PATHS TO ALZHEIMER S DISEASE PREVENTION: FROM MODIFIABLE RISK FACTORS TO BIOMARKER ENRICHMENT STRATEGIES

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1 PATHS TO ALZHEIMER S DISEASE PREVENTION: FROM MODIFIABLE RISK FACTORS TO BIOMARKER ENRICHMENT STRATEGIES S. LISTA 1,2, B. DUBOIS 1, H. HAMPEL 1,2 1. Sorbonne Universités, Université Pierre et Marie Curie, Paris 06, Institut de la Mémoire et de la Maladie d Alzheimer (IM2A) & Institut du Cerveau et de la Moelle épinière (ICM), Département de Neurologie, Hôpital de la Pitié-Salpétrière, Paris, France; 2. AXA Research Fund & UPMC Chair. Corresponding author: Simone Lista, PhD and Harald Hampel, MD, PhD, MA, MSc, AXA Research Fund & UPMC Chair, Sorbonne Universités, Université Pierre et Marie Curie, Paris 06, Institut de la Mémoire et de la Maladie d Alzheimer (IM2A) & Institut du Cerveau et de la Moelle épinière (ICM), Département de Neurologie, Pavillon François Lhermitte, Hôpital de la Pitié-Salpêtrière, 47 Boulevard de l Hôpital Paris, CEDEX 13 France, Phone: , Fax: , slista@libero.it (S. Lista), harald.hampel@upmc.fr; harald.hampel@med.uni-muenchen.de (H. Hampel) Abstract: Alzheimer s disease (AD) represents an increasing worldwide healthcare epidemic. Secondary preventive disease-modifying treatments under clinical development are considered most effective when initiated as early as possible in the pathophysiological course and progression of the disease. Major targets are to enhance clearance and to reduce cerebral accumulation of amyloid, decrease hyperphosphorylation of tau and the generation of neurofibrillary tangles, reduce inflammation, and finally progressive neurodegeneration. Comprehensive sets of biological markers are needed to characterize the pathophysiological mechanisms, indicate effects of treatment and to facilitate early characterisation and detection of AD during the prodromal or even at asymptomatic stages. No primary or secondary preventive treatments for AD have been approved. Epidemiological research, however, has provided evidence of specifically modifiable risk and protective factors. Among them are vascular, lifestyle and psychological risk factors that may act both independently and by potentiating each other. These factors may be substantially impacted by single or multi-domain strategies to prevent or postpone the onset of AD-related pathophysiology. Researchers have recently started the European Dementia Prevention Initiative (EDPI), an international consortium to improve strategies for preventing dementia. EDPI, in particular, includes the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) which aims at optimizing the early identification of subjects at increased risk of late-life cognitive deterioration, and at the evaluation of multi-domain intervention strategies. The ongoing discussion on new diagnostic criteria provided by the International Working Group (IWG), as well as by the recommendations summoned by the National Institute on Aging and Alzheimer s Association (NIA-AA) initiative, has inspired the creation of novel study designs and the definition of earlier target populations for trials in pre- and asymptomatic at-risk and prodromal stages of AD. As a result, a number of promising international prevention trials are currently ongoing. In this review, we critically discuss the main paths to AD prevention through control of modifiable risk factors and lifestyle changes. We will also review the role of biomarkers to identify subgroups of patients who would most likely benefit from secondary prevention strategies, and to evaluate the benefit of treatment in such patients. Key words: Alzheimer s disease, clinical trials, prevention, biomarkers, risk factors. Introduction Alzheimer s disease (AD) is the most prevalent neurodegenerative disease and is a leading cause of morbidity and mortality worldwide. At present, 35 million patients suffer from AD and this number is predicted to exponentially grow to million patients worldwide by 2050 (1). At histopathological level, AD presents accumulation of amyloid plaques, neurofibrillary tangles, inflammation and neuronal depletion accompanied by a progressive decay of cognition and functional abilities finally leading into the late-stage AD dementia stage (2). According to the Global Burden of Disease (GBD) project, dementia has been estimated to account for 11.2% of disability years in people older than 60 years, a value greater than the disability years caused by stroke, cardiovascular diseases, and all forms of cancer (3). These data highlight the evolving healthcare epidemic of AD and the urgent need of effective prevention strategies to prevent, halt, modify or delay pathophysiologic initiation and progression and therefore decrease the mounting catastrophic burden on healthcare systems and societies and ultimately aid those affected and their families (4). Current late-stage