Toward defining the preclinical stages of Alzheimer’s disease: Recommendations from the National Institute on Aging and the Alzheimer’s Association workgroup Reisa A. Sperling a, *, Paul S. Aisen b , Laurel A. Beckett c , David A. Bennett d , Suzanne Craft e , Anne M. Fagan f , Takeshi Iwatsubo g , Clifford R. Jack h , Jeffrey Kaye i , Thomas J. Montine j , Denise C. Park k , Eric M. Reiman l , Christopher C. Rowe m , Eric Siemers n , Yaakov Stern o , Kristine Yaffe p , Maria C. Carrillo q , Bill Thies q , Marcelle Morrison-Bogorad r , Molly V. Wagster r , Creighton H. Phelps r a Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women’s Hospital, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA b Department of Neurosciences, University of California San Diego, San Diego, CA, USA c Division of Biostatistics, School of Medicine, University of California, Davis, CA, USA d Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA e Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound; Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA, USA f Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA g Department of Neuropathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan h Department of Radiology, Mayo Clinic Minnesota, Rochester, MN, USA i Departments of Neurology and Biomedical Engineering, Layton Aging & Alzheimer’s Disease Center, Oregon Center for Aging & Technology, Oregon Health & Science University and Portland Veteran’s Affairs Medical Center, Portland, OR, USA j Department of Pathology, University of Washington, Seattle, WA, USA k Center for Vital Longevity, University of Texas at Dallas, Dallas, TX, USA l Banner Alzheimer’s Institute, Phoenix, AZ, USA m Austin Health, University of Melbourne, Melbourne, Australia n Eli Lilly and Company, Indianapolis, IN, USA o Cognitive Neuroscience Division, Taub Institute, Columbia University College of Physicians and Surgeons, NewYork, NY, USA p Departments of Psychiatry, Neurology, and Epidemiology and Biostatistics, University of California San Francisco, San Francisco VA Medical Center, San Francisco, CA, USA q Alzheimer’s Association, Chicago, IL, USA r Division of Neuroscience, National Institute on Aging, Bethesda, MD, USA Abstract The pathophysiological process of Alzheimer’s disease (AD) is thought to begin many years before the diagnosis of AD dementia. This long “preclinical” phase of AD would provide a critical opportunity for therapeutic intervention; however, we need to further elucidate the link between the pathological cascade of AD and the emergence of clinical symptoms. The National Institute on Aging and the Alzheimer’s Association convened an international workgroup to review the bio- marker, epidemiological, and neuropsychological evidence, and to develop recommendations to determine the factors which best predict the risk of progression from “normal” cognition to mild cognitive impairment and AD dementia. We propose a conceptual framework and operational research criteria, based on the prevailing scientific evidence to date, to test and refine these models with longitudinal clinical research studies. These recommendations are solely intended for research purposes and do not have any clinical implications at this time. It is hoped that these recommen- *Corresponding author. Tel.: 1 1-617-732-8085; Fax: 11-617-264-5212. E-mail address: [email protected]1552-5260/$ - see front matter Ó 2011 The Alzheimer’s Association. All rights reserved. doi:10.1016/j.jalz.2011.03.003 FLA 5.1.0 DTD ĸ JALZ1250_proof ĸ 16 April 2011 ĸ 12:04 pm ĸ ce Alzheimer’s & Dementia - (2011) 1–13
Transcript
Alzheimer’s & Dementia - (2011) 1–13
Toward defining the preclinical stages of Alzheimer’s disease:Recommendations from the National Institute on Aging and the
Alzheimer’s Association workgroupReisa A. Sperlinga,*, Paul S. Aisenb, Laurel A. Beckettc, David A. Bennettd, Suzanne Crafte,Anne M. Faganf, Takeshi Iwatsubog, Clifford R. Jackh, Jeffrey Kayei, Thomas J. Montinej,Denise C. Parkk, Eric M. Reimanl, Christopher C. Rowem, Eric Siemersn, Yaakov Sterno,
Kristine Yaffep, Maria C. Carrilloq, Bill Thiesq, Marcelle Morrison-Bogoradr, Molly V. Wagsterr,Creighton H. Phelpsr
aCenter for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women’s Hospital, Massachusetts General Hospital,
Harvard Medical School, Boston, MA, USAbDepartment of Neurosciences, University of California San Diego, San Diego, CA, USAcDivision of Biostatistics, School of Medicine, University of California, Davis, CA, USAdRush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA
eGeriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound; Department of Psychiatry and Behavioral Sciences,
University of Washington School of Medicine, Seattle, WA, USAfDepartment of Neurology, Washington University School of Medicine, St. Louis, MO, USA
gDepartment of Neuropathology, Graduate School of Medicine, University of Tokyo, Tokyo, JapanhDepartment of Radiology, Mayo Clinic Minnesota, Rochester, MN, USA
iDepartments of Neurology and Biomedical Engineering, Layton Aging & Alzheimer’s Disease Center, Oregon Center for Aging & Technology,
Oregon Health & Science University and Portland Veteran’s Affairs Medical Center, Portland, OR, USAjDepartment of Pathology, University of Washington, Seattle, WA, USA
kCenter for Vital Longevity, University of Texas at Dallas, Dallas, TX, USAlBanner Alzheimer’s Institute, Phoenix, AZ, USA
mAustin Health, University of Melbourne, Melbourne, AustralianEli Lilly and Company, Indianapolis, IN, USA
oCognitive Neuroscience Division, Taub Institute, Columbia University College of Physicians and Surgeons, New York, NY, USApDepartments of Psychiatry, Neurology, and Epidemiology and Biostatistics, University of California San Francisco, San Francisco VA Medical Center,
San Francisco, CA, USAqAlzheimer’s Association, Chicago, IL, USA
rDivision of Neuroscience, National Institute on Aging, Bethesda, MD, USA
Abstract The pathophysiological process of Alzheimer’s disease (AD) is thought to begin many years
*Corresponding au
E-mail address: re
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before the diagnosis of AD dementia. This long “preclinical” phase of AD would provide a criticalopportunity for therapeutic intervention; however, we need to further elucidate the link between thepathological cascade of AD and the emergence of clinical symptoms. The National Institute onAging and the Alzheimer’s Association convened an international workgroup to review the bio-marker, epidemiological, and neuropsychological evidence, and to develop recommendations todetermine the factors which best predict the risk of progression from “normal” cognition tomild cognitive impairment and AD dementia. We propose a conceptual framework and operationalresearch criteria, based on the prevailing scientific evidence to date, to test and refine these modelswith longitudinal clinical research studies. These recommendations are solely intended for researchpurposes and do not have any clinical implications at this time. It is hoped that these recommen-
dations will provide a common rubric to advance the study of preclinical AD, and ultimately, aidthe field in moving toward earlier intervention at a stage of AD when some disease-modifying ther-apies may be most efficacious.� 2011 The Alzheimer’s Association. All rights reserved.
