The Journal of Prevention of Alzheimer’s Disease - JPAD ... prevention.pdf · Update on Prevention Trials in Alzheimer’s Disease 170 population and the low conversion rate to

Update on Prevention Trials in Alzheimer’s Disease

B. Vellas UMR INSERM 1027, Gerontopole, CHU Toulouse, University Paul Sabatier, France

Corresponding Author: Bruno Vellas, M.D., PhD, [email protected]

AbstractAn evolving consensus about the need to treat AD in thepresymptomatic phase has emerged following thedisappointing results of several trials that enrolled subjects withmild to moderate disease, as well as accumulating researchdemonstrating that AD pathologic process begins decadesbefore the appearance of symptoms. Several lessons can belearned from past prevention trials. The targeted populationswere too diverse, the interventions probably not strong enough,and the time of exposure was most likely too short. We havelearned from these trials that future prevention trials must betargeted, use strong interventions with known biologicalactivity, and must be sustained with a long-term intervention.In this paper, we focus on three prevention trial approaches: A. Targeted therapy: Preventing AD by targeting a specificpopulation with a specific intervention. Such preventiveapproaches and trials must be based on biomarkers andimaging to select a study population in accordance with themechanism of the specific intervention; B. Multi-domain interventions targeting a larger, more diversepopulation over a longer time period with long-term exposureto non-specific, multi-domain intervention. The rationale forthis approach stems from studies showing that severalenvironmental factors are associated with the risk of developingdementia. These factors may include educational level, vascularand metabolic risk factors, physical activity, cognitivestimulation, and nutritional status. It may also be possible toidentify healthy adults at high risk of AD and likely to benefitfrom intervention based on subjective memory complaint,ApoEε4 carriage, family history of AD, or the presence offrailty; and use multidomain interventions to compensate forlow specificity; C. What will be probably the future of clinical practice: Apreventive approach, integrated into primary care settings thatbegins with longitudinal monitoring of memory function in ageneral population to identify decliners, followed by a specificintervention based on biomarkers and imaging discussed caseby case. Finally, preventing AD will require new and improvedinfrastructure.

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

In worldwide efforts to address the oncomingpublic health and economic crisis resulting fromthe rising prevalence of Alzheimer's disease (AD),

prevention has been recognized as a key goal (1, 2).Primary prevention by targeting modifiable risk factorscould potentially reduce disease incidence by millions of

cases by 2050 (3). Meanwhile, the field has coalescedaround the idea of secondary prevention, which involvesdiagnosing and treating the disease before symptomsbecome apparent (4). An evolving consensus about theneed to treat AD in the presymptomatic phase hasemerged following the disappointing results of severaltrials that enrolled subjects with mild to moderate disease(e.g., (5-7)), as well as accumulating researchdemonstrating that AD pathologic process beginsdecades before the appearance of symptoms (e.g., (8)).

Several lessons can be learned from past preventiontrials. For example, the GuidAge clinical trial -- thelargest preventive trial conducted in the EU -- testedwhether long-term use of a Ginkgo biloba extract couldreduce the risk of progression to AD among subjects overage 70 who spontaneously subjective memory complaintsreported to their primary-care physician (9). Thisrandomized, placebo-controlled trial enrolled 2840individuals and followed them for five years. At the endof the study, there were no statistically significantdifferences in AD incidence between the two groups.Three reasons were cited as contributing to thesedisappointing results: the targeted population was toodiverse, the intervention with Gingko biloba wasprobably not strong enough, and the time of exposurewas most likely too short. The population of individualswith subjective memory complaints is highly variable,with the overall incidence of dementia quite small,making it difficult to achieve statistical significance. Inaddition, progression to dementia is slow, so in order todemonstrate a slowing of progression, one would likelyneed either an intervention with a very robust effect orexposure for a very long time, taking into account that theimpact of exposure may not be proportional but mayincrease over time. Taken together, these factors suggestthat future preventive trials will need to consider novelstatistical approaches with pre-defined endpoints thattake into consideration the fact that the impact ofintervention could depends on the time of exposure.