symptomatic anti-dementia treatments based on the administration of approved compounds such as donepezil, rivastigmine, galantamine, and memantine have shown to slightly ameliorate the clinical signs and their progression (5). As a result, primary and secondary prevention during the early preclinical stage seems likely to provide the most effective approach to lower the incidence of AD (6). In this review, we critically discuss the main paths to AD prevention through control of modifiable risk factors and lifestyle changes. We will also review the role of biomarkers to identify subgroups of patients who would most likely benefit from secondary prevention strategies, and to evaluate the benefit of treatment in such patients. Received May 7, 2014 Accepted for publication August 8,

2 JNHA: CLINICAL NEUROSCIENCES Overview on the status of biomarker development for Alzheimer s disease Molecular and cellular alterations involving different pathways in the AD brain including protein misfolding, such as modifications in the amyloid precursor protein (APP) metabolism (7), tau hyperphosphorylation (8), as well as mitochondrial dysfunction, oxidative stress, neuroinflammatory mechanisms (9, 10), lipid pathways (11), membrane lipid dysregulation (12), and neurotransmitter pathway interferences (13) have been observed. Since these changes seem functionally interconnected in AD, a hypothesis-independent systemic approach is needed to depict a comprehensive picture of the pathogenesis of AD both at systems and at neural network level (14, 15). In the advent of these emerging conceptual developments, it has become relevant to develop suitable strategies for clinical procedures to detect markers in biofluids that provide information on the global systemic alterations in molecular/cellular networks (14). The current advances in discovery, development, and validation of AD related biomarkers, have embraced the era of multi-modal investigations using and integrating modalities and methodological specialties (16-18), such as neurogenetics as well as the emerging field of neuroepigenetics (19-21), structural/functional/metabolic neuroimaging and neurophysiology (22-24), neurobiochemistry on cerebrospinal fluid (CSF) (25-27) as well as blood (plasma/serum) (25-29). Moreover, the approach of combining different source markers (30) may help to identify subjects who will develop AD at asymptomatic and presymptomatic stages and who will consequently be potential targets for preventive and symptomatic pharmacological intervention trials. Finally, a number of critical opinions of regulatory bodies and industry stakeholders in AD biomarker discovery area have been reported (31, 32). The challenge at hand is to conceptualize the emerging approaches, standardize methods, study protocols, data and sample collection at baseline and at follow-up, analyse and integrate large-scale complex datasets. Biomarkers are currently utilized clinically as well as in therapy trials to indicate the underlying presence and can be utilized for detection, diagnosis, prediction, staging, enrichment, stratification or outcome assessment. The most relevant, so called core, feasible biomarkers consist of changes in CSF concentrations of Aβ1-42, t-tau, and p-tau; fibrillar amyloid deposits targeted by positron emission tomography (PET) ligands; regional atrophy on magnetic resonance imaging (MRI); regional pattern of hypometabolism on 18F-2-fluoro-2-deoxy-D-glucose PET (18F-FDG-PET) (16, 18, 25). According to the National Institute on Aging and Alzheimer s Association (NIA-AA) concept, these biomarkers have been categorized into those indicating (I) abnormalities of amyloid physiology (decreased CSF Aβ1-42 and increased amyloid uptake in PET imaging) and (II) neuronal injury (increases in CSF t-tau and p-tau, regional MRI atrophy, and pattern of hypometabolism in FDG-PET). Alternatively, the International Working Group (IWG) concept depicts biomarkers as (I) pathophysiologic markers including CSF core, feasible biomarkers (Aβ1-42, t-tau, p-tau) and 11C-Pittsburgh Compound B-positron emission tomography (PiB-PET) which correlate with the two assumingly causal degenerative mechanisms of AD, the amyloidogenic pathway leading to neuritic plaques and the tauopathy pathway resulting in hyperphosphorylation of tau protein and neurofibrillary tangles; and (II) topographic markers including regional MRI atrophy and pattern of hypometabolism in FDG-PET which are hypothesized to assess downstream brain alterations that correlate with the regional distribution of AD pathology (33). To tackle the challenge of biomarker standardization the Alzheimer s Association has commenced a global quality control program for CSF core, feasible biomarkers of AD, which involves over 70 laboratories worldwide (34). A central issue is represented by the still large variations in CSF biomarker measurements