Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status

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Abstract
Clinicopathologic correlation studies are critically important for the field of Alzheimer disease (AD) research. Studies on human subjects with autopsy confirmation entail numerous potential biases that affect both their general applicability and the validity of the correlations. Many sources of data variability can weaken the apparent correlation between cognitive status and AD neuropathologic changes. Indeed, most persons in advanced old age have significant non-AD brain lesions that may alter cognition independently of AD. Worldwide research efforts have evaluated thousands of human subjects to assess the causes of cognitive impairment in the elderly, and these studies have been interpreted in different ways. We review the literature focusing on the correlation of AD neuropathologic changes (i.e. β-amyloid plaques and neurofibrillary tangles) with cognitive impairment. We discuss the various patterns of brain changes that have been observed in elderly individuals to provide a perspective for understanding AD clinicopathologic correlation and conclude that evidence from many independent research centers strongly supports the existence of a specific disease, as defined by the presence of Aβ plaques and neurofibrillary tangles. Although Aβ plaques may play a key role in AD pathogenesis, the severity of cognitive impairment correlates best with the burden of neocortical neurofibrillary tangles.

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REVIEW ARTICLE
Correlation of Alzheimer Disease Neuropathologic Changes With
Cognitive Status: A Review of the Literature
Peter T. Nelson, MD, PhD, Irina Alafuzoff, MD, PhD, Eileen H. Bigio, MD, Constantin Bouras, MD,
Heiko Braak, MD, Nigel J. Cairns, MRCPath, PhD, Rudolph J. Castellani, MD, Barbara J. Crain, MD, PhD,
Peter Davies, PhD, Kelly Del Tredici, MD, PhD, Charles Duyckaerts, MD, PhD,
Matthew P. Frosch, MD, PhD, Vahram Haroutunian, PhD, Patrick R. Hof, MD, Christine M. Hulette, MD,
Bradley T. Hyman, MD, PhD, Takeshi Iwatsubo, MD, Kurt A. Jellinger, MD, Gregory A. Jicha, MD, PhD,
Eniko Kovari, MD, Walter A. Kukull, PhD, James B. Leverenz, MD, Seth Love, MBBCH, PhD,
Ian R. Mackenzie, MD, David M. Mann, MRCPath, FRCPath, PhD, Eliezer Masliah, MD,
Ann C. McKee, MD, Thomas J. Montine, MD, PhD, John C. Morris, MD, Julie A. Schneider, MD, MS,
Joshua A. Sonnen, MD, Dietmar R. Thal, MD, John Q. Trojanowski, MD, PhD, Juan C. Troncoso, MD,
Thomas Wisniewski, MD, Randall L. Woltjer, MD, PhD, and Thomas G. Beach, MD, PhD
Abstract
Clinicopathologic correlation studies are critically important for the
field of Alzheimer disease (AD) research. Studies on human subjects
with autopsy confirmation entail numerous potential biases that affect
both their general applicability and the validity of the correlations.
Many sources of data variability can weaken the apparent correlation
between cognitive status and AD neuropathologic changes. Indeed,
most persons in advanced old age have significant non-AD brain
lesions that may alter cognition independently of AD. Worldwide
research efforts have evaluated thousands of human subjects to
assess the causes of cognitive impairment in the elderly, and these
studies have been interpreted in different ways. We review the lit-
erature focusing on the correlation of AD neuropathologic changes
(i.e. A-amyloid plaques and neurofibrillary tangles) with cognitive
impairment. We discuss the various patterns of brain changes that
have been observed in elderly individuals to provide a perspective
for understanding AD clinicopathologic correlation and conclude that
evidence from many independent research centers strongly supports
the existence of a specific disease, as defined by the presence of AA
1J Neuropathol Exp Neurol
Volume 71, Number 5, May 2012
J Neuropathol Exp Neurol
Copyright Ó 2012 by the American Association of Neuropatholog ists, Inc.