Converging evidence from both genetic at-risk cohortsand clinically normal older individuals suggests that thepathophysiological process of Alzheimer’s disease (AD)begins years, if not decades, before the diagnosis of clinicaldementia [1]. Recent advances in neuroimaging, cerebrospi-nal fluid (CSF) assays, and other biomarkers now provide theability to detect evidence of the AD pathophysiological pro-cess in vivo. Emerging data in clinically normal older indi-viduals suggest that biomarker evidence of amyloid beta(Ab) accumulation is associated with functional and struc-tural brain alterations, consistent with the patterns of abnor-mality seen in patients with mild cognitive impairment(MCI) and AD dementia. Furthermore, clinical cohortstudies suggest that there may be very subtle cognitivealterations that are detectable years before meeting criteriafor MCI, and that predict progression to AD dementia. It isalso clear, however, that some older individuals with thepathophysiological process of AD may not become symp-tomatic during their lifetime. Thus, it is critical to better de-fine the biomarker and/or cognitive profile that best predictsprogression from the preclinical to the clinical stages ofMCIand AD dementia. The long preclinical phase of AD pro-vides a critical opportunity for potential intervention withdisease-modifying therapy, if we are able to elucidate thelink between the pathophysiological process of AD andthe emergence of the clinical syndrome.
A recent report on the economic implications of the im-pending epidemic of AD, as the “baby boomer” generationages, suggests that more than 13.5 million individuals justin the United States will manifest AD dementia by the year2050 (http://www.alz.org/alzheimers_disease_trajectory.asp). A hypothetical intervention that delayed the onset ofAD dementia by 5 years would result in a 57% reductionin the number of patients with AD dementia, and reducethe projected Medicare costs of AD from $627 to $344billion dollars. Screening and treatment programs institutedfor other diseases, such as cholesterol screening for cardio-vascular and cerebrovascular disease and colonoscopy forcolorectal cancer, have already been associated with a de-crease in mortality because of these conditions. The currentlifetime risk of AD dementia for a 65-year-old is estimated tobe at 10.5%. Recent statistical models suggest that a screen-ing instrument for markers of the pathophysiological processof AD (with 90% sensitivity and specificity) and a treatmentthat slows down progression by 50% would reduce that riskto 5.7%.
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Both laboratory work and recent disappointing clinicaltrial results raise the possibility that therapeutic interven-tions applied earlier in the course of AD would be morelikely to achieve disease modification. Studies with trans-genic mouse models suggest that Ab-modifying therapiesmay have limited effect after neuronal degeneration has be-gun. Several recent clinical trials involving the stages of mildto moderate dementia have failed to demonstrate clinicalbenefit, even in the setting of biomarker or autopsy evidenceof decreased Ab burden. Although the field is already mov-ing to earlier clinical trials at the stage of MCI, it is possiblethat similar to cardiac disease and cancer treatment, ADwould be optimally treated before significant cognitiveimpairment, in the “presymptomatic” or “preclinical” stagesof AD. Secondary prevention studies, which would treat“normal” or asymptomatic individuals or those with subtleevidence of impairment due to AD so as to delay the onsetof full-blown clinical symptoms, are already in the planningstages. The overarching therapeutic objective of thesepreclinical studies would be to treat early pathological pro-cesses (e.g., lower Ab burden or decrease neurofibrillary tan-gle pathology) to prevent subsequent neurodegeneration andeventual cognitive decline.
For these reasons, our working group sought to examinethe evidence for a definable preclinical stage of AD, and toreview the biomarker, epidemiological, and neuropsycho-logical factors that best predict the risk of progression fromasymptomatic toMCI andADdementia. To narrow the scopeof our task, we chose to specifically focus on predictors ofcognitive decline thought to be due to the pathophysiologicalprocess of AD. We did not address cognitive aging in theabsence of recognized pathological changes in the brain, orcognitive decline because of other common age-related braindiseases; however, we readily acknowledge that these braindiseases, in particular, cerebrovascular disease, Lewy bodydisease, and other neurodegenerative processes, may signif-icantly influence clinical manifestations of AD and possiblyits pathophysiology. Although there are likely lifelongcharacteristics and midlife risk factors that influence thelikelihood of developing cognitive impairment late in life,for feasibility in current studies, we chose to focus onthe 10-year period before the emergence of cognitiveimpairment.
Furthermore, we propose a research framework to providea common language to advance the scientific understandingof the preclinical stages of AD and a foundation for the eval-uation of preclinical AD treatments. These criteria areintended purely for research purposes, and have no clinical
or diagnostic utility at the present time. We hope these crite-ria will enable researchers to characterize further thesequence of biological events over the course of preclinicalAD, refine biomarker criteria that will best predict clinicaloutcome, and ultimately aid in selecting appropriate popula-tions for preclinical therapeutic intervention.
2. Redefining the earliest stages of AD
The term “Alzheimer’s disease” has referred in some con-texts to the neuropathological criteria for AD and in othercontexts to the clinical syndrome of progressive cognitiveand behavioral impairment, typically at the stage of ADdementia. As we move toward defining the earliest stagesof AD, the dissociation between these two connotations ofthe term “Alzheimer’s disease” becomes particularly salient.It has become increasingly clear that both the underlyingpathophysiological process of AD and its clinical symptom-atology are best conceptualized as a continuum or a trajec-tory, and that these processes may evolve in parallel buttemporally offset trajectories.
To facilitate the possibility of future presymptomatic/pre-clinical treatment of AD, our working group, as well as theother two groups, felt it was important to define AD asencompassing the underlying pathophysiological diseaseprocess, as opposed to having “AD” connote only the clini-cal stages of the disease [2]. To disambiguate the term “AD,”it may be useful to refer to evidence of the underlying braindisease process as AD-pathophysiological process (abbrevi-ated as AD-P) and the clinical phases of the illness as “AD-Clinical” (abbreviated as AD-C), which would include notonly AD dementia but also individuals with MCI due toAD-P. AD-P is thought to begin years before the emergenceof AD-C. In particular, emerging evidence from both geneticat-risk and aging cohorts suggests that there may be a timelag of a decade or more between the beginning of the path-ological cascade of AD and the onset of clinically evidentimpairment. We postulate that AD begins with a longasymptomatic period during which the pathophysiologicalprocess is progressing, and that individuals with biomarkerevidence of early AD-P are at increased risk for developingcognitive and behavioral impairment and progression to ADdementia (AD-C). The extent to which biomarkers of AD-Ppredict a cognitively normal individual’s subsequent clinicalcourse remains to be clarified, and we acknowledge thatsome of these individuals will never manifest clinical symp-toms in their lifetime. Thus, it is critical to better define thepreclinical stage of AD, to determine the factors that bestpredict the emergence of clinical impairment and progres-sion to eventual AD dementia, and to reveal the biomarkerprofile that will identify individuals most likely to benefitfrom early intervention.
