, et al. The Clock Drawing Test: utility for dementia detection in multiethnic elders. J Gerontol A Biol Sci Med Sci. 1999 Nov;54(11):M534–40. 

55. Dubois B, Touchon J, Portet F, Ousset PJ, Vellas B, Michel B. [“The 5 words”: a simple and sensitive test for the diagnosis of Alzheimer’s disease]. Presse Médicale Paris Fr 1983. 2002 Nov 9;31(36):1696–9. 

56. Villars H, Oustric S, Andrieu S, Baeyens JP, Bernabei R, Brodaty H, et al. The primary care physician and Alzheimer’s disease: an international position paper. J Nutr Health Aging. 2010 Feb;14(2):110–20. 

57. Wimo A, Ballard C, Brayne C, Gauthier S, Handels R, Jones RW, et al. Health economic evaluation of treatments for Alzheimer’s disease: impact of new diagnostic criteria. J Intern Med. 2014 Mar;275(3):304–16. 

58. Ngandu T, von Strauss E, Helkala E-L, Winblad B, Nissinen A, Tuomilehto J, et al. Education and dementia: what lies behind the association? Neurology. 2007 Oct 2;69(14):1442–50. 

59. Stern Y, Gurland B, Tatemichi TK, Tang MX, Wilder D, Mayeux R. Influence of education and occupation on the incidence of Alzheimer’s disease. JAMA. 1994 Apr 6;271(13):1004–10. 

60. Ferrari C, Nacmias B, Bagnoli S, Piaceri I, Lombardi G, Pradella S, et al. Imaging and cognitive reserve studies predict dementia in presymptomatic Alzheimer’s disease subjects. Neurodegener Dis. 2014;13(2-3):157–9. 

61. Wang H-X, Gustafson DR, Kivipelto M, Pedersen NL, Skoog I, Windblad B, et al. Education halves the risk of dementia due to apolipoprotein ε4 allele: a collaborative study from the Swedish brain power initiative. Neurobiol Aging. 2012 May;33(5):1007.e1–7. 

62. Mortamais M, Portet F, Brickman AM, Provenzano FA, Muraskin J, Akbaraly TN, et al. Education Modulates the Impact of White Matter Lesions on the Risk of Mild Cognitive Impairment and Dementia. Am J Geriatr Psychiatry Off J Am Assoc Geriatr Psychiatry. 2013 Sep 7; 

63. Soldan A, Pettigrew C, Li S, Wang M-C, Moghekar A, Selnes OA, et al. Relationship of cognitive reserve and cerebrospinal fluid biomarkers to the emergence of clinical symptoms in preclinical Alzheimer’s disease. Neurobiol Aging. 2013 Dec;34(12):2827–34. 

64. EClipSE Collaborative Members, Brayne C, Ince PG, Keage HAD, McKeith IG, Matthews FE, et al. Education, the brain and dementia: neuroprotection or compensation? Brain J Neurol. 2010 Aug;133(Pt 8):2210–6. 

65. Bennett DA, Schneider JA, Tang Y, Arnold SE, Wilson RS. The effect of social networks on the relation between Alzheimer’s disease pathology and level of cognitive function in old people: a longitudinal cohort study. Lancet Neurol. 2006 May;5(5):406–12. 

66. Boyle PA, Buchman AS, Wilson RS, Yu L, Schneider JA, Bennett DA. Effect of purpose in life on the relation between Alzheimer disease pathologic changes on cognitive function in advanced age. Arch Gen Psychiatry. 2012 May;69(5):499–505. 

67. Håkansson K, Rovio S, Helkala E-L, Vilska A-R, Winblad B, Soininen H, et al. Association between mid-life marital status and cognitive function in later life: population based cohort study. BMJ. 2009;339:b2462. 

68. Wilson RS, Scherr PA, Schneider JA, Tang Y, Bennett DA. Relation of cognitive activity to risk of developing Alzheimer disease. Neurology. 2007 Nov 13;69(20):1911–20. 