among and within laboratories; such a variability is too high to permit assignment of universal biomarker cut-off values for a specific intended use. Further standardization of laboratory procedures and enhancement of kit performance is expected to increase the usefulness and performance of these first generation hypothesis-driven core biomarkers both in research and in clinical settings (35). Blood-based biomarkers are highly desirable developments, but at present, their immense potential for widespread and generalizable risk screening has yet to be fully unfolded. Actually, it is challenging to standardize a worldwide bloodbased biomarker panel given the differences in the intrinsic features of the population under study, the type and variety of the samples, and the measurement platforms exploited by the different research groups (36). In particular, strategies should be adopted to enhance laboratory quality, including internal quality control procedures, external quality assessment programs, licensing of lab professionals, and adoption of strict pre-analytical, analytical and post-analytical requirements. In this scenario, the Blood-Based Biomarker Interest Group (BBBIG), an international working group of leading AD biomarker researchers from academia and industry, has been recently established to inspect the present scenario of biomarker discovery in blood and to identify current needs that will enable the field to advance (36). Similarly, the aim of the Biomarkers for Alzheimer s disease and Parkinson s disease ( BIOMARKAPD ) project within the EU Joint Programme Neurodegenerative Disease (JPND) Research (a joint transnational call has therefore been launched to encourage novel approaches to the development of optimally informative biomarkers and harmonization of their use) is to standardize the assessment of established and new fluid biomarkers for AD (see the website eu/initiatives/biomarker-transnational-call/results-of-fundingcall/biomarkapd/). Unfortunately, some major limitations still remain, including the fact that the biomarker model assumes 155

3 PATHS TO AD PREVENTION: FROM MODIFIABLE RISK FACTORS TO BIOMARKER ENRICHMENT STRATEGIES pure AD (but mixed subtypes are common) and that significant caveats exist both related to costs and acceptabilityy (especially for CSF biomarkers). The sequence of pathophysiological mechanisms linked to sporadic AD is believed to initiate a minimum of years before the disease onset (37-39). Notably, a theoretical model explaining the temporal ordering of AD biomarkers has been developed within the Alzheimer s Disease Neuroimaging Initiative (ADNI) (40) and later commented and extended (41) (Figure 1). This model hypothesizes the onset and progression of AD with biomarkers based on the following notions: (I) biomarkers become abnormal before the appearance of the clinical symptoms; (II) Aβ levels become abnormal first, followed by alterations in tau protein levels and other biomarkers of neurodegeneration; (III) tau and neurodegenerative biomarkers are more closely associated than Aβ with the severity of the clinical disease; and (IV) Aβ, tau, and neurodegenerative biomarkers can be chronologically arranged to reproduce steps in the onset and progression of AD. Increasing evidence seems to support these concepts, as reported by Jack and colleagues (38). This model is currently being tested by researchers of the World Wide ADNI (WW-ADNI) network that includes an array of international collaborating projects and global initiatives (42). Further classification of biomarkers During the past decades, biomarkers have gained an important role in drug development throughout all therapeutic areas. Given the recent advancement in explicating the pathophysiological mechanisms of diseases at the molecular level as well as in the areas of diagnostics and pharmacogenomics, biomarkers are considered promising tools to enhance all phases of drug discovery & development programs by allowing validation of mechanisms of action (MoA) (43). They can be employed in clinical trials to improve diagnostic accuracy in trial participants, thus enabling cohorts of patients to be enriched with cases of AD (patient enrichment) (25, 44). They facilitate the stratification of patients to improve clinical response, monitoring the progression of disease and response to therapy, identification of prognostic signatures, and development of diagnostic assays (25, 44). Consequently, biomarkers are now being integrated in research & development strategies for detecting new candidate drugs, from the discovery step to the regulatory authorization (31, 45). They can be arranged in several categories: (I) target engagement biomarkers, verifying the hypothesis on the interaction of the candidate drug with its molecular target; (II) MoA biomarkers, assessing downstream biochemical effects; (III) outcome biomarkers, evaluating