Vol. 71, No. 5
May 2012
pp. 00Y00
Copyeditor: Jam Polintan
From the Sanders-Brown Center on Aging (PTN, GAJ) and Departments of
Pathology (PTN) and Neurology (GAJ), University of Kentucky, Lexington,
Kentucky; Department of Genetics and Pathology (IA), Rudbeck Labo-
ratory, Uppsala University, Uppsala, Sweden; Department of Pathology
(EHB), Northwestern Alzheimer Disease Center, Northwestern University
Feinberg School of Medicine, Chicago, Illinois; Department of Psychiatry
(CB, EK), Geneva University School of Medicine, Geneva, Switzerland;
Institute of PathologyYLaboratory of Neuropathology (HB, KDT, DRT),
University of Ulm, Ulm, Germany; Departments of Neurology (NJC, JCM)
and Pathology and Immunology (NJC), Washington University School of
Medicine, St. Louis, Missouri; Department of Pathology (RJC), University
of Maryland School of Medicine; Departments of Pathology (BJC, JCT),
Oncology (BJC), and Neurology (JCT), Johns Hopkins School of Medicine,
Baltimore, Maryland; Department of Pathology (PD) and Dominick P.
Purpura Department of Neurosciencey (PD), Feinstein Institute of Medical
Research, Albert Einstein University, Manhasset, New York; Service de
Neuropathologie Raymond Escourolle (CD), Hopital de la Salpetriere, Paris,
France; C.S. Kubik Laboratory for Neuropathology (MPF) and Department
of Neurology (BTH), Massachusetts General Hospital, Harvard Medical
School, Boston, Massachusetts; Departments of Psychiatry (VH) and Neu-
roscience (PRH), The Mount Sinai School of Medicine, New York, New
York; Departments of Pathology (CMH) and Neurology (CMH), Duke
University School of Medicine, Durham, North Carolina; Department of
Neuropathology (TI), Graduate School of Medicine at the University of
Tokyo, Tokyo, Japan; Institute of Clinical Neurobiology (KAJ), Vienna,
Austria; Department of Epidemiology (WAK), School of Public Health
and Departments of Neurology (JBL) and Pathology (JBL, TJM, JAS),
School of Medicine, University of Washington, Seattle, Washington;
Department of Neuropathology (SL), Institute of Clinical Neurosciences,
Frenchay Hospital and School of Clinical Sciences (SL), University of
Bristol, Bristol, United Kingdom; Department of Pathology (IRM), Uni-
versity of British Columbia, Vancouver, British Columbia, Canada;
Department of Neuropathology at Hope Hospital (DMM), University of
Manchester, Salford, United Kingdom; Departments of Neurosciences
(EM) and Pathology (EM), School of Medicine, University of California,
San Diego, La Jolla, California; Department of Pathology (ACM) and
Bedford Veterans Administration Medical Center (ACM), Boston Uni-
versity, Bedford, Massachusetts; Departments of Pathology and Neuro-
logical Sciences and Rush University Alzheimer’s Disease Center (JAS),
Rush University Medical Center, Chicago, Illinois; Department of Path-
ology and Laboratory Medicine (JQT), Institute on Aging, Center for
Neurodegenerative Disease Research, University of Pennsylvania School
of Medicine, Philadelphia, Pennsylvania; Departments of Neurology,
Pathology, and Psychiatry and NYU Alzheimer’s Disease Center (TW),
NYU Langone Medical Center, New York; Department of Pathology
(RLW), Oregon Health and Science University, Portland, Oregon; and
Civin Laboratory for Neuropathology (TGB), Banner Sun Health
Research Institute, Sun City, Arizona.
Send correspondence and reprint requests to: Peter T. Nelson, MD, PhD, Room
311, Sanders-Brown Center on Aging, 800 S Limestone, University of
Kentucky, Lexington, KY 40536-0230; E-mail: pnels2@email.uky.edu
Support ed by Grants AG05136, AG02219, AG13854, AG05138,
AG06647, AG10124, AG016976, AG035071, AG08051, AG008 017,
and AG05681 from the National Institutes of Health/National Alzhei-
mer’s Coordinating Ce nter. Additiona l grants were from the Deutsche
Forschungsgemeinschaft, Alzheimer Forschung Initiative, Michael J. Fox
Foundation for Parkinson’s Research, Medical Research Council (UK),
Alzheimer’s Research UK, Alzheimer’s Society, and BRACE AQ1.
Page 2
plaques and neurofibrillary tangles. Although AA plaques may play a
key role in AD pathogenesis, the severity of cognitive impairment
correlates best with the burden of neocortical neurofibrillary tangles.
Key Words: Aging, Alzheimer disease, Amyloid, Dementia, Epi-
demiology, Neuropathology, MAPT, Neurofibrillary tangles.