The concept of a preclinical phase of disease should notbe too foreign because medical professionals readilyacknowledge that cancer can be detected at the stage of “car-cinoma in situ” and that hypercholesterolemia and athero-
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sclerosis can result in narrowing of coronary arteries thatis detectable before myocardial infarction. It is widelyacknowledged that symptoms are not necessary to diagnosehuman disease. Type II diabetes, hypertension, renal insuffi-ciency, and osteoporosis are frequently detected through lab-oratory tests (i.e., biomarkers), and effective treatment canprevent the emergence of symptoms. Thus, we should beopen to the idea that AD could one day be diagnosed pre-clinically by the presence of biomarker evidence of AD-P,which may eventually guide therapy before the onset ofsymptoms.
The difficulty in the field of AD is that we have not yetestablished a firm link between the appearance of anyspecific biomarker in asymptomatic individuals and the sub-sequent emergence of clinical symptomatology. If we can,however, definitively determine the risk of developing ADdementia and the temporal course of clinical progression as-sociated with AD-P in individuals without dementia or MCI,we will open a crucial window of opportunity to intervenewith disease-modifying therapy. Although we hypothesizethat the current earliest detectable pathological change willbe in the form of Ab accumulation, it is possible that Abaccumulation is necessary but not sufficient to produce theclinical manifestations of AD. It is likely that cognitivedecline would occur only in the setting of Ab accumulationplus synaptic dysfunction and/or neurodegeneration, includ-ing paired helical filament tau formation and neuronal loss. Italso remains unknown whether there is a specific thresholdor regional distribution of AD pathology, and/or a specificcombination of biomarker abnormalities that will best pre-dict the emergence of clinical symptoms. Evidence also sug-gests that additional factors, such as brain and cognitivereserve, and conversely, the presence of other age-relatedbrain diseases, may modulate the relationship betweenAD-P and AD-C. We also recognize that some individualscan evidence all of the diagnostic neuropathological featuresof AD at autopsy but never express dementia during theirlife; it remains unknown whether these individuals wouldhave manifested clinical symptoms should they have livedlonger. It is also possible that some individuals are relativelyresistant to AD-P because of cognitive or brain reserve, pro-tective genetic factors, or environmental influences. Recentadvances in antemortem biomarkers now allow us to testthe hypothesis that many individuals with laboratory evi-dence of AD-P are indeed in the preclinical stages of AD,and determine which biomarker and cognitive profiles aremost predictive of subsequent clinical decline and emer-gence of AD-C.
3. The continuum of AD
The other twoworking groups established by the NationalInstitute on Aging/Alzheimer’s Association are focused ondeveloping diagnostic criteria for the clinical stages ofMCI and dementia due to underlying AD-P [3–5]. Ourgroup focused on developing research recommendations
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Fig. 1. Model of the clinical trajectory of Alzheimer’s disease (AD). The
stage of preclinical AD precedes mild cognitive impairment (MCI) and
encompasses the spectrumof presymptomatic autosomal dominantmutation
carriers, asymptomatic biomarker-positive older individuals at risk for pro-
gression to MCI due to AD and AD dementia, as well as biomarker-positive
individuals who have demonstrated subtle decline from their own baseline
that exceeds that expected in typical aging, but would not yet meet criteria
for MCI. Note that this diagram represents a hypothetical model for the
pathological-clinical continuum of AD but does not imply that all
individuals with biomarker evidence of AD-pathophysiological process
will progress to the clinical phases of the illness.
for the study of individuals who have evidence of early ADpathological changes but do not meet clinical criteria forMCI or dementia. It is likely that even this preclinicalstage of the disease represents a continuum fromcompletely asymptomatic individuals with biomarkerevidence suggestive of AD-P at risk for progression to ADdementia to biomarker-positive individuals who are alreadydemonstrating very subtle decline but not yet meeting stan-dardized criteria forMCI (refer to accompanyingMCI work-group recommendations by Albert et al). This latter group ofindividuals might be classified as “Not normal, not MCI” butwould be included under the rubric of preclinical AD(Fig. 1). Importantly, this continuum of preclinical ADwould also encompass (1) individuals who carry one ormore apolipoprotein E (APOE) 34 alleles who are knownto have an increased risk of developing AD dementia, atthe point they are AD-P biomarker-positive, and (2) carriersof autosomal dominant mutations, who are in the presymp-tomatic biomarker-positive stage of their illness, and whowill almost certainly manifest clinical symptoms and prog-ress to dementia.
Our group carefully considered several monikers to bestcapture this stage of the disease, including “asymptomatic,”“presymptomatic,” “latent,” “premanifest,” and “preclini-cal.” The term “preclinical” was felt to best encompassthis conceptual phase of the disease process but is not meantto imply that all individuals who have evidence of early ADpathology will necessarily progress to clinical AD dementia.Individuals who are biomarker positive but cognitively nor-mal might currently be defined as “asymptomatic at risk forAD dementia.” Indeed, our goal is to better define the factorswhich best predict cognitive decline in biomarker-positiveindividuals, so as to move toward an accurate profile of pre-clinical AD.
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Fig. 2. Hypotheticalmodel of theAlzheimer’s disease (AD) pathophysiolog-
ical sequence leading to cognitive impairment. This model postulates that
amyloid beta (Ab) accumulation is an “upstream” event in the cascade that
is associated with “downstream” synaptic dysfunction, neurodegeneration,
and eventual neuronal loss. Note that although recent work from animal
models suggests that specific formsofAbmay cause both functional andmor-
phological synaptic changes, it remains unknown whether Ab is sufficient to
incite the neurodegenerative process in sporadic late-onset AD. Age and
genetics, as well as other specific host factors, such as brain and cognitive
reserve, or other brain diseases may influence the response to Ab and/or
the pace of progression toward the clinical manifestations of AD.
4. Models of the pathophysiological sequence of AD
To facilitate the discussion of the concept of a preclinicalstage of AD, we propose a theoretical model of the patho-physiological cascade of AD (Fig. 2). It is important toacknowledge that this model, although based on the prevail-ing evidence, may be incorrect, is certainly incomplete, andwill evolve as additional laboratory and clinical studies arecompleted. Indeed, this model should be viewed as an initialattempt to bring together multiple areas of research into ourbest estimate of a more coherent whole.