Phase 3 trials of solanezumab and bapineuzumab, bothmonoclonal antibodies directed against beta-amyloid(Aβ), provide additional lessons (6, 7). Despite the factthat both trials enrolled subjects who met criteria formild-to-moderate AD, biomarker studies revealed that asubstantial number of subjects (nearly 30% of those withmild dementia) had no amyloid in the brain (10).Moreover, amyloid-negative subjects receiving placebo

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showed almost no disease progression during the 18-month study period, suggesting that they did not haveAD. After this trial, the sponsor Eli Lilly launched a third,targeted solanezumab trial (Expedition III), whichenrolled only individuals with biomarker evidence ofbrain amyloid. Interestingly, the practice of conductingtargeted trials in other disease areas such as oncology iscredited with much of the progress achieved indeveloping effective drugs.

We have learned from these trials that futureprevention trials must be targeted, must use stronginterventions with known biological activity, and must besustained with a long-term intervention. Here, wepropose three prevention trial approaches: - Targeting a specific population with a specific

intervention- Multi-domain interventions on a large, more diverse

population over a longer time period. - What will be probably the future of clinical practice: A

preventive approach, integrated in primary care settingthat begins with longitudinal monitoring of memoryfunction in a general population to identify decliners,followed by a specific intervention based onbiomarkers and imaging if the disease progress

Targeted therapy: Preventing AD by targetinga specific population with a specificintervention

One approach to the development of an effectivedisease-slowing therapy is to select a study population inaccordance with the mechanism of a specific intervention(11). Targeting therapies in this way depends onidentification of biomarkers or genetic markers thatprovide evidence of the stage or type of disease, ashypothesized by Jack and colleagues (12) anddemonstrated in subsequent studies (8, 13). For example,trials of anti-amyloid therapies would enroll subjects atearly disease stages when deposition of amyloid isunderway, but not so far along that neurodegenerationhas ensued.

In 2011, the National Institute on Aging and theAlzheimer's Association (NIA-AA) proposedmodifications to the diagnostic criteria for AD, whichincluded a category called “preclinical AD,” subdividedinto three stages based on biomarker findings (Figure 1):stage 1 is defined by the presence of amyloid, evidencedusing PET imaging or a CSF analysis; stage 2 by thepresence of amyloid plus markers of neurodegeneration,indicated by hypometabolism on fluorodeoxyglucosepositron emission tomography (FDG-PET), elevated CSFtau or phospho-tau, or structural MRI findings ofhippocampal atrophy or cortical thinning; or stage 3,where in addition to amyloidosis and neurodegeneration,there is evidence of subtle cognitive decline (14).Subsequent refinement of the criteria added two

additional preclinical stages: stage 0, where allbiomarkers are normal and there is no cognitiveimpairment; and suspected non-Alzheimer'spathophysiology, i.e., markers of neurodegeneration butnot amyloidosis (SNAP) (15).

Vos et al. used these criteria to classify 311 cognitivelynormal (CDR 0) subjects living in the community. Theyfound that 41% were classed as stage 0, 15% as stage 1,12% as stage 2, 4% as stage 3, 23% as SNAP, and 5%remained unclassified. They also determined the 5-yearprogression rate to symptomatic AD (CDR ≥ 0.5). Only2% of stage 0 subjects progressed, whereas, 11% of stage 1subjects, 26% of stage 2 subjects, 56% of stage 3 subjects,and 5% of SNAP subjects progressed (16). These datasupport the temporal order of biomarkers proposed Jacket al, and its relevance for clinical progression (12, 13), inparticular that amyloid accumulation begins in thepreclinical stage of the disease and that this could be theappropriate time to intervene with anti-amyloidtherapies.

Johnson et al used florbetapir PET imaging to assessamyloid load in healthy controls, demonstrating that themean SUVR increases with age even among cognitivelynormal subjects, from 5.3% positive in those aged 50 to59, 10.5% in those 60-69, 15.0% in those 70-79, and 33 % inthose 80 years or older (17). These results suggest that itmay be possible to enroll subjects based on the presenceof brain amyloid (by CSF or amyloid PET), with noobjective cognitive decline, possible subjective memorycomplaints, and preserved activities of daily living. Theadvantages of such a trial targeting amyloid are itsspecificity and the ability to treat at a very early stagebefore non-reversible lesions have developed. Thedrawbacks are the difficulty of demonstrating a slowingof cognitive decline in an already slowly-declining

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



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population and the low conversion rate to dementia.These drawbacks result in long and costly trials.