INTRODUCTION
Decades of research worldwide have generated a large
body of clinicopathologic correlation (CPC) scholarship related
to Alzheimer disease (AD). Here we review the literature from
the perspective of neuropathologists and clinicians performing
research in this field. The review is designed for a broad target
audience. We discuss the pathognomonic features of AD (1Y3),
highlight some of the challenges in CPC studies, discuss the
specificity of AD neuropathologic changes, and, mindful of
the controversies in this field of research, describe particular
combinations of concomitant lesions that are found in human
brains. We then review CPC studies that have doc umented
observations on patients along the spectrum from intact cog-
nition to end-stage dementia linked with AD-type neuropath-
ologic changes. Pertinent reviews of historical background are
available (4Y10). Terms used in this review are defined in
T1 Table 1.
OVERVIEW OF CHALLENGES TO
CPC STUDIES IN AD
There are many challenges related to the study of the
neuropathologic correlates of cognitive impairment in the
elderly. Sources of potential bias in AD CPC studies are
summarized in
T2 Table 2; some of these are virtually impossible
to avoid in the design of a research study. Autopsy is required
for definitive AD diagnosis, yet autops y rates are generally
low and autopsy inevitably confers a selection bias. Further-
more, CPC studies rarely are a random sample of the pop-
ulation and clinic- and hospital-based CPCs are subject to
other potential biases. For example, because persons with
behavioral problems are more likely to require help than those
with isolated memory problems, the prevalence and types of
Lewy body disease derived from a clinic are likely to be dif-
ferent from those from a broader community (11). Most prior
studies have been performed in countries with the most ad-
vantageous socioeconomic conditions and have concentrated
on middle- and upper-income whites. T hus, overall, ideal
conditions have not yet been achieved for comprehensive,
population-level epidemiologic study in which information
from detailed, longit udinal neurocogn itive assessme nt s can
be combined with that from state-of-the-art postmortem
examinations. Another challenge of CPC studies is that the
molecular, anatom ic, and clinical changes of AD may not
progress in a uniform fashion (7, 12Y15 ). This proble m may
notbeeasilysolvedusingstatistical models because the
progressi on of both the cl in ical and the pathologic disease
are not necessarily parametrically dist ributed. The tendency
to dichotomize the disease (i.e. ‘‘demented vs nondemented’’)
and overreliance on ordinal variables may also obscure
important relationships. Variation in the elapsed time between
final clinical evaluation and autopsy and competing mortality
risks add more uncertainty. Studies on CPC are additionally
complicated by the high prevalence and high morbidity of
concurrent diseases (16, 17) (discussed in more detail below).
Some researchers tend to focus on unusual or extreme cases
with atypical presentations, whereas others describe the dis-
tribution of outcomes in larger and perhaps more representative
samples. Both approaches can provide insights; CPC data must
be reconciled or at least better understood with reference to
multiple variables and potential confounders. In sum, both cli-
nical and pathologic assessments are imperfect, variably applied,
and constantly evolving. These complexities should be kept in
mind as we assess the sometimes- controversial CPC literature.
AAPS AND NEUROFIBRILLARY TANGLES: THE
HISTOPATHOLOGIC HALLMARKS LINKED TO AD
The neuropathologic hallmarks of AD are neurofibrillary
tangles (NFTs; including pretangles) and AAPs (including
diffuse and neuritic plaques, which may also be referred to as
TABLE 1. Definition of Terms
Pathologic terms:
Neurofibrillary pathology: Neurofibrillary pathology comprises aberrant,
partly insoluble, protease-resistant, hyperphosphorylated tau aggregates;
by electron microscopy, some have a paired helical filament appearance
inside various cellular compartments or extracellular after death of the
parent cell.
Neurofibrillary tangles (NFTs) and pretangles: The term NFT describes
neurofibrillary pathology found in cell bodies. A pretangle is contains
abnormal hyperphosphorylated tau in nonfibrillar (partially soluble)
and nonargyrophilic form. Some pretangles are capable of developing
into NFTs.
Amyloid plaques that contain the AA peptide (AAPs):AAPs are
extracellular, often roughly spherical structures containing AA peptide
and other material. AAPs in histological preparations may be detected
using Congo red, silver stains, and thioflavin-like molecules. Diffuse
AAPs may be visualized using silver stains and anti-AA immunostains.
Neuritic AA plaques (NPs): NPs are AAPs that are invested by swollen,
degenerating neurites and glial cell processes. The swollen neurites
may contain filamentous tau protein aggregates identical structurally to
the inclusions within the NFT. The density of NPs is graded according
to the Consortium to Establish A Registry for Alzheimer’s Disease
(CERAD) criteria (51). By definition, diffuse plaques lack dystrophic
tau-immunoreactive neurites.