The proposed model of AD views Ab peptide accumula-tion as a key early event in the pathophysiological process ofAD. However, we acknowledge that the etiology of ADremains uncertain, and some investigators have proposedthat synaptic, mitochondrial, metabolic, inflammatory, neu-ronal, cytoskeletal, and other age-related alterations mayplay an even earlier, or more central, role than Ab peptidesin the pathogenesis of AD [6,7]. There also remainssignificant debate in the field as to whether abnormalprocessing versus clearance of Ab42 is the etiologic event
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in sporadic, late-onset AD [8]. Some investigators have sug-gested that sequestration of Ab into fibrillar forms may evenserve as a protective mechanism against oligomeric species,which may be the more synaptotoxic forms of Ab [9–11].However, of all the known autosomal dominant, earlyonset forms of AD are thought to be, at least in part, dueto alterations in amyloid precursor protein (APP)production or cleavage. Similarly, trisomy 21 invariably
results in AD-P in individuals who have three intact copiesof the APP coding region located on chromosome 21.Finally, APOE, the major genetic risk factor for late-onsetAD, has been implicated in amyloid trafficking and plaqueclearance. Both autopsy and biomarker studies (see later inthe text) similarly suggest that Ab42 accumulation increaseswith advanced aging, the greatest risk factor for developingAD. At this point, it remains unclear whether it is meaning-ful or feasible to make the distinction between Ab as a riskfactor for developing the clinical syndrome of AD versus Abaccumulation as an early detectable stage of AD becausecurrent evidence suggests that both concepts are plausible.
Also, it is clear that synaptic depletion, intracellular hy-perphosphorylated forms of tau, and neuronal loss invariablyoccur in AD, and at autopsy, these markers seem to correlatebetter than plaque counts or total Ab load with clinicalimpairment. Although we present evidence later that thepresence of markers of “upstream” Ab accumulation is asso-ciated with markers of “downstream” pathological change,including abnormal tau, neural dysfunction, glial activation,and neuronal loss and atrophy, it remains to be proven thatAb accumulation is sufficient to incite the downstream path-ological cascade of AD. It remains unknown whether thisneurodegenerative process could be related to direct synaptictoxicity due to oligomeric forms of Ab, disruption of axonaltrajectories from fibrillar forms of Ab, or a “second hit” thatresults in synaptic dysfunction, neurodegeneration, neurofi-brillary tangle formation, and eventually neuronal loss.
Epidemiological data suggest there are significant modu-lating factors that may alter the pace of the clinical expressionof AD-P, although evidence that these factors alter the under-lying pathophysiological process itself is less secure. Largecohort studies have implicated multiple health factors thatmay increase the risk for developing cognitive decline and de-mentia thought to be caused byAD [12]. In particular, vascularrisk factors such as hypertension, hypercholesterolemia, anddiabetes have been associated with an increased risk ofdementia, and may contribute directly to the effect of ADpathology on the aging brain [13,14]. Depressive sym-ptomatology, apathy, and chronic psychological distresshave also been linked to increased risk of manifesting MCIand dementia [15–17]. It also remains unclear whether thereare specific environmental exposures, such as head trauma,that may influence the progression of the pathophysiologicalsequence or the clinical expression of the pathology. On thepositive side, there is some evidence that engagement inspecific activities, including cognitive, physical, leisure, andsocial activity, may be associated with decreased risk ofMCI and AD dementia [18].
The temporal lag between the appearance of AD-P and theemergence of AD-C also may be altered by factors such asbrain or cognitive reserve [19]. The concept of reserve wasoriginally invoked to provide an explanation for the observa-tion that the extent of AD histopathological changes atautopsy did not always align with the degree of clinicalimpairment, and can be thought of as the ability to tolerate
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higher levels of brain injury without exhibiting clinical symp-toms. “Brain reserve” refers to the capacity of the brain towithstand pathological insult, perhaps because of greater syn-aptic density or larger number of healthy neurons, such thatsufficient neural substrate remains to support normal func-tion. In contrast, “cognitive reserve” is thought to representthe ability to engage alternate brain networks or cognitivestrategies to cope with the effects of encroaching pathology.It is not clear, however, that the data support a sharp demarca-tion between these two constructs becausemany factors, suchas higher socioeconomic status or engagement in cognitivelystimulating activities, may contribute to both forms ofreserve. Higher education and socioeconomic status havebeen associated with lower age-adjusted incidence of ADdiagnosis. Recent studies suggest that high reserve may pri-marily influence the capability of individuals to tolerate theirAD-P for longer periods, but may also be associated withrapid decline after a “tipping point” is reached and compen-satory mechanisms begin to fail [20,21].
5. Biomarker model of the preclinical stage of AD
A biomarker model has been recently proposed in whichthe most widely validated biomarkers of AD-P becomeabnormal and likewise reach a ceiling in an ordered manner[22]. This biomarker model parallels the hypothetical patho-physiological sequence of AD discussed previously, and isparticularly relevant to tracking the preclinical stages ofAD (Fig. 3). Biomarkers of brain Ab amyloidosis includereductions in CSF Ab42 and increased amyloid tracer reten-tion on positron emission tomography (PET) imaging. Ele-vated CSF tau is not specific to AD and is thought to bea biomarker of neuronal injury. Decreased fluorodeoxyglu-cose 18F (FDG) uptake on PET with a temporoparietal pat-tern of hypometabolism is a biomarker of AD-relatedsynaptic dysfunction. Brain atrophy on structural magneticresonance imaging (MRI) in a characteristic pattern involv-ing the medial temporal lobes, paralimbic and temporoparie-tal cortices is a biomarker of AD-related neurodegeneration.
This biomarker model was adapted from the originalgraph proposed by Jack et al [22] to expand the preclinicalphase, and has the following features: (1) Ab accumulationbiomarkers become abnormal first and a substantial Ab loadaccumulates before the appearance of clinical symptoms.The lag phase between Ab accumulation and clinical symp-toms remains to be quantified, but current theories suggestthat the lag may be for more than a decade. Similar to the hy-pothetical pathophysiological model described previously,interindividual differences in this time lag are likely causedby differences in brain reserve, cognitive reserve, and theadded contributions of coexisting pathologies. Note that inthis biomarker model, brain Ab accumulation is necessarybut not sufficient to produce the clinical symptoms of MCIand dementia, (2) biomarkers of synaptic dysfunction,including FDG and functional MRI (fMRI), may demon-strate abnormalities very early, particularly in APOE gene
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Fig. 3. Hypothetical model of dynamic biomarkers of the AD expanded to explicate the preclinical phase: Ab as identified by cerebrospinal fluid Ab42 assay or
PET amyloid imaging. Synaptic dysfunction evidenced by fluorodeoxyglucose (F18) positron emission tomography (FDG-PET) or functional magnetic
resonance imaging (fMRI), with a dashed line to indicate that synaptic dysfunction may be detectable in carriers of the 34 allele of the apolipoprotein E
gene before detectable Ab deposition. Neuronal injury is evidenced by cerebrospinal fluid tau or phospho-tau, brain structure is evidenced by structural magnetic
resonance imaging. Biomarkers change from normal to maximally abnormal (y-axis) as a function of disease stage (x-axis). The temporal trajectory of two key
indicators used to stage the disease clinically, cognitive and behavioral measures, and clinical function are also illustrated. Figure adapted with permission from
34 allele carriers, who may manifest functional abnormali-ties before detectable Ab deposition [23–25]. The severityand change over time in these synaptic markers correlatewith clinical symptoms during MCI and AD dementia, (3)structural MRI is thought to become abnormal a bit later,as a marker of neuronal loss, and MRI retains a closerelationship with cognitive performance through theclinical phases of MCI and dementia [26], (4) none of thebiomarkers is static; rates of change in each biomarkerchange over time and follow a nonlinear time course, whichis hypothesized to be sigmoid shaped, and (5) anatomic in-formation from imaging biomarkers provides useful diseasestaging information in that the topography of disease-relatedimaging abnormalities changes in a characteristic mannerwith disease progression.
