Toward defining the preclinical stages of Alzheimer's disease:
Recommendations from the National Institute on Aging-
Alzheimer's Association workgroups on diagnostic guidelines
for Alzheimer's disease
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 Jr.
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
, and 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, New York, 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
© 2011 The Alzheimer's Association. All rights reserved.
*
Corresponding author. Tel.: 1 1-617-732-8085; Fax: 11-617-264-5212. address: reisa@rics.bwh.harvard.edu.
NIH Public Access
Author Manuscript
Alzheimers Dement
. Author manuscript; available in PMC 2012 May 01.
Published in final edited form as:
Alzheimers Dement
. 2011 May ; 7(3): 280–292. doi:10.1016/j.jalz.2011.03.003.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
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
biomarker, 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
recommendations will provide a common rubric to advance the study of preclinical AD, and
ultimately, aid the field in moving toward earlier intervention at a stage of AD when some disease-
modifying therapies may be most efficacious.
Keywords
Preclinical Alzheimer's disease; Biomarker; Amyloid; Neurodegeneration; Prevention
1. Introduction
Converging evidence from both genetic at-risk cohorts and clinically normal older
individuals suggests that the pathophysiological process of Alzheimer's disease (AD) begins
years, if not decades, before the diagnosis of clinical dementia [1]. Recent advances in
neuroimaging, cerebrospinal fluid (CSF) assays, and other biomarkers now provide the
ability to detect evidence of the AD pathophysiological process in vivo. Emerging data in
clinically normal older individuals suggest that biomarker evidence of amyloid beta (Aβ)
accumulation is associated with functional and structural brain alterations, consistent with
the patterns of abnormality seen in patients with mild cognitive impairment (MCI) and AD
dementia. Furthermore, clinical cohort studies suggest that there may be very subtle
cognitive alterations that are detectable years before meeting criteria for MCI, and that
predict progression to AD dementia. It is also clear, however, that some older individuals
with the pathophysiological process of AD may not become symptomatic during their
lifetime. Thus, it is critical to better define the biomarker and/or cognitive profile that best
predicts progression from the preclinical to the clinical stages of MCI and AD dementia. The
long preclinical phase of AD provides a critical opportunity for potential intervention with
disease-modifying therapy, if we are able to elucidate the link between the
pathophysiological process of AD and the emergence of the clinical syndrome.
A recent report on the economic implications of the impending epidemic of AD, as the
“baby boomer” generation ages, suggests that more than 13.5 million individuals just in the
United States will manifest AD dementia by the year 2050 (http://www.alz.org/
alzheimers_disease_trajectory.asp). A hypothetical intervention that delayed the onset of AD
dementia by 5 years would result in a 57% reduction in the number of patients with AD
dementia, and reduce the projected Medicare costs of AD from $627 to $344 billion dollars.
Screening and treatment programs instituted for other diseases, such as cholesterol screening
for cardiovascular and cerebrovascular disease and colonoscopy for colorectal cancer, have
already been associated with a decrease in mortality because of these conditions. The current
lifetime risk of AD dementia for a 65-year-old is estimated to be at 10.5%. Recent statistical
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models suggest that a screening instrument for markers of the pathophysiological process of
AD (with 90% sensitivity and specificity) and a treatment that slows down progression by
50% would reduce that risk to 5.7%.
Both laboratory work and recent disappointing clinical trial results raise the possibility that
therapeutic interventions applied earlier in the course of AD would be more likely to achieve
disease modification. Studies with trans-genic mouse models suggest that Aβ-modifying
therapies may have limited effect after neuronal degeneration has begun. Several recent
clinical trials involving the stages of mild to moderate dementia have failed to demonstrate
clinical benefit, even in the setting of biomarker or autopsy evidence of decreased Aβ
burden. Although the field is already moving to earlier clinical trials at the stage of MCI, it
is possible that similar to cardiac disease and cancer treatment, AD would be optimally
treated before significant cognitive impairment, in the “presymptomatic” or “preclinical”
stages of AD. Secondary prevention studies, which would treat “normal” or asymptomatic
individuals or those with subtle evidence of impairment due to AD so as to delay the onset
of full-blown clinical symptoms, are already in the planning stages. The overarching
therapeutic objective of these preclinical studies would be to treat early pathological
processes (e.g., lower Aβ burden or decrease neurofibrillary tangle pathology) to prevent
subsequent neurodegeneration and eventual cognitive decline.