69. Chang M, Jonsson PV, Snaedal J, Bjornsson S, Saczynski JS, Aspelund T, et al. The effect of midlife physical activity on cognitive function among older adults: AGES–Reykjavik Study. J Gerontol A Biol Sci Med Sci. 2010 Dec;65(12):1369–74. 

70. Sofi F, Valecchi D, Bacci D, Abbate R, Gensini GF, Casini A, et al. Physical activity and risk of cognitive decline: a meta-analysis of prospective studies. J Intern Med. 2011 Jan;269(1):107–17. 

71. Ahlskog JE, Geda YE, Graff-Radford NR, Petersen RC. Physical exercise as a preventive or disease-modifying treatment of dementia and brain aging. Mayo Clin Proc. 2011 Sep;86(9):876–84. 

72. Scarmeas N, Luchsinger JA, Schupf N, Brickman AM, Cosentino S, Tang MX, et al. Physical activity, diet, and risk of Alzheimer disease. JAMA. 2009 Aug 12;302(6):627–37. 

73. Rovio S, Kåreholt I, Helkala E-L, Viitanen M, Winblad B, Tuomilehto J, et al. Leisure-time physical activity at midlife and the risk of dementia and Alzheimer’s disease. Lancet Neurol. 2005 Nov;4(11):705–11. 

74. Rovio S, Kåreholt I, Viitanen M, Winblad B, Tuomilehto J, Soininen H, et al. Work-related physical activity and the risk of dementia and Alzheimer’s disease. Int J Geriatr Psychiatry. 2007 Sep;22(9):874–82. 

75. Verghese J, Cuiling Wang  null, Katz MJ, Sanders A, Lipton RB. Leisure activities and risk of vascular cognitive impairment in older adults. J Geriatr Psychiatry Neurol. 2009 Jun;22(2):110–8. 

76. Nelson ME, Rejeski WJ, Blair SN, Duncan PW, Judge JO, King AC, et al. Physical activity and public health in older adults: recommendation from the American College of Sports Medicine and the American Heart Association. Med Sci Sports Exerc. 2007 Aug;39(8):1435–45. 

77. WHO | Global recommendations on physical activity for health [Internet]. WHO. [cited 2014 Nov 19]. Available from: http://www.who.int/dietphysicalactivity/factsheet_recommendations/en/

78. O’Donovan G, Blazevich AJ, Boreham C, Cooper AR, Crank H, Ekelund U, et al. The ABC of Physical Activity for Health: a consensus statement from the British Association of Sport and Exercise Sciences. J Sports Sci. 2010 Apr;28(6):573–91. 

79. Rebok G. Cognitive Training: Influence on Neuropsychological and Brain Function in Later Life. 2008; 

80. Hertzog C, Kramer A, Wilson R, Lindenberger U. Enrichment effects on adult cognitive development: Can the functional capacity of older adults be preserved and enhanced? 2008;1–65. 

81. Ball K, Berch DB, Helmers KF, Jobe JB, Leveck MD, Marsiske M, et al. Effects of cognitive training interventions with older adults: a randomized controlled trial. JAMA. 2002 Nov 13;288(18):2271–81. 

82. Willis SL, Tennstedt SL, Marsiske M, Ball K, Elias J, Koepke KM, et al. Long-term effects of cognitive training on everyday functional outcomes in older adults. JAMA J Am Med Assoc. 2006 Dec 20;296(23):2805–14. 

83. Rebok GW, Ball K, Guey LT, Jones RN, Kim H-Y, King JW, et al. Ten-year effects of the advanced cognitive training for independent and vital elderly cognitive training trial on cognition and everyday functioning in older adults. J Am Geriatr Soc. 2014 Jan;62(1):16–24. 