Nonetheless, a trial based on this strategy alreadystarted this year. The Anti-Amyloid Treatment inAsymptomatic Alzheimer’s (A4 trial) will be the firstprevention trial in subjects determined to be at risk basedon brain amyloid demonstrated with PET imaging (18).This placebo-controlled trial will use solanezumab as thetreatment and a composite of well-validateneuropsychological tests known to be sensitive in theearly stages of cognitive decline as the primary outcome.

The A4 trial aims to exclude older persons withoutcognitive impairment who, based on the absence of brainamyloid, are much less likely to develop AD. Overall, inour point of view, amyloid PET or CSF seems to be bestfor selecting trial participants. As tau PET imagingcontinues to develop, it may be useful for assessingdisease-stage and perhaps response to treatment.

We must underline, however, that such trials areexpensive and raise cost effectiveness issues. It will behard to use such treatment for very long period of time,e.g., decades. There are also ethical concerns raised bytreating individuals who may never develop AD withdrugs that have unknown long-term safety profiles,particularly in people who may develop other chronicdiseases. Moreover initiating treatment based onbiomarker findings has the potential to affect the life andwell-being of subjects. For example, when we detectamyloid and propose treatment in still-normal older

adults, we will likely induce stress and other life-alteringdecisions, which must be taken into consideration. Whilewe hope to prevent the development of AD in some olderpeople, we must realize that not all would have gone onto develop AD and that many other diseases can alsooccurs at this age.

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

Another possible target population for preventivetrials is late MCI due to AD. Individuals at this stagehave objective decline in memory, for instance evidencedby low scores in logical memory testing, and a positiveamyloid signature (CSF or amyloid-PET), but generallypreserved activities of daily living. The advantage oftargeting this population is the fact that they have ahigher likelihood of converting to AD and, because theyare already symptomatic, are more likely to comply withthe study protocol. However, they are difficult to screendue to the low prevalence and the high cost of screeningwith imaging, CSF biomarkers, or extensive cognitivetesting. Moreover the cut-off at which cognitive

Review Article

Table 1. Drug trialsPopulation Dvt Identifier

clinical trial.govInclusioncriteria

Intervention Mechanism ofaction

Sponsor N Primaryendpoint

MCI-AD andmild tomoderate AD

I NCT01837641 Amyloid PET LY3002813 Nootropic Eli Lilly 100 Safety

Prodromal AD I NCT01978548 Amyloid PET orCSF Aβ1-42

JNJ-54861911 BACE inhibitor Janssen 24 Pharmacokinetics anddynamics

MCI-AD andmild AD

I NCT02094729 CDR=0.5WMS-R memoryII

BAN2401 Monoclonalantibody anti-Aβ

Eisai 24 Safety

MCI-AD II NCT01255163 CSF Aβ1-42 Exendin-4(Exenatide)

Neuroprotectiveaction

NIA 100 Safety

MCI-AD andmild AD

II NCT01767311 CDR=0.5WMS-RAmyloid PET

BAN2401 Monoclonalantibody anti-Aβ

Eisai 800 DerivedCompositeClinical Score

MCI-AD II NCT01227564 CDR=0.5Amyloid PET

ACC-001 ActiveimmunotherapyAnti-Aβ

Pfizer 63 Safety

MCI-AD andmild AD

II - Amyloid PET orCSF Aβ1-42

AZD3293 BACE inhbitor Astra 1310 ADAS-CogFAQ

Prodromal AD III NCT01953601 Amyloid PET orCSF Aβ1-42

MK-8931 BACE inhibitor Merck Zeneca 1500 CDR-SB

Prodromal AD III NCT01224106 Amyloid PET Gantenerumab Monoclonalantibody anti-Aβ

Hoffmann-LaRoche

770 CDR-SB

Prodromal AD - LipiDiDiet Dubois et al,2007

Souvenaid MedicalNutrition(omega-3)

Nutricia 312 NTN


impairment represents MCI is still unclear, and isimpacted by education, sleep, general health, life events,and other factors. Finally the learning effect must betaken into consideration in this population when arepetitive test is used as a screening tool. In the GuidAgetrial, for example, the learning effect with the free andcued selective reminding test (FCSRT) was observedover 2 years both in subjects with CDR 0 and CDR 0.5(personal data). CDR-SB may be a reasonable end point inlate MCI, (ADNI and MAPT personal analysis), while inthose with early MCI, a composite score appears to bemore appropriate. Recently a composite score composedof tests for Word Recall, Delayed Word Recall,Orientation, the CDR-SB, and the FAQ was proposed(21).