6. Biomarker and autopsy evidence linking ADpathology to early symptomatology
Several multicenter biomarker initiatives, including theAlzheimer’s Disease Neuroimaging Initiative; the AustralianImaging, Biomarkers and Lifestyle Flagship Study of Aging;as well as major biomarker studies in preclinical populationsat several academic centers, are ongoing. These studies havealready provided preliminary evidence that biomarker abnor-malities consistent with AD pathophysiological process aredetectable before the emergence of overt clinical symptom-atology and are predictive of subsequent cognitive decline.Many of the recent studies have focused on markers of Abusing either CSF assays of Ab42 or PET amyloid imaging
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with radioactive tracers that bind to fibrillar forms of Ab.BothCSFandPETamyloid imaging studies suggest that a sub-stantial proportion of clinically normal older individuals dem-onstrate evidence of Ab accumulation [27–32]. The exactproportion of “amyloid-positive” normal individuals isdependent on the age and genetic background of the cohort,but ranges from approximately 20% to 40% and is veryconsonant with large postmortem series [33,34]. Furth-ermore, there is evidence that the AD-P detected at autopsyis related to episodic memory performance even within the“normal” range [35]. Interestingly, the percentage of “amy-loid-positive”normal individuals at autopsydetectedat a givenage closely parallels the percentage of individuals diagnosedwith AD dementia a decade later [36,37] (Fig. 4). Similarly,genetic at-risk cohorts demonstrate evidence of Ab accumula-tion many years before detectable cognitive impairment[38–41]. These data support the hypothesis that there isa lengthy temporal lag between the appearance of detectableAD-P and the emergence of AD-C.
Multiple groups have now reported that cognitively normalolder individuals with low CSF Ab1–42 or high PET amyloidbinding demonstrate disruption of functional networks[42–44] and decreased brain volume [45–49], consistentwith the patterns seen in AD. There have been variablereports in the previously published data thus far, regardingwhether Ab-positive individuals demonstrate lowerneuropsychological test scores at the time of biomarkerstudy [50–54], which may represent heterogeneity in wherethese individuals fall on the preclinical continuum, thecognitive measures evaluated, and the degree of cognitive
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Fig. 4. Postulated temporal lag of approximately a decade between the de-
position of Ab (% of individuals with amyloid plaques in a large autopsy se-
ries [68]) and the clinical syndrome of AD dementia (estimated prevalence
from three epidemiological studies [69–71]). Figure courtesy of Mark
reserve in the cohorts. A few early studies have reported thatAb positivity in clinically normal older individuals isassociated with an increased rate of atrophy [55] and an in-creased risk of cognitive decline and progression to dementia[56–62]. Multiple studies focused on other biomarkers,including volumetric MRI, FDG-PET, or plasma biomarkers,in cohorts of clinically normal older individuals have also re-ported evidence that these markers are predictive of cognitivedecline (refer [63,64] for recent examples). Additionallongitudinal studies are clearly needed to confirm thesefindings and to elucidate the combination of factors that bestpredict likelihood and rate of decline, and to betterunderstand individual diff-erences in risk for decline.
As a complement to longitudinal studies in the populationat risk by virtue of age, researchers continue to detect andtrack the biological and cognitive changes associated withthe predisposition to AD in cognitively normal people at dif-ferential genetic risk for AD alone or in conjunction withother risk factors (such as a person’s reported family historyof the disease). To date, the best established genetic risk fac-tors for AD include common allelic variants of APOE; themajor late-onset AD susceptibility gene; uncommon early-onset AD-causing mutations in the presenilin 1, presenilin2, and APP genes; and trisomy 21 (Down syndrome). Bio-marker studies in presymptomatic carriers of these geneticrisk factors have revealed evidence of Ab accumulation on
CSF and PET amyloid imaging, as well as FDG-PET hypo-metabolism, fMRI abnormalities, and brain atrophy that mayprecede symptoms by more than a decade.
7. Cognitive studies
Despite the clear potential of biomarkers for detectingevidence of the AD pathophysiological process, it is impor-tant not to lose sight of the potential that behavioral markershold for early identification. Tests developed by bothneuropsychological and cognitive aging researchers haveprovided evidence that normal aging is accompanied by de-clines in speed of information processing, executive function(working memory, task switching, inhibitory function), andreasoning. Studies that have conducted assessments of cog-nitive function at multiple time points before dementia havealso shown consistently a long period of gradual cognitivedecline in episodic memory as well as nonmemory domainsprogressing up to a decade before onset of dementia. Impor-tantly, in studies that have modeled the curve of cognitivechange versus time, the preclinical trajectory suggests notonly a long- and slow rate of presymptomatic change butalso a period of acceleration of performance decrementthat may begin several years before MCI onset [65]. Recentstudies also suggest that self-report of subtle cognitivedecline, even in the absence of significant objective impair-ment on testing, may portend future decline in older individ-uals. Despite the existence of multiple studies spanningthousands of participants, the promise of both subjectiveand objective cognitive measures for assessing risk ofprogression to AD in individual elders has not yet been fullyrealized. It is likely that measured change in cognition overtime will be more sensitive than any one-time measure.Additional longitudinal studies of older individuals, perhapscombining biomarkers with measures sensitive to detectingvery subtle cognitive decline, are clearly needed.
8. Caveats
Although the aforementioned studies provide compellingevidence that markers of Ab in “normal” older individualsare associated with other brain alterations consistent thoseseen in AD dementia, and that specific factors may
CSF)
Markers of neuronal injury
(tau, FDG, sMRI)
Evidence of subtle
cognitive change
e Negative Negative
e Positive Negative
e Positive Positive
ion tomography; CSF, cerebrospinal fluid; FDG, fluorodeoxyglucose (18F);
accurately predict those individuals who are at a higher riskof progression to AD-C, it is important to note several poten-tial confounding issues in the majority of these studies. It islikely that many of these studies suffer from cohort biases. Inparticular, the biomarker and cognitive studies likely are notrepresentative of the general older population because theyare typically “samples of convenience,” that is, volunteer co-horts who tend to come from highly educated and socioeco-nomic status backgrounds. These individuals may also beless likely to harbor typical age-related comorbidities thatmay influence the rate of cognitive decline. Older individ-uals who are willing to participate in such intensive studiesmay also represent the “volunteer gene,” and may be moreactively engaged than the typical aging population. Con-versely, these cohorts may include individuals who self-select for this research because of subjective concerns abouttheir own memory function or positive family history, as re-flected by the high rate of APOE 34 carriers in some of thesecohorts.