84. Mahncke HW, Connor BB, Appelman J, Ahsanuddin ON, Hardy JL, Wood RA, et al. Memory enhancement in healthy older adults using a brain plasticity-based training program: a randomized, controlled study. Proc Natl Acad Sci U S A. 2006 Aug 15;103(33):12523–8. 

85. Smith GE, Housen P, Yaffe K, Ruff R, Kennison RF, Mahncke HW, et al. A cognitive training program based on principles of brain plasticity: results from the Improvement in Memory with Plasticity-based Adaptive Cognitive Training (IMPACT) study. J Am Geriatr Soc. 2009 Apr;57(4):594–603. 

86. Rebok GW, Balcerak LJ. Memory self-efficacy and performance differences in young and old adults: The effect of mnemonic training. Dev Psychol. 1989;25(5):714–21. 

87. Rasmusson DX, Rebok GW, Bylsma FW, Brandt J. Effects of Three Types of Memory Training in Normal Elderly. Aging Neuropsychol Cogn. 1999 Mar 1;6(1):56–66. 

88. Lachman ME, Weaver SL, Bandura M, Elliott E, Lewkowicz CJ. Improving memory and control beliefs through cognitive restructuring and self-generated strategies. J Gerontol. 1992 Sep;47(5):P293–9. 

89. Baltes PB, Willis SL. Plasticity and Enhancement of Intellectual Functioning in Old Age. In: Craik FIM, Trehub S, editors. Aging and Cognitive Processes [Internet]. Springer US; 1982 [cited 2014 Nov 19]. p. 353–89. Available from: http://link.springer.com/chapter/10.1007/978-1-4684-4178-9_19

90. Willis SL. Cognitive training and everyday competence. Annu Rev Gerontol Geriatr. 1987;7:159–88. 

91. Ball KK, Beard BL, Roenker DL, Miller RL, Griggs DS. Age and visual search: expanding the useful field of view. J Opt Soc Am A. 1988 Dec 1;5(12):2210–9. 

92. Ball K, Owsley C. Increasing mobility and reducing accidents of older drivers. Springer Publishing Company; 2000. 372 p. 

93. Tyas SL, White LR, Petrovitch H, Webster Ross G, Foley DJ, Heimovitz HK, et al. Mid-life smoking and late-life dementia: the Honolulu-Asia Aging Study. Neurobiol Aging. 2003 Aug;24(4):589–96. 

94. Rusanen M, Kivipelto M, Quesenberry CP, Zhou J, Whitmer RA. Heavy smoking in midlife and long-term risk of Alzheimer disease and vascular dementia. Arch Intern Med. 2011 Feb 28;171(4):333–9. 

95. Rusanen M, Rovio S, Ngandu T, Nissinen A, Tuomilehto J, Soininen H, et al. Midlife smoking, apolipoprotein E and risk of dementia and Alzheimer’s disease: a population-based cardiovascular risk factors, aging and dementia study. Dement Geriatr Cogn Disord. 2010;30(3):277–84. 

96. Kim JW, Lee DY, Lee BC, Jung MH, Kim H, Choi YS, et al. Alcohol and cognition in the elderly: a review. Psychiatry Investig. 2012 Mar;9(1):8–16. 

97. Panza F, Frisardi V, Seripa D, Logroscino G, Santamato A, Imbimbo BP, et al. Alcohol consumption in mild cognitive impairment and dementia: harmful or neuroprotective? Int J Geriatr Psychiatry. 2012 Dec;27(12):1218–38. 

98. Piazza-Gardner AK, Gaffud TJB, Barry AE. The impact of alcohol on Alzheimer’s disease: a systematic review. Aging Ment Health. 2013;17(2):133–46. 

99. Sinforiani E, Zucchella C, Pasotti C, Casoni F, Bini P, Costa A. The effects of alcohol on cognition in the elderly: from protection to neurodegeneration. Funct Neurol. 2011 Jun;26(2):103–6. 

