Opinion
EDITORIAL
The Challenge of Defining Alzheimer Disease
Based on Biomarkers in the Absence of Symptoms
Teresa Gomez-Isla, MD, PhD; Matthew P. Frosch, MD, PhD
The search for biomarkers in Alzheimer disease (AD) has been
driven by the expectation that such markers will facilitate diag-
nosis in advance of significant clinical impairment, as well as
serve as surrogate markers for clinical trials. The leading bio-
markers now in practice are di-
Related article page 1174
rected at early identification of
the 2 neuropathologic hall-
marks of the disorder, namely, amyloid plaques and neuro-
fibrillary tangles. The widely defended view is that these patho-
logic changes silently accumulate in the brain over years if not
decades before symptoms occur. Therefore, having meaning-
ful biomarkers would have the potential to shape diagnosis,
disease-modifying therapies, and preventive measures in the
future. However, the definition of disease through biomarkers
rather than symptoms can lead to confusion.
For example, consider a 50-year-old man with a sedentary
lifestyle, documented hyperlipidemia that is only moderately
controlled by diet, and moderate hypertension for which he is
poorly adherent to prescribed medications. Because he does not
participate in any strenuous activities, always opts to drive rather
than walk, and takes the elevator rather than climb stairs, he has
not experienced symptomatic angina. If he underwent coro-
nary angiography, it would be expected that atherosclerosis in-
volving multiple coronary artery territories would be docu-
mented. At autopsy for an unrelated cause, coronary artery
atherosclerosis would not be a surprise to the pathologist. From
either diagnostic approach, it would be routine to establish a di-
agnosis of atherosclerotic coronary artery disease, without con-
cern as to whether he had been symptomatic with the typical
manifestations, such as angina. This scenario highlights the need
to use distinct language to describe disease processes as re-
flected in pathologic and biomarker findings vs clinical symp-
tom complexes (coronary artery atherosclerosis vs angina).
Unfortunately, the historical intermingling of clinical
neurology and neuropathology has commonly masked such
distinctions for neurologic diseases, as is well exemplified by the
description more than 100 years ago by Alois Alzheimer of both
the clinical syndrome and the histologic hallmarks of the dis-
order that bears his name. A National Institute on Aging–
Alzheimer Association (NIA-AA) workgroup has recently
proposed a research framework in which AD is defined by neu-
ropathologic or biomarker evidence of amyloid and tau lesions
regardless of the presence or absence of clinical symptoms.1 The
hypothetical benefit is to assist in identifying asymptomatic in-
dividuals who are at the greatest risk of developing clinically
manifest AD to intervene before irreversible damage has oc-
curred in their brains. The challenge is to accurately predict who
will develop symptoms and when, if ever, they will appear. For
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diseases that most commonly affect older adults, there is the
complicating association of other processes that determine life
span. However, when faced with a similar conundrum of relat-
ing neuropathologic findings to symptomatic disease, the neu-
ropathologic community opted for the terminology of Alzhei-
mer disease neuropathologic changes because of the expected
mismatch between lesions and symptoms.2,3
In this issue of JAMA Neurology, Jack and colleagues4 re-
port their evaluation in 3 nested cohorts of the Mayo Clinic
Study of Aging (MCSA) of sex- and age-specific prevalence of
the following 3 imaging biomarker–based definitions of the AD
spectrum from the NIA-AA research framework: Alzheimer
continuum (abnormal amyloid regardless of tau status), Alz-
heimer pathologic change (abnormal amyloid but normal tau),
and AD (abnormal amyloid and tau). They compared them with
the prevalence of 3 clinically defined diagnostic entities com-
monly linked to AD, including mild cognitive impairment or
dementia, dementia, and clinically defined probable AD. The
authors found that biologically defined AD is more prevalent
than clinically defined probable AD at any age and is 3 times
more prevalent at age 85 years in men and women. Because
this difference is mostly driven by asymptomatic individuals
with imaging biomarker–defined AD, they suggest that these
findings illustrate the magnitude of the potential conse-
quences on public health by intervening on asymptomatic in-
dividuals with positive AD imaging biomarkers.