It is also important to note that although these biomarkershave revolutionized the field of early AD, these markers aremerely “proxies” for the underlying disease and may not fullyreflect the biological processes in the living brain. For exam-ple, both CSF and PET amyloid imaging markers seem to beestimates of the deposition of fibrillar forms of Ab, and maynot provide information about oligomeric forms, which maybe the relevant species for synaptic toxicity. Similarly, ourproxy measurements for synaptic dysfunction, such as fMRIor FDG-PET, are indirect measurements of neural function.Other markers of neurodegeneration such as CSF tau and vol-umetric MRI are not specific to the AD process. Finally, it isimportant to acknowledge that the relationship between bio-markers and cognition may vary significantly across age andgenetic cohorts. In particular, the dissociation between thepresence or absence of AD-P and clinical symptomatologyin the oldest-old needs to be better understood.
Finally, it is important to re-emphasize that although Abdeposition and neuritic plaque formation are required for thediagnosis of definite AD, and that current evidence suggeststhat Ab accumulation is an early detectable stage of thepathological-clinical continuum of AD, the role of Ab asthe etiologic agent in sporadic late-onset AD remains to beproven. There may be pathophysiological events that are “up-stream” of Ab accumulation yet to be discovered, and the re-lationship between Ab and neurodegeneration is not yet clear.In particular, the failure of biologically active Ab-loweringtherapies to demonstrate clinical benefit thus far is of concern.Thus, it is important to continue research in alternativepathophysiological pathways and therapeutic avenues.
9. Draft operational research framework for stagingpreclinical AD
To facilitate future studies, we propose draft operationalresearch criteria to define study cohorts at risk for develop-ing AD dementia for use in (1) longitudinal natural history
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studies to determine whether the presence of Ab markers,either in isolation or in combination with additional markersof neurodegeneration, is predictive of cognitive decline inclinically normal older individuals, and (2) clinical trialsof potential disease-modifying agents to investigate effectson biomarker progression and/or the emergence of clinicalsymptoms.
We emphasize again that this framework is not intendedto serve as diagnostic criteria for clinical purposes. Use ofthese biomarkers in the clinical setting is currently unwar-ranted because many individuals who satisfy the proposedresearch criteria may not develop the clinical features ofAD in their lifetime. Inappropriate use of this informationin this context could be associated with unwarranted concernbecause there is currently insufficient information to relatepreclinical biomarker evidence of AD to subsequent ratesof clinical progression with any certainty.
These research criteria are based on the postulate that ADis characterized by a sequence of biological events thatbegins far in advance of clinical dementia. On the basis ofcurrent evidence from both genetic at-risk and older cohortstudies, we put forth the hypothesis that Ab accumulation,or the stage of cerebral amyloidosis, is currently one of theearliest measurable stages of AD, and occurs before anyother evidence of cognitive symptomatology. We postulatethat the presence of biomarker “positivity” for Ab in clini-cally normal older individuals, particularly in combinationwith evidence of abnormality on other biomarkers ofAD-P, may have implications for the subsequent course ofAD-C and the responsiveness to treatments targeting AD-P.
Recognizing that the preclinical stages of AD representa continuum, including individuals who may never progressbeyond the stage of Ab accumulation, we further suggest thefollowing staging schema (see Table 1), which may proveuseful in defining research cohorts to test specific hypothe-ses. Research cohorts could be selected on the basis of thesestaging criteria, to optimize the ability to ascertain the spe-cific outcomes important for a given type (e.g., natural his-tory or treatment trial) and duration of the study. Evidenceof “downstream” biomarkers or subtle cognitive symptomsin addition to evidence of Ab accumulation may increasethe likelihood of rapid emergence of cognitive symptomatol-ogy and clinical decline to MCI within several years. Thepresence of one or more of these additional biomarkerswould indicate that individuals are already experiencingearly neurodegeneration, and as such, it is possible thatamyloid-modifying therapies may be less efficacious afterthe downstream pathological process is set in motion. Thereare specific circumstances, however, such as pharmaceuticalindustry trials that may require a cognitive or clinical end-point, rather than relying solely on biomarker outcomes. Inthese cases, it may be advantageous to enrich the study pop-ulation with individuals in late preclinical stages of AD withevidence of very subtle cognitive change, who would bemost likely to rapidly decline and manifest MCI withina short period (see Fig. 5). We recognize that these stages
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web4C=FPO
web4C=FPO
Fig. 5. Graphic representation of the proposed staging framework for preclinical AD. Note that some individuals will not progress beyond Stage 1 or Stage 2.
Individuals in Stage 3 are postulated to be more likely to progress to MCI and AD dementia. Abbreviations: AD, Alzheimer’s disease; Ab, amyloid beta; PET,
position emission tomography; CSF, cerebrospinal fluid; FDG, fluorodeoxyglucose, fMRI, functional magnetic resonance imaging, sMRI, structural magnetic
will likely require further modification as new findingsemerge, and that the feasibility of delineating these stagesin recruiting clinical research cohorts remains unclear. Itmay be easiest to recruit individuals on the basis of Ab pos-itivity and perform post hoc analyses to determine thepredictive value of specific combinations of biomarker ab-normalities. These proposed research criteria are intendedto facilitate the standardized collection of new data to betterdefine the spectrum of preclinical AD, and to elucidate theendophenotype of individuals who are most likely toprogress toward AD-C.
9.1. Stage 1: The stage of asymptomatic cerebralamyloidosis
These individuals have biomarker evidence of Abaccumulation with elevated tracer retention on PET amy-loid imaging and/or low Ab42 in CSF assay, but no detect-able evidence of additional brain alterations suggestive ofneurodegeneration or subtle cognitive and/or behavioralsymptomatology. The standards for determining “amy-loid-positivity” are still evolving (refer to the next section).Although recent work suggests there may be a CSF Ab42cutoff value that is predictive of progression from MCIto AD dementia [66], it is unknown whether a similarthreshold will be optimal in prediction of decline in indi-viduals with normal or near normal cognition. Similarly,using PET imaging techniques, it remains unknownwhether a summary numeric threshold within an aggregatecortical region or within specific anatomic region will pro-vide the most useful predictive value. Recent data suggestthat although CSF Ab42 is strongly inversely correlatedwith quantitative PET amyloid imaging measures (distribu-tion value ratio or standardized uptake value), there aresome individuals who demonstrate decreased CSF Ab42
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and who would not be considered amyloid positive onPET scans [67]. It remains unclear whether this finding re-flects different thresholds used across these techniques or ifdecreased CSF Ab42 is an earlier marker of accumulation.In addition, there may be genetic effects that are specific toCSF or PET markers of Ab.