Several drugs with varying mechanisms of action havebeen, or plan to be, used in preclinical, MCI, and ADtrials. A phase 3 trial of the gamma-secretase inhibitorsemagacestat was tested in patients with mild-to-moderate AD but did not improve cognition and, in fact,was associated with a worsening of functional abilitiesamong those receiving a high dose of the drug. Therewere also more adverse side effects among thosereceiving drug compared to placebo (5). Beta-secretaseinhibitors may be more efficacious (22). Despite evidenceof hepatic toxicity with some of these compounds, at leastone (MK-8931) is recruiting subjects for a phase 3 study.Other approaches include monoclonal antibodies such assolanezumab and gantenerumab, which are also in phase3 studies. Less advanced molecules targeting alphasecretase or tau protein, as well as neuroprotectivecompounds still in early development. Some studieshave been terminated, for example a study of themicrotubule stabilizer epothilone D.

Table I summarizes prevention trials in MCI due to ADand prodromal AD currently underway. However,questions remain about whether treating at these stages istoo late. While it makes sense to treat beforeneurodegeneration begins, the progression of the diseaseis still slow in prodromal AD and MCI, suggesting thatthere may be some benefit to treating at these stages.

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

An alternative approach for prevention trials is to havea larger more diverse population group with long-termexposure to non-specific, multi-domain intervention. Therationale for this approach stems from studies showingthat several environmental factors are associated with therisk of developing dementia. These factors may includeeducational level, vascular and metabolic risk factors,physical activity, cognitive stimulation, and nutritionalstatus. In addition, recent studies suggest a declining

incidence and prevalence of AD over the last ten years,thought to be due to improvements in overall health andeducational levels (23, 24). Finally, a recent autopsystudy of 1599 older people compared amyloid depositionin subjects 65 yrs. and older who died between 1972 and2006. Lower amyloid deposition was seen in the 2006cohort and was particularly marked in the oldest agegroups, providing preclinical evidence supportingrecently described decreases in AD incidence (25). Theseaccumulating data recently led the U.S. National Instituteon Aging (NIA) to encourage all adults to exerciseregularly, eat a healthy diet rich in fruits and vegetables,engage in social and intellectual activities, control type 2diabetes, lower high blood pressure, lower cholesterollevels, maintain a healthy weight, stop smoking, and gettreatment for depression.

Targeting the general population for interventional ADprevention trials may not be feasible or even desirable,although there is the potential to promote more informeddecision-making by the general public on low-riskapproaches that could improve brain health and reducethe risk of dementia (26). In addition, it may be possibleto identify healthy adults at high risk of AD and likely tobenefit from intervention based on subjective memorycomplaints (SMC, also called subjective memoryimpairment [SMI] or subjective cognitive impairment[SCI]), ApoEε4 carriage, family history of AD, or thepresence of frailty. Multidomain interventions maycompensate for low specificity in these populations.

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

Individuals with SMC have, by definition, no objectivecognitive decline and preserved activities of daily living(ADL). The prevalence has been estimated at between11% in 65-85 year olds (27) to over 88% in those over age85 (28), and some studies have suggested that thepresence of SMC may predict subsequent dementia (29).Progression to dementia among those with SMC iselevated in individuals with a family history of dementia,expressed concern about memory, onset over theprevious 5 years, and when the concern is severe enoughto motivate consultation with a primary care provider(PCP)

The advantages of targeting individuals with SMC arethat there are large numbers of potential subjects who arerelatively easy to identify through PCPs, and thatengaging PCPs in the process may increase compliance.Disadvantages of this approach include very highheterogeneity, slow decline, and minimal conversion toMCI or AD. The endpoint for a trial in this populationcould be a composite score including measures of logicalmemory or the FCSRT and measures of executivefunction.

Another large population that could be targeted fornon-specific multi-domain trials are older persons with

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physical and/or cognitive frailty. In the longitudinalRush Memory and Aging study, frailty was shown to beassociated with both cognitive decline and incident AD(30). Indeed, the definition of frailty -- increasedvulnerability resulting from decline across multiplephysiologic systems (31) -- has recently been expanded toinclude cognitive decline (32). In 2013, a consensus grouporganized by the International Academy on Nutritionand Aging (IANA) and the International Association ofGerontology and Geriatrics (IAGG) proposed a definitionof cognitive frailty that includes both physical frailty andcognitive impairment (e.g., CDR 0.5) in the absence ofdementia (33). Individuals meeting this definition aretypically 80 yrs. or older with preserved basic ADLs, butsome decline in instrumental ADL (IADLs), due mostlyto physical frailty.