both efficacy and safety; (IV) safety biomarkers, evaluating and predicting tolerability as well as adverse side effects; and (V) theragnostic biomarkers (43). Specifically, theragnostic biomarkers can be defined as markers that support treatment choices through the prediction of both the most appropriate treatment (or response to treatement) for an individual and the most correct dose. The use of theragnostic biomarkers is aimed at maximizing drug efficacy and minimizing toxicity, by providing a more informed treatment choice through the investigation of the effects of a drug on disease-related biochemical pathways or pathogenic mechanisms (25). Theragnostic biomarkers are usually separated into primary and downstream (46). Primary biomarkers are exploited to identify and monitor the pharmacodynamic effect of the drug, thus showing indication for target engagement. In an anti-aβ clinical trial, these might include CSF (and plasma) Aβ1-42 and Aβ1-40 together with the α- and β-cleaved soluble forms of APP (sappα, and sappβ) (44). Downstream biomarkers are employed to monitor effects downstream of the primary target of the drug (46). In an anti-aβ clinical trial, these might be represented by neuronal proteins, such as t-tau, reflecting the extent of the neuronal degeneration. Theragnostic biomarkers are believed to achieve a crucial position along the different phases of AD drug development, from early clinical to late registration trials (44). Risk factors and protective factors of Alzheimer s disease AD has been unquestionably accepted as a complex multifactorial disease given the presence of numerous interconnected genetic and environmental factors. Approximately two decades of research intended to scrutinize the field of AD prevention have led to perform several studies that have unveiled a number of risk and protective factors (47). Basically, risk factors are grouped into two categories: those that cannot be altered such as age and family history and those it is possible modify (Table 1). Age is the best known risk factor for AD; the risk of developing the disease doubles every 5 years after age 65 (48). The more researchers learn about AD, the more they realize the significant role of genes in its development. Specifically, three mutations in the amyloid precursor protein (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2) genes have been related to the early-onset form of AD (EOAD). Regarding the late-onset form of AD (LOAD), the by far best established genetic risk factor is the ε4 allele in the apolipoprotein E (APOE ε4) gene. The successive progress through genome-wide association studies (GWAS) has led to disclose other susceptibility genes (49). The AlzGene database (available at org/) (50) provides an up-to-date overview of all genes that have been examined for evidence of genetic association and disease risk. Interestingly, not only risk but also protective genetic variants toward the development of AD have been recently identified. In particular, an A673T substitution within the amyloid-β precursor protein (APP) gene has been shown to be protective against cognitive decline in the elderly without AD (51). It is expected that rare genetic variants may play a role in modulating the risk of developing complex diseases like 156

4 JNHA: CLINICAL NEUROSCIENCES AD, and that new discoveries will shed further light into the biological underpinnings of pathological processes. Non-modifiable Table 1 Main proposed risk factors for AD Age After age 65, AD risk doubles every five years. Age is the strongest risk factor for AD Family history Three genetic mutations have been linked with familial AD in the APP, PSEN1, and PSEN2 genes Genetic background APOE ε4 allele is the best established risk factor for sporadic AD. GWAS have led to disclose a growing number of susceptibility genes in sporadic AD populations (AlzGene database, Modifiable Cardiovascular risk factors Hypertension Hypercholesterolemia Diabetes mellitus Obesity Cerebrovascular lesions Cardiovascular diseases Lifestyle-related risk factors Diet rich in saturated fats Excessive alcohol consumption Smoking Cognitive inactivity Physical inactivity Low education Social inactivity Abbreviations: AD, Alzheimer s disease; APP, amyloid precursor protein; PSEN1, presenilin-1; PSEN2, presenilin-2; APOE ε4, ε4 allele of apolipoprotein E gene; GWAS, genome-wide association studies. The cardiovascular risk factors for AD include hypertension, high cholesterol levels, and diabetes. These make the affected subject susceptible to cognitive decline both independently and also by potentiating reciprocally. Longitudinal analyses have revealed an accumulation of midlife cardiovascular risk factors that can elevate the risk of cognitive deterioration and dementia in late life after several years of follow-up (52-54). Hypertension, a well-known risk factor for cardiovascular