100. Barberger-Gateau P, Raffaitin C, Letenneur L, Berr C, Tzourio C, Dartigues JF, et al. Dietary patterns and risk of dementia: the Three-City cohort study. Neurology. 2007 Nov 13;69(20):1921–30. 

101. Scarmeas N, Stern Y, Tang M-X, Mayeux R, Luchsinger JA. Mediterranean diet and risk for Alzheimer’s disease. Ann Neurol. 2006 Jun;59(6):912–21. 

102. Devore EE, Grodstein F, van Rooij FJA, Hofman A, Stampfer MJ, Witteman JCM, et al. Dietary antioxidants and long-term risk of dementia. Arch Neurol. 2010 Jul;67(7):819–25. 

103. Morris MC, Evans DA, Bienias JL, Tangney CC, Bennett DA, Aggarwal N, et al. Dietary fats and the risk of incident Alzheimer disease. Arch Neurol. 2003 Feb;60(2):194–200. 

104. Poulain JP, Tibère L. Évolutions des représentations nutritionnelles des jeunes seniors : 1966/1998. Cah Nutr Diététique. 2000;35(1):40–6. 

105. Poulain JP. Les tendances actuelles du comportement alimentaire. Appfelbaum M, Romon M, Abrégé de Nutrition, Masson. 2005; 

106. Poulain J-P. Sociologies de l’alimentation : les mangeurs et l’espace social alimentaire. Édition : 3e édition. Paris: PRESSES UNIVERSITAIRES DE FRANCE – PUF; 2013. 287 p. 

107. French ministry of health. The French National Nutrition and Health Program: 2011-2015. Int J Public Health [Internet]. 2011 [cited 2014 Nov 19]; Available from: http://www.sante.gouv.fr/IMG/pdf/PNNS_UK_INDD_V2.pdf

108. Dorval V, Nelson PT, Hébert SS. Circulating microRNAs in Alzheimer’s disease: the search for novel biomarkers. Front Mol Neurosci. 2013;6:24. 

109. Sonnen JA, Montine KS, Quinn JF, Kaye JA, Breitner JCS, Montine TJ. Biomarkers for cognitive impairment and dementia in elderly people. Lancet Neurol. 2008 Aug;7(8):704–14. 

110. Dubois B, Feldman HH, Jacova C, Dekosky ST, Barberger-Gateau P, Cummings J, et al. Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS-ADRDA criteria. Lancet Neurol. 2007 Aug;6(8):734–46. 

111. Dubois B, Feldman HH, Jacova C, Cummings JL, Dekosky ST, Barberger-Gateau P, et al. Revising the definition of Alzheimer’s disease: a new lexicon. Lancet Neurol. 2010 Nov;9(11):1118–27. 

112. Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, et al. Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement J Alzheimers Assoc. 2011 May;7(3):280–92. 

113. Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, et al. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement J Alzheimers Assoc. 2011 May;7(3):270–9. 

114. McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR, Kawas CH, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement J Alzheimers Assoc. 2011 May;7(3):263–9. 

115. Bocchetta M, Galluzzi S, Kehoe PG, Aguera E, Bernabei R, Bullock R, et al. The use of biomarkers for the etiologic diagnosis of MCI in Europe: An EADC survey. Alzheimers Dement J Alzheimers Assoc. 2014 Aug 20; 

116. Monte SM, Ghanbari K, Frey WH, Beheshti I, Averback P, Hauser SL, et al. Characterization of the AD7C-NTP cDNA expression in Alzheimer’s disease and measurement of a 41-kD protein in cerebrospinal fluid. J Clin Invest. 1997 Dec 15;100(12):3093–104. 

117. Zhang J, Shi S. A literature review of AD7c-ntp as a biomarker for Alzheimer’s disease. Ann Indian Acad Neurol. 2013 Jul;16(3):307–9. 