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

Multi-domain prevention trials in these twopopulations should include both pharmacological andnon-pharmacologic therapies. Possiblepharmacotherapies include anti-diabetic drugs such aspioglitazone. This drug is used in the oncomingTOMMORROW trial (34), which will enroll subjectsbased on their APOE and TOMM40 genotype. Otheragents that could be considered for prevention trialsinclude insulin (35), selective serotonin receptor agonists(SSRIs) (36), and a variety of nutrients such as resveratrol(37), the Ginkgo biloba extract EGB 761 (38), Vitamin D(39), B vitamins, including folate (40), and omega-3 fattyacids (41).

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

Physical exercise has been studied extensively in recenttrials and found to be related to improvement ofcognitive function (44), decreased MRI hippocampalbrain atrophy (45), improved brain metabolism and somein amyloid deposit (ref…). Cognitive stimulation hasbeen largely shown to improve cognition (46) and loweramyloid burden (47) in older adults.

Multi-domain intervention aims to bring together thebenefits of nutritional intervention, physical exercise,cognitive stimulation, social activities, and vascular andmetabolic risk control to increase the effect of eachintervention, reach a threshold, and achieve clinicallysignificant effects. The first and largest trial to have beendesigned is the Multi-domain Alzheimer’s PreventionTrial (MAPT) (48), a randomized, placebo-controlledstudy of 1680 subjects, 70 years of age or older living inthe community and presenting with SMC (99% ofsubjects). The cohort was enriched for frail subjects withslow walking speed (4 meters test) in 11.9% of the sampleand limitation in one IADL in 11.2%. Demented patientsas well as those dependent for basic ADL were excluded.Subjects were randomized into four treatment rms:Omega 3 alone, Placebo alone, Omega 3 plus multi-domain intervention, and Placebo plus multi-domainintervention. The multi-domain intervention includedphysical and cognitive exercises, dietary counseling andweight maintenance, increased social activities, control ofvascular and metabolic risk factors, and correction ofvision and hearing impairments. The length of theintervention was 3 years plus 2 years of observationalfollow-up. Outcome measures included cognitive declineusing the FCRST, cerebral and hippocampal volumes(n=500), cerebral glucose metabolism using FDG-PET(n=68) and amyloid PET scanning with florbetapir (n=271).

The MAPT multi-domain intervention was shown befeasible with good compliance demonstrated by only22.5% drop outs over the 3-year study. The MAPT trial isnow completed and results will be released shortly.

Other multi-domain trials include the Finnish GeriatricIntervention Study to Prevent Cognitive Impairment andDisability (FINGER Study), a 2-year interventional trialtargeting 1200 subjects at risk for dementia (49), thePrevention of Dementia by Intensive Vascular Care (Pre-DIVA) trial, the Vitamin D3, Omega-3, Home ExerciseHealthy Ageing and Longevity Trial (DO-HEALTH), andthe Healthy Aging through Internet Counseling of theElderly (HATICE) program (50). Results presented fromthe FINGER study at the 2014 Alzheimer's AssociationInternational Conference (AAIC) indicate positive effectson cognitive function (51). The Pre-Diva, MAPT andFINGER trials have been brought together under theumbrella of the European Dementia Prevention Initiativein order to share data and collaborate on new studies.

The advantages of multi-domain trials with largepopulation targets and non-specific but multi-domain


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intervention delivered over a long time period are thatthese interventions are likely to be less expensive, easierto implement in daily clinical practice or at thepopulation level, and safe for long-term exposure; andmay act on different therapeutic targets. Thedisadvantages are interventions themselves are non-specific, the cohorts are highly variable and with differentrisks of developing dementia, and the potential for lowcompliance with the study protocol. For example, withregard to the variability in risk of dementia, amyloid PETscans performed in 271 subjects enrolled in the MAPTtrial showed that 38.0% had significant brain amyloid(cortical SUVR > 1.17). Moreover these individuals werefound to have lower cognitive function at baseline andmore cognitive decline over the trial period, similar towhat has been seen in observational studies (48).