diseases, has been linked to AD in many studies; however, the association appears to be age-dependent. High blood pressure in midlife has been related to an amplified risk of AD (55, 56). Elevated levels of total serum cholesterol in midlife have been associated with a grown risk of AD (56): it is acknowledged that high amounts of cholesterol induce atherosclerosis leading to a high risk of cardiovascular and cerebrovascular disorders. Furthermore, elevated cholesterol concentrations have been correlated with higher amounts of amyloid deposits in the brain (57). Diabetes mellitus has been associated with an increased risk of dementia and clinical AD (58). It displays its effects in clinical manifestation of AD by interacting with many vascular risk factors including hypertension, smoking, and the presence of the APOE ε4 allele through a rise in the number of cerebrovascular lesions (59). Modifiable risk factors also consist of those directly linked to practical aspects of lifestyle including nutrition, education, physical activity, smoking, alcohol consumption, and social relations. Nutrition has been scrutinized for a long time as a possible modifiable risk factor for dementia. Even though no certain dietary recommendations have been established (60, 61), numerous longitudinal studies have associated a higher observance to the Mediterranean diet with reduced cognitive decline, lowered the risk of progression from mild cognitive impairment (MCI) to AD, decreased risk of AD and a reduction in all-cause mortality in AD. These data have led to propose that adherence to the Mediterranean diet may impact not only on AD risk, but also on that of predementia syndromes and their advancement to overt dementia (60-62). The Mediterranean diet consists of a high consumption of vegetables, fruits, unrefined cereals and legumes as well as moderate-to-high intake of fats derived from fish, much less emphasis on dairy and meat products, and moderate wine intake. Olive oil seems to play a dominant role in the diet and, as it contains large amounts of mono-unsaturated fats and antioxidants, it has been associated with a decreased risk for coronary heart disease and better cholesterol modulation; moreover, it is assumed to show anti-hypertensive and anti-inflammatory effects (60, 61). As another part of the Mediterranean diet, docosahexaenoic acid (DHA) has been suggested to play a key role in neural function. Accordingly, reduced plasma DHA levels have been associated with cognitive decline in healthy elderly (63) and a higher DHA intake is inversely associated with the relative risk of developing AD (64). Analyses of the link between alcohol consumption and cognition have produced divergent data; as a result, efforts to establish what might be supposed beneficial levels of alcohol intake in terms of cognitive performance are still considered challenging (65). According to recent studies, mild-moderate alcohol consumption appears to be protective against dementia while excessive intake seems to amplify the risk of cognitive decline and dementia (65-67). However, more studies on the association between alcohol and AD are needed before drafting clinical guidelines (67). Data obtained from epidemiological analyses in smokers on AD are inconsistent; current investigations of the effects of nicotine and nicotinic agonists on cognitive activity in nondemented subjects and AD patients are not entirely convincing. Multifaceted connections between nicotine, nicotinic agonists, smoking, and nicotinic acetylcholine receptors involved in AD etiology are assumed to exist (68). People who are heavy 157

5 PATHS TO AD PREVENTION: FROM MODIFIABLE RISK FACTORS TO BIOMARKER ENRICHMENT STRATEGIES smokers in their midlife years are more than doubling their risk of developing AD more than two decades later. This association is not affected even after adjusting for stroke, a pathology for which smoking is a recognized risk factor (69). In the Cardiovascular Risk Factors, Aging and Incidence of Dementia (CAIDE) study cohort, midlife smoking increases the risk of dementia and AD among APOE ε4 allele carriers, but not among APOE ε4 non-carriers. These results demonstrate the existence of an intricate gene-environment interaction between smoking and AD risk (70). It should be emphasized that the impact of risk factor modification on any specific individual is probably interdependent on the specific genetic risk and protective pattern, environment, and lifestyle of that subject. In this regard, there is growing evidence that three components namely physical, mental, and social may modulate the risk of cognitive decline, dementia and AD. Aerobic physical activity displays a series of effects that could decrease the risk of AD. Regular exercise in midlife has led to a reduced risk of dementia which can be caused by the impact of the cardiovascular risk profile and