For these reasons, our working group sought to examine the evidence for a definable
preclinical stage of AD, and to review the biomarker, epidemiological, and
neuropsychological factors that best predict the risk of progression from asymptomatic to
MCI and AD dementia. To narrow the scope of our task, we chose to specifically focus on
predictors of cognitive decline thought to be due to the pathophysiological process of AD.
We did not address cognitive aging in the absence of recognized pathological changes in the
brain,or cognitive decline because of other common age-related brain diseases; however, we
readily acknowledge that these brain diseases, in particular, cerebrovascular disease, Lewy
body disease, and other neurodegenerative processes, may significantly influence clinical
manifestations of AD and possibly its pathophysiology. Although there are likely lifelong
characteristics and midlife risk factors that influence the likelihood of developing cognitive
impairment late in life, for feasibility in current studies, we chose to focus on the 10-year
period before the emergence of cognitive impairment.
Furthermore, we propose a research framework to provide a common language to advance
the scientific understanding of the preclinical stages of AD and a foundation for the
evaluation of preclinical AD treatments. These criteria are intended purely for research
purposes, and have no clinical or diagnostic utility at the present time. We hope these
criteria will enable researchers to characterize further the sequence of biological events over
the course of preclinical AD, refine biomarker criteria that will best predict clinical outcome,
and ultimately aid in selecting appropriate populations for preclinical therapeutic
intervention.
2. Redefining the earliest stages of AD
The term “Alzheimer's disease” has referred in some contexts to the neuropathological
criteria for AD and in other contexts to the clinical syndrome of progressive cognitive and
behavioral impairment, typically at the stage of AD dementia. As we move toward defining
the earliest stages of AD, the dissociation between these two connotations of the term
“Alzheimer's disease” becomes particularly salient. It has become increasingly clear that
both the underlying pathophysiological process of AD and its clinical symptomatology are
best conceptualized as a continuum or a trajectory, and that these processes may evolve in
parallel but temporally offset trajectories.
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To facilitate the possibility of future presymptomatic/preclinical treatment of AD, our
working group, as well as the other two groups, felt it was important to
define AD as
encompassing the underlying pathophysiological disease process,
as opposed to having
“AD” connote only the clinical stages of the disease [2]. To disambiguate the term “AD,” it
may be useful to refer to evidence of the underlying brain disease process as AD-
pathophysiological process (abbreviated as AD-P) and the clinical phases of the illness as
“AD-Clinical” (abbreviated as AD-C), which would include not only AD dementia but also
individuals with MCI due to AD-P. AD-P is thought to begin years before the emergence of
AD-C. In particular, emerging evidence from both genetic at-risk and aging cohorts suggests
that there may be a time lag of a decade or more between the beginning of the pathological
cascade of AD and the onset of clinically evident impairment. We postulate that AD begins
with a long asymptomatic period during which the pathophysiological process is
progressing, and that individuals with biomarker evidence of early AD-P are at increased
risk for developing cognitive and behavioral impairment and progression to AD dementia
(AD-C). The extent to which biomarkers of AD-P predict a cognitively normal individual's
subsequent clinical course remains to be clarified, and we acknowledge that some of these
individuals will never manifest clinical symptoms in their lifetime. Thus, it is critical to
better define the preclinical stage of AD, to determine the factors that best predict the
emergence of clinical impairment and progression to eventual AD dementia, and to reveal
the biomarker profile that will identify individuals most likely to benefit from early
intervention.
The concept of a preclinical phase of disease should not be too foreign because medical
professionals readily acknowledge that cancer can be detected at the stage of “carcinoma
in
situ
” and that hypercholesterolemia and atherosclerosis can result in narrowing of coronary
arteries that is detectable before myocardial infarction. It is widely acknowledged that
symptoms are not necessary to diagnose human disease. Type II diabetes, hypertension,
renal insufficiency, and osteoporosis are frequently detected through laboratory tests (i.e.,
biomarkers), and effective treatment can prevent the emergence of symptoms. Thus, we
should be open to the idea that AD could one day be diagnosed preclinically by the presence
of biomarker evidence of AD-P, which may eventually guide therapy before the onset of
symptoms.