As mentioned previously, we note that the currently avail-able CSF and PET imaging biomarkers of Ab primarily pro-vide evidence of amyloid accumulation and deposition offibrillar forms of amyloid. Although limited, current datasuggest that soluble or oligomeric forms of Ab are likelyin equilibrium with plaques, which may serve as reservoirs,but it remains unknown whether there is an identifiable pre-plaque stage in which only soluble forms of Ab are present.Because laboratory data increasingly suggest that oligo-meric forms of amyloid may be critical in the pathologicalcascade, there is ongoing work to develop CSF and plasmaassays for oligomeric forms of Ab. There are also emergingdata from genetic-risk cohorts that suggest early synapticchangesmay be present before evidence of amyloid accumu-lation using currently available amyloid markers. Thus, itmay be possible in the future to detect a stage of diseasethat precedes stage 1.
9.2. Stage 2: Amyloid positivity 1 evidence of synapticdysfunction and/or early neurodegeneration
These individuals have evidence of amyloid positivityand presence of one or more markers of “downstream”AD-P-related neuronal injury. The current markers of neuro-nal injury with the greatest validation are: (1) elevated CSFtau or phospho-tau, (2) hypometabolism in an AD-like pat-tern (i.e., posterior cingulate, precuneus, and/or temporopar-ietal cortices) on FDG-PET, and (3) cortical thinning/graymatter loss in a specific anatomic distribution (i.e., lateral
and medial parietal, posterior cingulate, and lateral temporalcortices) and/or hippocampal atrophy on volumetric MRI.Future markers may also include fMRI measures of defaultnetwork connectivity. Although previous studies have dem-onstrated that, on average, amyloid-positive individualsdemonstrate significantly greater abnormalities on thesemarkers as compared with amyloid-negative individuals,there is significant interindividual variability. We hypothe-size that amyloid-positive individuals with evidence of earlyneurodegeneration may be farther down the trajectory (i.e.,in later stages of preclinical AD). It remains unclear whetherit will be feasible to detect differences among these otherbiomarkers of AD-P, but there is some evidence that earlysynaptic dysfunction, as assessed by functional imagingtechniques such as FDG-PET and fMRI, may be detectablebefore volumetric loss.
We postulate that individuals with biomarker evidence ofamyloid accumulation, early neurodegeneration, and evidenceof subtle cognitive decline are in the last stage of preclinicalAD, and are approaching the border zone with the proposedclinical criteria for MCI. These individuals may demonstrateevidence of decline from their own baseline (particularly ifproxies of cognitive reserve are taken into consideration),even if they still perform within the “normal” range on stan-dard cognitive measures. There is emerging evidence thatmore sensitive cognitivemeasures, particularly with challeng-ing episodic memorymeasures, may detect very subtle cogni-tive impairment in amyloid-positive individuals. It remainsunclear whether self-complaint of memory decline or othersubtle neurobehavioral changes will be a useful predictor ofprogression, but it is possible that the combination of bio-markers and subjective assessment of subtle changewill proveto be useful.
10. Need for additional study
We propose a general framework with biomarker criteriafor the study of the preclinical phase of AD; however, morework is needed to clarify the optimal CSF assays, PET orMRI analytic techniques, and in particular, the specificthresholds needed to meet these criteria. There are signifi-cant challenges in implementing standardized biomarker“cut-off” values across centers, studies, and countries.Work to standardize and validate both fluid-based and imag-ing biomarker thresholds is ongoing in multiple academicand pharmaceutical industry laboratories, as well as inseveral multicenter initiatives. These criteria will need tobe validated in large multicenter natural history studies, oras provisional criteria for the planning of preventative clini-cal trials. For instance, it will be important to establish thetest–retest and cross-center reliability of biomarker measure-ments, further characterize the sequence of biomarker
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changes, and the extent to which these biomarkers predictsubsequent clinical decline or clinical benefit. In particular,there is an important need to evaluate methods for determin-ing “amyloid-positivity” because it remains unclear whetherthere is a biologically relevant continuum of Ab accumula-tion, or whether there is a clear threshold or “cut-off” valuethat could be defined on the basis of predictive value forsubsequent clinical decline, as has been suggested in severalCSF studies [28,66]. It also remains unknown whether thesethresholds should be adjusted for age or genotype. Afterthese thresholds are established, it may be most feasible toselect research cohorts for large studies solely on the basisof “amyloid-positivity” on CSF or PET amyloid imaging,and to use additional biomarker and cognitive measures forpost hoc analyses to determine additional predictive value.
Although recent advances in biomarkers have revolution-ized our ability to detect evidence of early AD-P there is stilla need for novel biomarker development. In particular, al-though the current biomarkers provide evidence of Abdeposition, an in vivo marker of oligomeric forms of Abwould be of great value. Imaging markers of intraneuronalpathology, including specific markers of specific forms oftau/tangles and alpha-synuclein, are also needed. In addi-tion, more sensitive imaging biomarkers that can detect earlysynaptic dysfunction and functional and structural discon-nection, such as fMRI and diffusion tensor imaging, mayone day prove to be useful to track early response toamyloid-lowering therapies. Finally, we may be able to usethe currently available biomarkers as a new “gold standard”to re-evaluate simple blood and urine markers that were dis-carded on the basis of excessive overlap between clinicallynormal and AD patients. The significant proportion of clin-ically normal individuals who are “amyloid-positive” onboth CSF and PET imaging may have confounded previousstudies attempting to differentiate “normal” controls frompatients with AD.
Similarly, additional work is required to identify andvalidate neuropsychological and neurobehavioral measuresto detect the earliest clinical manifestations of AD. We needto develop sensitive measures in multiple cognitive and be-havioral domains that will reveal evidence of early synapticdysfunction in neural networks vulnerable to AD pathology.We also need to develop measures of very early functionalchanges in other domains, including social interaction,mood, psychomotor aspects of function, and decisionmaking.These measures would allow us to link better the pathologicalprocesses to the emergence of clinical symptoms, and may beparticularly useful to monitor response to potential disease-modifying therapies in these very early stages.