a decline of brain tissue degeneration and loss (71). A prospective study with healthy individuals has demonstrated that higher Mediterraneantype diet adherence and increased physical activity are independently associated with decreased risk of AD (72). Of note, a subsequent study has shown that exercise may influence not only the risk for AD but also disease duration: more physical activity is associated with prolonged survival in AD (73). Interestingly, the association between physical activity played during leisure-time and reduced AD risk is more prominent among genetically susceptible individuals (74). Generally, it seems advantageous to begin and sustain regular and individually suitable aerobic exercise early and life into old age to. Excessive, short term, and late life physical activity seems much less preventive. Positively gained biological benefits are soon lost after training has been discontinued as shown by structural and functional neuroimaging studies. There is evidence that the risk of AD is increased among people who have received shorter periods of education in life. Advanced education is assumed to be associated with higher cognitive reserve that decreases the impact of AD on cognitive function, even in subjects with a more disadvantageous genetic background (i.e. APOE ε4 carriers) (75). Genetic and environmental (i.e. education) factors are recognized to be not only independently but also interactively connected to dementia risk; high degree of education may neutralize the negative effect of APOE ε4 allele on dementia incidence (76). The investigation of cortical thickness and brain volume by structural MRI in a multicenter longitudinal study cohort has revealed that more years of education rise the threshold before which brain atrophy appears clinically evident among AD patients; this result can be due to neuroplasticity changes and augmented cognitive reserve and brain resilience (77). Interventions with cognitive stimulation paradigms (78) have demonstrated improved global cognitive functioning and abilities of daily living, reduced behavioral disturbances, and positive effects on quality of life in subjects with MCI (79) or patients with mild-to-moderate AD (80). Functional neuroimaging studies show that changes in attention underpin many of the improvements in cognitive performance. Moreover, cognitive interventions that support global functioning could slow the onset of AD by a number of years in patients who will eventually develop this condition. Among the mental components that may modulate the risk of AD, the role of chronic stress and depression has been receiving increasing attention (81). A meta-analysis by Ownby and colleagues (2006) (82) has shown that a diagnosis of depression and AD is positively related to an increased risk of developing AD, suggesting that rather than a prodrome, depression may be a risk factor for AD. In this regard, Aznar & Knudsen (2011) (83) have hypothesized that depressive episodes that compromise the brain s ability to cope with stress may constitute risk factors for the development of AD. Social characteristics encompass a large range of traits such as higher education and socioeconomic status and position, purpose in life, highly active social networking, participation in cognitively challenging tasks, and being in a relationship. All these factors are assumed to play a protective role against AD (4, 47, 48). The path to Alzheimer s disease prevention Given the mounting evidence from epidemiological studies associating several modifiable risk factors to AD and given the multifactorial nature of the sporadic form of the disease, large-scale randomized controlled trials (RCTs) with multidomain interventions have been highly encouraged and designs developed (4, 47, 48). Establishing international collaborations is of paramount importance to enable and assist the efficient development and management of dementia prevention trials. The first promising initiatives showing a broad international perspective include the European Dementia Prevention Initiative (EDPI; available at (6, 84). Accordingly, three large ongoing multidomain interventional RCTs focused on dementia prevention have been established: the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) (85), the Multidomain Alzheimer Preventive Trial (MAPT) (86), and the Prevention of Dementia by Intensive Vascular Care (PreDIVA) study (87) (Table 2). The most important commonality in these prevention trials is the systematic multi-domain approach aiming at simultaneously targeting a number of relevant vascular and lifestyle-related risk factors for dementia and targeting older at risk adult populations (4, 47). All these RCTs do not include patients with established dementia and employ batteries of neuropsychological examinations and clinical assessment to identify cognitive alterations and dementia incidence as main outcomes. Moreover, both FINGER and MAPT comprise 158