The difficulty in the field of AD is that we have not yet established a firm link between the
appearance of any specific biomarker in asymptomatic individuals and the subsequent
emergence of clinical symptomatology. If we can, however, definitively determine the risk
of developing AD dementia and the temporal course of clinical progression associated with
AD-P in individuals without dementia or MCI, we will open a crucial window of
opportunity to intervene with disease-modifying therapy. Although we hypothesize that the
current earliest detectable pathological change will be in the form of Aβ accumulation, it is
possible that Aβ accumulation is necessary but not sufficient to produce the clinical
manifestations of AD. It is likely that cognitive decline would occur only in the setting of
Aβ accumulation plus synaptic dysfunction and/or neurodegeneration, including paired
helical filament tau formation and neuronal loss. It also remains unknown whether there is a
specific threshold or regional distribution of AD pathology, and/or a specific combination of
biomarker abnormalities that will best predict the emergence of clinical symptoms. Evidence
also suggests that additional factors, such as brain and cognitive reserve, and conversely, the
presence of other age-related brain diseases, may modulate the relationship between AD-P
and AD-C. We also recognize that some individuals can evidence all of the diagnostic
neuropathological features of AD at autopsy but never express dementia during their life; it
remains unknown whether these individuals would have manifested clinical symptoms
should they have lived longer. It is also possible that some individuals are relatively resistant
to AD-P because of cognitive or brain reserve, protective genetic factors, or environmental
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influences. Recent advances in antemortem biomarkers now allow us to test the hypothesis
that many individuals with laboratory evidence of AD-P are indeed in the preclinical stages
of AD, and determine which biomarker and cognitive profiles are most predictive of
subsequent clinical decline and emergence of AD-C.
3. The continuum of AD
The other two working groups established by the National Institute on Aging/Alzheimer's
Association are focused on developing diagnostic criteria for the clinical stages of MCI and
dementia due to underlying AD-P [3–5]. Our group focused on developing
research
recommendations
for the study of individuals who have evidence of early AD pathological
changes but do not meet clinical criteria for MCI or dementia. It is likely that even this
preclinical stage of the disease represents a continuum from completely asymptomatic
individuals with biomarker evidence suggestive of AD-P at risk for progression to AD
dementia to biomarker-positive individuals who are already demonstrating very subtle
decline but not yet meeting standardized criteria for MCI (refer to accompanying MCI
workgroup recommendations by Albert et al). This latter group of individuals might be
classified as “Not normal, not MCI” but would be included under the rubric of preclinical
AD (Fig. 1). Importantly, this continuum of preclinical AD would also encompass (1)
individuals who carry one or more apolipoprotein E (
APOE
)
ε
4 alleles who are known to
have an increased risk of developing AD dementia,
at the point they are AD-P biomarker-
positive
, and (2) carriers of autosomal dominant mutations, who are in the presymptomatic
biomarker-positive stage of their illness, and who will almost certainly manifest clinical
symptoms and progress to dementia.
Our group carefully considered several monikers to best capture this stage of the disease,
including “asymptomatic,” “presymptomatic,” “latent,” “premanifest,” and “preclinical.”
The term “preclinical” was felt to best encompass this conceptual phase of the disease
process but is not meant to imply that all individuals who have evidence of early AD
pathology will necessarily progress to clinical AD dementia. Individuals who are biomarker
positive but cognitively normal might currently be defined as “asymptomatic at risk for AD
dementia.” Indeed, our goal is to better define the factors which best predict cognitive
decline in biomarker-positive individuals, so as to move toward an accurate profile of
preclinical AD.
4. Models of the pathophysiological sequence of AD
To facilitate the discussion of the concept of a preclinical stage of AD, we propose a
theoretical model of the pathophysiological cascade of AD (Fig. 2). It is important to
acknowledge that this model, although based on the prevailing evidence, may be incorrect,
is certainly incomplete, and will evolve as additional laboratory and clinical studies are
completed. Indeed, this model should be viewed as an initial attempt to bring together
multiple areas of research into our best estimate of a more coherent whole.
The proposed model of AD views Aβ peptide accumulation as a key early event in the
pathophysiological process of AD. However, we acknowledge that the etiology of AD
remains uncertain, and some investigators have proposed that synaptic, mitochondrial,
metabolic, inflammatory, neuronal, cytoskeletal, and other age-related alterations may play
an even earlier, or more central, role than Aβ peptides in the pathogenesis of AD [6,7].
There also remains significant debate in the field as to whether abnormal processing versus
clearance of Aβ
42
is the etiologic event in sporadic, late-onset AD [8]. Some investigators
have suggested that sequestration of Aβ into fibrillar forms may even serve as a protective
mechanism against oligomeric species, which may be the more synaptotoxic forms of Aβ
[9–11]. However, of all the known autosomal dominant, early onset forms of AD are
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