118. Okamura N, Harada R, Furumoto S, Arai H, Yanai K, Kudo Y. Tau PET Imaging in Alzheimer’s Disease. Curr Neurol Neurosci Rep. 2014 Nov;14(11):500. 

119. Mattsson N, Zetterberg H, Hansson O, Andreasen N, Parnetti L, Jonsson M, et al. CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment. JAMA. 2009 Jul 22;302(4):385–93. 

120. Paraskevas GP, Kapaki E, Papageorgiou SG, Kalfakis N, Andreadou E, Zalonis I, et al. CSF biomarker profile and diagnostic value in vascular dementia. Eur J Neurol Off J Eur Fed Neurol Soc. 2009 Feb;16(2):205–11. 

121. Frankfort SV, Tulner LR, van Campen JPCM, Verbeek MM, Jansen RWMM, Beijnen JH. Amyloid beta protein and tau in cerebrospinal fluid and plasma as biomarkers for dementia: a review of recent literature. Curr Clin Pharmacol. 2008 May;3(2):123–31. 

122. Folin M, Baiguera S, Conconi MT, Di Liddo R, De Carlo E, Parnigotto PP, et al. Apolipoprotein E as vascular risk factor in neurodegenerative dementia. Int J Mol Med. 2004 Oct;14(4):609–13. 

123. Blennow K, Zetterberg H. Use of CSF biomarkers in Alzheimer’s disease clinical trials. J Nutr Health Aging. 2009 Apr;13(4):358–61. 

124. Ko FC-Y. The clinical care of frail, older adults. Clin Geriatr Med. 2011 Feb;27(1):89–100. 

125. Epstein AM, Hall JA, Besdine R, Cumella E, Feldstein M, McNeil BJ, et al. The emergence of geriatric assessment units. The “new technology of geriatrics.” Ann Intern Med. 1987 Feb;106(2):299–303. 

126. Frisoni GB, Fratiglioni L, Fastbom J, Guo Z, Viitanen M, Winblad B. Mild Cognitive Impairment in the Population and Physical Health Data on 1,435 Individuals Aged 75 to 95. J Gerontol A Biol Sci Med Sci. 2000 Jun 1;55(6):M322–8. 

127. Desai AK, Grossberg GT, Chibnall JT. Healthy brain aging: a road map. Clin Geriatr Med. 2010 Feb;26(1):1–16. 

128. AAIC Press Release | AAIC 2014 [Internet]. AAIC. [cited 2014 Nov 18]. Available from: http://www.alz.org/aaic/releases_2014/mon-730pm-finger.asp

129. Qiu C, von Strauss E, Bäckman L, Winblad B, Fratiglioni L. Twenty-year changes in dementia occurrence suggest decreasing incidence in central Stockholm, Sweden. Neurology. 2013 May 14;80(20):1888–94. 

130. Qiu C, Kivipelto M, von Strauss E. Epidemiology of Alzheimer’s disease: occurrence, determinants, and strategies toward intervention. Dialogues Clin Neurosci. 2009 Jun;11(2):111–28. 

131. Duron E, Hanon O. Vascular risk factors, cognitve decline, and dementia. Vasc Health Risk Manag. 2008 Apr;4(2):363–81. 

132. Matthews FE, Arthur A, Barnes LE, Bond J, Jagger C, Robinson L, et al. A two-decade comparison of prevalence of dementia in individuals aged 65 years and older from three geographical areas of England: results of the Cognitive Function and Ageing Study I and II. Lancet. 2013 Oct 26;382(9902):1405–12. 

133. Baum EE, Jarjoura D, Polen AE, Faur D, Rutecki G. Effectiveness of a group exercise program in a long-term care facility: a randomized pilot trial. J Am Med Dir Assoc. 2003 Apr;4(2):74–80. 

134. Van de Winckel A, Feys H, De Weerdt W, Dom R. Cognitive and behavioural effects of music-based exercises in patients with dementia. Clin Rehabil. 2004 May;18(3):253–60.