6 additional ancillary investigations on structural/functional neuroimaging, CSF, and blood-based markers linked to AD pathophysiology to examine the effects of prevention on brain biochemistry, structure, and metabolism and detect biomarkers (outcomes) that can help assess effects of interventions (4, 47). The first results of these major international prevention trials are expected to be reported this year. These data will be highly informative for the development and refinement of new trials. International collaborations and data sharing procedures among different RCTs are thought to improve the methodological aspects of prevention trials such as, for instance, identification of ideal target populations. This is expected to simplify the design of the optimal study for upcoming multi-national dementia prevention trials (4). An indication in this direction comes from the Healthy Aging Through Internet Counseling in the Elderly program (HATICE; available at HATICE, a European Union-funded project initiated by the EDPI members, aims at preventing dementia and cardiovascular diseases in the elderly. It sustains the management of vascular and lifestyle-related risk factors in older adults by developing an innovative, interactive internet intervention platform. Interactive support by practice nurses and patient s own physician and monitoring of adverse events are also integrated (48). In order to assess the efficacy of such novel internet platform, a randomized controlled clinical trial among 4,600 elderly patients with multiple cardiovascular diseases is planned within HATICE to begin in Primary outcome is optimization of management of cardiovascular diseases. Secondary outcomes are novel cardiovascular events, handicap, cognition and survival (see Additional lifestyle-related trials giving emphasis JNHA: CLINICAL NEUROSCIENCES on physical activity as the main intervention have been commenced. Outcomes are represented by cognitive change/ functional status and biomarkers of AD and cognitive decline. The Centre for Studies on Prevention of AD (StoP-AD Centre) at the Douglas Institute in Montreal, Canada, has established a PREVENT-Alzheimer program aimed at testing several preventive interventions in people over age 60 with a family history of AD; such program (available at page/prevent-alzheimer) wants to recruit 500 participants. The Australian Imaging Biomarkers and Lifestyle Flagship Study of Aging (AIBL) is designed to explore the possibility of delaying AD by reducing vascular risks through physical activity (88) (available at AIBL2011FINAL.pdf). The exciting discussion on the newly proposed AD diagnostic criteria has encouraged the development of novel study designs for prevention trials in at-risk and prodromal stages of AD. Three complementary prevention trials have been initiated to decide whether anti-amyloid treatments are effective in asymptomatic and presymptomatic AD populations. The Alzheimer s Prevention Initiative (API) trial (89) is evaluating the preventive effects of a specific monoclonal anti-aβ antibody crenezumab (Genentech, Inc., South San Francisco, CA, USA) in asymptomatic subjects from an extended family in Colombia carrying the Paisa PSEN1 E280A mutation (90) predisposing carriers to EOAD. The Dominantly Inherited Alzheimer Network (DIAN) (91) is a cooperative effort of international AD centers leading a multifaceted prospective biomarker study in individuals at-risk for autosomal dominant AD (ADAD). In particular, the DIAN Trials Unit (DIAN-TU) has launched the first prevention trial for ADAD families Table 2 Ongoing multi-domain prevention RCTs within the EDPI initiative RCT FINGER MAPT PreDIVA Sample size Age at enrolment, years Over Inclusion criteria Dementia Risk Score >6 Frail elderly people Elderly people visiting and mild degree of (subjective memory the general practitioner, cognitive impairment complaint, slow walking non demented speed, limitation in IADL) (MMSE >23) Design Multi-center, randomized, Multi-center, randomized, Multi-center, randomized, single-blind, parallel-group controlled trial controlled trial Intervention Nutritional guidance, Vascular care, nutritional Nurse-led vascular care physical activity, cognitive advice, exercise advice, including medical training, increased social cognitive training, treatment of risk factors, activity and intensive and/or DHA 800 mg/day diet advice, exercise advice monitoring and management of metabolic and vascular risk factors Duration of follow-up (years) Duration of the intervention (years) Abbreviations: DHA, docosahexaenoic acid; EDPI, European Dementia Prevention Initiative; FINGER, Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability; IADL, Instrumental Activities of Daily Living; MMSE, Mini Mental State Examination; PreDIVA, Prevention of Dementia by Intensive Vascular Care; RCTs, randomized controlled trials. 159