Jack and colleagues4 have carefully studied participants
in the MCSA cohort who underwent amyloid positron emis-
sion tomography (PET) (n = 1524) or both amyloid and tau PET
(n = 576) along with longitudinally assessed cognition. This
large sample is particularly informative because, in addition
to its size, it is a population-based and not a clinic-based co-
hort. However, their study also represents key challenges that
need to be addressed before imaging biomarker–based defi-
nitions of AD can be implemented in clinical settings, al-
though such definitions are already being used in clinical trials
conducted in asymptomatic individuals, such as the A4 study.5
In the study by Jack and colleagues,4 amyloid PET imaging
was performed with Pittsburgh Compound B (PiB) and tau PET
with flortaucipir. Amyloid and tau PET standardized uptake
value ratios (SUVRs) were formed by normalizing composite
multiregion target regions of interest to the cerebellar crus gray
matter. Cut points to determine normal vs abnormal studies
were SUVR 1.48 (centiloid 22) for amyloid PET and SUVR 1.25
for tau PET. While the field has gained extensive experience
with PiB, detailed studies on the correlation between in vivo
PiB-PET uptake and quantitative measures Aβ pathology bur-
den at postmortem, which are the most critical for the correct
(Reprinted) JAMA Neurology October 2019 Volume 76, Number 10 1143
 Opinion Editorial

interpretation of PET images, continue to be scarce.6-8 Expe-
rience with flortaucipir is much more limited because tau PET
imaging remains an emerging field. It has been shown that this
tracer binds with strong affinity to tangles in AD and those that
form as a function of age in the setting of some off-target pro-
cesses as well9; however, detailed imaging-postmortem cor-
relation studies on flortaucipir-imaged individuals are still
missing, and cutoffs for flortaucipir in vivo retention have yet
to be defined. These are critical aspects for considering this tau
tracer as a disease- and progression-specific biomarker.
An additional challenge that needs to be addressed is that,
while it is widely assumed that plaques and tangles are caus-
ally related to the cognitive symptoms in AD, observations from
multiple studies suggest that associations between plaques,
tangles, and cognition are not particularly strong and do not suf-
fice to reliably predict clinical outcome at an individual level.10
Multiple other factors contribute to the wide heterogeneity of
the clinical expression in the form of dementia for classic brain
AD neuropathologic changes, including the high prevalence of
age-related intercurrent pathologies, different burden and re-
gional lesion distribution, inflammatory or vascular factors,
heterogeneous individual profiles of risk and protective fac-
tors, overlapping clinical symptoms among syndromes, or
variable interindividual rates of cognitive decline. Such hetero-
geneity is one of the main obstacles for the rational design of
prevention clinical trials among asymptomatic individuals who
harbor plaques and tangles in their brains. Moreover, although
the prevalence of both plaques and tangles and dementia cer-
tainly increases with age, not everyone with brain AD pathol-
ogy will experience cognitive decline during their lifetime. Even
excluding individuals who die of other diseases before becom-
ing symptomatic from the lesions in their brains, not all the older
adults who are positive for amyloid and tau by in vivo imaging
but are clinically unimpaired will develop dementia. There is
strong evidence that some individuals may be resilient to the
insult of amyloid and tau deposition in their brains.11 In this sce-
nario, decisions regarding potential therapies might not be trivial
for an asymptomatic imaging-positive individual, and it would
greatly enhance the power of secondary prevention trials to be
able to precisely predict which asymptomatic biomarker-
positive elderly persons will develop clinical symptoms of
dementia and over what time frame.
The study by Jack and colleagues4 represents a step for-
ward in demonstrating by in vivo neuroimaging the high preva-
lence of age-associated amyloid and tau abnormalities among
asymptomatic individuals. This is in agreement with findings
from traditional large autopsy series,12 highlighting a conun-
drum (pathologic and biomarker findings vs clinically defined
entities) that can be both confusing and troubling to patients,
families, and physicians and that may require the introduction
of new nomenclature for the clinical state and/or the patho-
logic process. The existence of a long clinically silent phase in
AD poses a serious challenge for the design of outcome mea-
sures in prevention trials and drives up the cost and length of
these trials, particularly in the absence of another surrogate
marker that can be measured in vivo to estimate how far any
given individual could be from theoretically entering a symp-
tomatic phase. Subsequent future investigations must be di-
rected to understanding the pathologic and biochemical brain
changes, as well as individual genetic and epigenetic factors that,
beyond just the presence of plaques and tangles, drive the clini-
cal course in these imaging-positive individuals. Such work has
the potential to accurately predict the future for an individual
who is cognitively normal yet “imaging positive.” Understand-
ing who and when will allow personalized assessment of the
need and optimal timing for preventive intervention.