The proposed criteria apply primarily to individuals at riskby virtue of advanced age because inclusion criteria for trialsin autosomal dominant mutation carriers and homozygousAPOE 34 carriers will be likely defined primarily on geneticstatus. Trials in genetic-risk populationsmight use these crite-ria to stage individuals within the preclinical phase of AD. Ingenetic-risk cohorts, it may even be possible to detect an even
earlier stage of presymptomatic AD, before the point whenthere is already detectable cerebral amyloidosis. SeveralFDG-PET and fMRI studies have suggested that evidenceof synaptic dysfunction may be present in young andmiddle-aged APOE 34 carriers (see Fig. 3), and there maybe other biological alterations that are present before signifi-cant deposition of fibrillar forms of amyloid that would bepreferentially responsive to presymptomatic intervention.
The emerging concept of preclinical AD and the role ofbiomarkers in the detection and tracking in this stage ofthe disease have important implications for the developmentof effective treatments. Therapies for preclinical AD wouldbe intended to postpone, reduce the risk of, or completelyprevent the clinical stages of the disorder. As recently noted,the use of clinical endpoints in clinical trials of such treat-ments would require large numbers of healthy volunteers,large amounts of money, and many years of study.Researchers have raised the possibility of evaluating bio-marker endpoints for these treatments in cognitively normalpeople at increased risk for AD because these studies mightbe performed more rapidly than otherwise possible. Subjectsenrolled in these studies could include individuals with auto-somal dominant mutation carriers (with essentially a 100%chance of developing clinical AD) or those at increasedrisk of developing sporadic AD (e.g., APOE 34 carriers orsubjects with biomarker evidence of preclinical AD pathol-ogy). The use of biomarkers rather than clinical outcomescould accelerate progress in these trials; however, regulatoryagencies must be assured that a given biomarker is “reason-ably likely” to predict a clinically meaningful outcome be-fore they would grant approval for treatments tested intrials using biomarkers as surrogate endpoints. Researchstrategies have been proposed to provide this evidence byembedding the most promising biomarkers in preclinicalAD trials of people at the highest imminent risk of clinicalonset to establish a link between a biomarker effect andthe onset of clinical symptoms of AD. We envision thetime when the scientific means and accelerated regulatoryapproval pathway support multiple preclinical AD trials us-ing biomarkers to identify subjects and provide shorter termoutcomes, such that demonstrably effective treatments toward off the clinical stages of AD are found as quickly aspossible. There are several burgeoning efforts to designand conduct clinical trials in both genetic at-risk andamyloid-positive older individuals, including the Domi-nantly Inherited Alzheimer Network (study of familialAD), the Alzheimer Prevention Initiative, and Anti-Amyloid Treatment in Asymptomatic AD (A4) trial beingconsidered by the Alzheimer’s Disease Cooperative Study.
Finally, the ethical and practical implications surroundingthe issues of future implementation of making a “diagnosis”of AD at a preclinical stage need to be studied, should thepostulates put forth previously prove to be correct. Althoughat this point our recommendations are strictly for researchpurposes only, the public controversy surrounding the iden-tification of asymptomatic individuals with evidence of AD-
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P raised several important points that the field must consider.In particular, the poignant question of “why would anyonewant to know they have AD a decade before they might de-velop symptoms, if there is nothing they can do about it?”should be carefully considered well before any resultsfrom research is translated into clinical practice. First, theremay be important reasons, including social and financialplanning, why some individuals would want to know theirlikelihood of developing AD dementia within the nextdecade, even in the absence of an available disease-modifying therapy. It is our hope, however, that the advancesin preclinical detection of AD-P will enable earlier, moreeffective treatment, just as nearly all of therapeutic gainsin cancer, cardiovascular disease, osteoporosis, and diabetesinvolve treatment before significant clinical symptoms arepresent. It is entirely possible that promising drugs, particu-larly amyloid-modifying agents, will fail to affect the clini-cal course of AD at the stage of dementia or evenMCI, whenthe neurodegenerative process is well entrenched, but maybe efficacious at the earliest stages of the AD-P, before theonset of symptoms.
The definitive studies to determine whether the majorityof asymptomatic individuals with evidence of AD-P areindeed destined to develop AD dementia, to elucidate thebiomarker and/or cognitive endophenotype that is mostpredictive of cognitive decline, and to determine whetherintervention with potential disease-modifying therapies inthe preclinical stages of AD will prevent dementia arelikely to take more than a decade to fully accomplish.Thus, we must move quickly to test the postulates put forthpreviously, and adjust our models and study designs as newdata become available. Because potential biologically ac-tive treatments may be associated with small but significantrisk of adverse side effects, we will need to determinewhether we can predict the emergence of cognitive symp-toms with sufficient certainty to appropriately weigh therisk/benefit ratios to begin treatment in asymptomatic indi-viduals. It is clear that many questions remain to beanswered, and that there may be additional factors whichwill influence the probability of developing clinicalAD. However, the considerable progress made over thepast two decades now enables a strategic path forward totest these hypotheses, move the field toward earlier inter-vention, and ultimately, toward the prevention of ADdementia.
Acknowledgments
The chair (Reisa Sperling) acknowledges the invaluableassistance of Dr. Cerise Elliott at National Institute on Ag-ing, as well as thoughtful input solicited from several indi-viduals, in particular, Drs. Keith Johnson, Dorene Rentz,Peter Davies, Deborah Blacker, Steve Salloway, Sanjay As-thana, and Dennis Selkoe, as well as the helpful public com-mentary provided by our colleagues in the field.
Reisa Sperling has served as a site investigator and/or con-sultant to several companies developing imaging biomarkersand pharmacological treatments for early AD, includingAvid, Bayer, Bristol-Myers-Squibb, Elan, Eisai, Janssen,Pfizer, and Wyeth. Paul Aisen serves on a scientific advisoryboard for NeuroPhage; serves as a consultant to Elan Corpo-ration, Wyeth, Eisai Inc., Bristol-Myers Squibb, Eli Lilly andCompany, NeuroPhage, Merck & Co., Roche, Amgen, Ab-bott, Pfizer Inc., Novartis, Bayer, Astellas, Dainippon, Bio-marin, Solvay, Otsuka, Daiichi, AstraZeneca, Janssen, andMedivation Inc.; receives research support from Pfizer Inc.and Baxter International Inc.; and has received stock optionsfrom Medivation Inc. and NeuroPhage. Clifford Jack servesas a consultant for Eli Lilly, Eisai, and �Elan; is an investigatorin clinical trials sponsored by Baxter and Pfizer Inc.; andowns stock in Johnson and Johnson. Denise Park has re-ceived research support from Avid Pharmaceuticals. EricSiemers is an employee of Eli Lilly and Company, which ac-quired Avid Pharmaceuticals. Yaakov Stern has consulted toBayer Pharmaceuticals and has received research supportfrom Bayer, Janssen, Eli Lilly, and Elan; Maria Carrillo isan employee of the Alzheimer’s Association and reports noconflicts; Bill Thies is an employee of the Alzheimer’s Asso-ciation and reports no conflicts; Creighton Phelps is an em-ployee of the U.S. Government and reports no conflicts.
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