In fact, these two preventive approaches: targeting aspecific population with a specific intervention ortargeting a larger at risk population with a multi-domainintervention are complementary and may both beappropriate at different time-points over the life time ofan older adult. Indeed, this may be what is required infuture clinical practice.

The future of clinical practice: A preventiveapproach, integrated in primary care settingthat begins with longitudinal monitoring ofmemory function in a general population toidentify decliners, followed by a specificintervention based on biomarkers anddiscussed case by case if the disease progress(FIG 2)

A prevention approach could start by making generalrecommendations to a large, diverse population (e.g.,those age 50 years or older with normal cognition) ondiet, physical and cognitive exercise, and risk factorcontrol; then identify decliners through longitudinalmonitoring of biomarkers or cognitive markers; andfinally test interventions targeted specifically. Thesepreventive approaches must start in primary care settingsand integrate the family practitioners.

Among those with SMC and/or a family history ofdementia, a tailored multi-domain intervention might beproposed, including nutrition, physical and cognitiveexercise, and risk factor control, such as was used in theMAPT or FINGER trials. Ideally, these interventionscould be delivered by PCPs who, at the same time, couldbegin longitudinal monitoring of cognition as a way toidentify decliners for the next level of prevention trials.Some web resources will be probably helpful in the nearfuture, such as the Brain Health Registry(www.brainhealthregistry.org)

If subjects with early MCI, biomarkers (e.g., CSF

amyloid, tau, as well as PET scans) may be considereddespite the fact that they are expensive and invasive.Plasma biomarkers would greatly enhance the ability toconduct large, longitudinal progression studies. A recentstudy identified 10 plasma proteins that are stronglyassociated with structural MRI findings and appear to beable to predict conversion from MCI to AD with anaccuracy of 87%, sensitivity of 85%, and specificity of 88%(52). In another study, a set of ten peripheral plasmaphospholipids were identified that predicted conversionto MCI or AD over a 2–3 year timeframe with over 90%accuracy (53). However these findings have to bereplicated and their clinical utility validated. At thatpoint, it should be possible to offer multi-domaininterventions to those who are biomarker-negative andoral drugs such as anti-amyloid drugs to those who arebiomarker positive or those who transition to biomarkerpositivity during the trial. However, as mentionedearlier, there are those who believe that the MCI stage istoo late to begin treatment with anti-amyloid therapy andthat what is needed is better characterization of thetransition from amyloid negativity to amyloid positivity.Anti-amyloid monoclonal antibodies will be alsoprobably useful if the ongoing clinical trials of thesedrugs are successful.

If the disease progress to late MCI/prodromal ADstages of the disease, new therapies are needed, such asthose that target tau; or it may be necessary to usecombination therapies that simultaneously act onmultiple therapeutic targets (e.g., amyloid plus tau). Anti-amyloid monoclonal antibodies may also be useful inthese patients, depending on the outcome of ongoingstudies of these agents. However these results will have

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Figure 2. A preventive approach, integrated in primarycare setting that begins with longitudinal monitoring ofmemory function in a general population to identifydecliners, followed by a specific intervention based onbiomarkers and discussed case by case if the diseaseprogress


to be scrutinized closely to assess the real impact of suchtherapies (54).

Comments and Research DirectionsTo achieve our goal of preventing AD, changes are

needed in the way clinical trials are designed andconducted:• Clinical trials must target specific populations

according to the intervention.• The interventions need to be robust and appropriate

for the targeted population, e.g., a multi-domainintervention for a large heterogeneous population vs.an intervention with a specific mechanism of action fortargeted populations.

• Trials must be of sufficient length to assess long-termexposure to intervention

• Trials will need to be implemented in clinical settings,beginning with the involvement of generalpractitioners and other primary care providers. Theseproviders are in an ideal position to monitorlongitudinally the cognition of elderly patients andidentify decliners who can then be referred for moreintensive assessment of progression using biomarkers.

• Trial designs are needed that will enable the testing ofcombined approaches, including multi-domainapproaches as well as combined pharmacotherapyagainst multiple therapeutic targets.

Moreover, preventing AD will require new andimproved infrastructure. In the war against AD we neednot only new weapons (drugs) but also the fleet(infrastructures, clinical research facilities) and thenetwork (international collaborations). We must alsolearn from our failures to obtain clinically relevant andinnovative results

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

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

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