ARTICLE INFORMATION
Author Affiliations: Department of Neurology,
Massachusetts General Hospital, Boston
(Gomez-Isla); Massachusetts Alzheimer’s Disease
Research Center, Boston (Gomez-Isla, Frosch); C. S.
Kubik Laboratory for Neuropathology,
Massachusetts General Hospital, Boston (Frosch).
Corresponding Authors: Teresa Gomez-Isla, MD,
PhD, Department of Neurology (tgomezisla@mgh.
harvard.edu), and Matthew P. Frosch, MD, PhD, C.
S. Kubik Laboratory for Neuropathology (mfrosch@
mgh.harvard.edu), Massachusetts General Hospital,
55 Fruit St, Boston, MA 02114.
Published Online: July 15, 2019.
doi:10.1001/jamaneurol.2019.1667
Conflict of Interest Disclosures: Dr Gomez-Isla
reported receiving personal fees from Eli Lilly,
reported participating as a speaker in an Eli Lilly–
sponsored educational symposium, and reported
serving as a member of an Eli Lilly data monitoring
committee. No other disclosures were reported.
REFERENCES
1. Jack CR Jr, Bennett DA, Blennow K, et al;
Contributors. NIA-AA research framework: toward a
biological definition of Alzheimer’s disease.
Alzheimers Dement. 2018;14(4):535-562. doi:10.
1016/j.jalz.2018.02.018
2. Montine TJ, Phelps CH, Beach TG, et al; National
Institute on Aging; Alzheimer’s Association.
National Institute on Aging–Alzheimer’s Association
guidelines for the neuropathologic assessment of
Alzheimer’s disease: a practical approach. Acta
Neuropathol. 2012;123(1):1-11. doi:10.1007/s00401-
011-0910-3
3. Hyman BT, Phelps CH, Beach TG, et al. National
Institute on Aging–Alzheimer’s Association
guidelines for the neuropathologic assessment of
Alzheimer’s disease. Alzheimers Dement. 2012;8(1):
1-13. doi:10.1016/j.jalz.2011.10.007
4. Jack CR Jr, Therneau TM, Weigand SD, et al.
Prevalence of biologically vs clinically defined
Alzheimer spectrum entities using the National
Institute on Aging–Alzheimer’s Association research
framework [published online July 15, 2019]. JAMA
Neurol. doi:10.1001/jamaneurol.2019.1971
5. Sperling RA, Rentz DM, Johnson KA, et al. The
A4 study: stopping AD before symptoms begin? Sci
Transl Med. 2014;6(228):228fs13.
6. Ikonomovic MD, Klunk WE, Abrahamson EE,
et al. Post-mortem correlates of in vivo PiB-PET
amyloid imaging in a typical case of Alzheimer’s
disease. Brain. 2008;131(pt 6):1630-1645. doi:10.
1093/brain/awn016
7. Driscoll I, Troncoso JC, Rudow G, et al.
Correspondence between in vivo 11C-PiB PET
amyloid imaging and postmortem, region-matched
assessment of plaques. Acta Neuropathol. 2012;124
(6):823-831. doi:10.1007/s00401-012-1025-1
8. Seo SW, Ayakta N, Grinberg LT, et al. Regional
correlations between [11C]PiB PET and
post-mortem burden of amyloid-beta pathology in
a diverse neuropathological cohort. Neuroimage Clin.
2016;13:130-137. doi:10.1016/j.nicl.2016.11.008
9. Marquié M, Normandin MD, Vanderburg CR,
et al. Validating novel tau positron emission
tomography tracer [F-18]-AV-1451 (T807) on
postmortem brain tissue. Ann Neurol. 2015;78(5):
787-800. doi:10.1002/ana.24517
10. Ingelsson M, Fukumoto H, Newell KL, et al.
Early Aβ accumulation and progressive synaptic
loss, gliosis, and tangle formation in AD brain.
Neurology. 2004;62(6):925-931. doi:10.1212/01.WNL.
0000115115.98960.37
11. Perez-Nievas BG, Stein TD, Tai HC, et al.
Dissecting phenotypic traits linked to human
resilience to Alzheimer’s pathology. Brain. 2013;136
(pt 8):2510-2526. doi:10.1093/brain/awt171
12. Braak H, Thal DR, Ghebremedhin E, Del Tredici
K. Stages of the pathologic process in Alzheimer
disease: age categories from 1 to 100 years.
J Neuropathol Exp Neurol. 2011;70(11):960-969.
doi:10.1097/NEN.0b013e318232a379

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