7 PATHS TO AD PREVENTION: FROM MODIFIABLE RISK FACTORS TO BIOMARKER ENRICHMENT STRATEGIES and is assessing the effects of the monoclonal anti-aβ antibodies solanezumab (LY , Eli Lilly and Company, Indianapolis, IN, USA) and gantenerumab (RO , F. Hoffmann-La Roche Ltd., Basel, Switzerland). Another trial, named Anti-Amyloid Treatment of Asymptomatic Alzheimer s (A4) (92), is testing solanezumab in elderly patients who are at high-risk of developing disease, as assessed by amyloid imaging. The three prevention initiatives are kept strictly interconnected under the umbrella group referred to as Collaboration for Alzheimer s Prevention (CAP) (93). Future directions The proposed hypothetical biomarker model of AD, established using data gathered by the DIAN and from the ADNI (Figure 1) (38), is currently receiving support as further data are being reported. The time-based ordering of biomarkers serves to further elucidate a comprehensive biomarker driven AD landscape navigation system to aid future prevention trials. A recent study has reported that a decrease in CSF Aβ1-42 may present the earliest detected upstream marker of AD (94) and that CSF t-tau and hippocampal volume indicate disease progression immediately preceding and throughout symptomatic phases (95). Figure 1 According to Sperling and colleagues (2012), researchers should start reflecting on AD in conceptual terms along disease stages of primary, secondary, and tertiary prevention (96). Even though primary prevention seems to be the best way to follow, the vision of large primary prevention trials for sporadic LOAD is quite discouraging and unrealistic given the substantial length of treatment and follow-up needed to attain a meaningful clinical endpoint. In addition, it should also be considered the issue of the costs and safety of treating a large numbers of subjects who may never develop the disease (96). Therefore, the most appropriate stage for conducting trials in sporadic LOAD seems that of detectable asymptomatic amyloid accumulation (amyloid positive or amyloid progressors), based on the hypothesis that brain amyloidosis is associated with early stages of AD. These studies can be defined secondary prevention trials intended to prevent or delay the onset and progression of the clinical syndrome in patients in which detectable pathophysiological mechanisms of AD have manifested (96, 97). For these reasons, efforts to develop disease-modifying treatments may require clinical trials to be conducted much earlier in the disease process (97). Towards this end, a large-scale mono-center study of a cohort of amyloid positive subjects at risk for AD is currently ongoing at Pierre and Marie Curie University (UPMC) and the Pitié-Salpêtrière Hospital in Paris (France), led by Dubois and Hampel and colleagues. This INveStIGation of AlzHeimer s PredicTors in Subjective Memory Complainers (INSIGHT) has a follow-up of several years with serial assessments of comprehensive batteries of clinical, neuropsychological, and multi-modal biomarkers. First results are expected soon and will be informative both for charting a more complete AD biomarker chart and for designing clinical prevention trials (98). It seems necessary to continually refine definitions and criteria as well as conceptual models of AD and focus on the need for better research methods and infrastructure. Only a constant and concerted international commitment to solve these challenging issues will allow the translation of newly emerging and encouraging biomarker developments and those of biomarker aided prevention trials into practical clinically useful applications (47). The accomplishment of any substantial campaign for AD prevention demands significant modifications in the way of approaching AD research (48). To this aim, initiatives with an international and global perspective have been initiated and are ongoing: the EU/US Task Force on Clinical Trial Development in AD (EU/US CTAD task force) (45), the Organisation for Economic Co-operation and Development (OECD, available at Task Force on AD, and, most excitingly, the non-profit corporation Prevent Alzheimer s Disease by 2020 (PAD2020, available at (99) which emphasizes the importance of integrating/expanding existing cohorts and registries in order to create a world-wide database. Conflict of interests: The authors declare no conflict of interest. Funding: The Fondation Université Pierre et Marie Curie (HH), the IHU-A-ICM (HH, SL), and the Fondation pour la Recherche sur Alzheimer (FRA) (HH), Paris, France. References 1. Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP. The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement 2013;9:63-75.e2. 2. Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E. Alzheimer s disease. Lancet 2011;377:

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