Braak stages: Braak stages (60) refer to the hypothetically predictable
progression of NFT-type pathologic features in the brain during the
course of Alzheimer disease (AD). In early stages (IYIII), the pathologic
finding is mostly isolated to the medial temporal lobe structures;
later stages (IVYVI) progressively affect the neocortex.
Anatomic terms:
Medial temporal lobe structures (MTLs): MTLs comprise amygdala and
allocortical structures including the entorhinal cortex, and the cornu
ammonis (CA) fields and subiculum of the hippocampus. MTLs play
an important role in consolidating short-term memory. Hippocampal
pathology is ubiquitous in AD patients but is not relevant for
clinicopathologic correlation due to strong ‘‘floor-and-ceiling’’ effects.
Isocortex or neocortex: ‘‘Neocortex’’ refers to the areas of cerebral cortex
outside allocortical areas. Neocortical areas subserve higher-order
functions including aspects of judgment and executive function. The
distinction between MTL areas and neocortical areas is important
in comprehending the predictable, but nonlinear, progression of
pathology in AD.
Nelson et al J Neuropathol Exp Neurol
Volume 71, Number 5, May 2012
Ó 2012 American Association of Neuropathologists, Inc.
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‘‘senile plaques’ [2, 18, 19];F1 Fig. 1 and Table 1). Additional
changes that may also occur in the brains of AD patients
include amyloid angiopathy, age-related brain atrophy, syn-
aptic pathology, white matter rarefaction, granulovacuolar
degeneration, neuron loss, TDP-43 proteinopathy, and neuro-
inflammation (20Y26), which may contribute to cognitive im-
pairment; however, these are not considered pathognomonic
features of AD (3). Therefore, we focus this review only on the
defining features of AD neuropathologic changes: AAPs and
NFTs (3). Excellent reviews are available about the molecular
characteristics of NFTs and AAPs (27, 28).
Neurofibrillary tangles are not specific for AD (29Y32);
indeed, they are found in almost every class of brain disease
and are universal (yet topographically restricted) in normal
aging subjects (33). Neurofibrillary tangles are found in the
brains of individuals who experienced frontotemporal lobar
degeneration with tauopathy (FTLD-MAPT), focal cortical
dysplasia, myotonic dystrophy, prion diseases, metabolic/
storage diseases, some brain tumors, chronic traumatic ence-
phalopathy, viral encephalitis, and other brain diseases (34Y37)
(
T3 Table 3). This suggests that NFTs are, at least under some
conditions, a secondary response to injury. On the other hand,
tau gene mutations can produce clinical dementia with NFTs;
this indicates that, under some conditions, NFTs may be directly
linked to the primary or at least proximal neurodegenerative
changes (29, 31, 37).
Both the density and the neuroanatomic localization of
NFTs are important parameters in AD neuropathology. The
findings report ed by Tomlinson et al (38) in 1970 have been
replicated many times: ‘‘[NFTs are] found in both controls
and dements [demented subjects] in the hippocampus, but
elsewhere in the cortex was only severe or widespread in the
dements; severe generalized neurofibrillary change in the
cortex was not seen in any control; it seems possible that its
occurrence always indicates dementia.’’ This passage under-
scores the key point that may be relevant to the study of tau
biomarkers, that is, a modest number of medial temporal lobe
NFTs are universally present in subjects older than 70 years
(33), even in persons who have intact cognit ion. Recently, it
has been reported that NFTs are also very common in certain
brainstem nuclei in subjects without dementia (39Y44). As
such, neurofibrillary degeneration restricted to subcortical sites
is often subclinical, whereas widespread neocortical NFTs are
almost always associated with severe cognitive impairment in
more than 1 disease state.
In contrast to NFTs, AAPs are extracellular (45, 46) and
are found in a high proportion of all elderly persons but are
not universal (44, 47, 48). A particularly important subtype
of AAPs are ‘‘neuritic plaques’’ (NPs), as they are more likely
to be associated with cognitive impairment than ‘‘diffuse
plaques’’ (49Y51). Neuritic plaques are AAPs surrounded by
degenerating axons and dendrites that often contain hyper-
phosphorylated tau aggregates. This subset of AAPs is a hall-
mark of the current diagnostic criteria for AD, although there
is no universally accepted definition of a NP. Indeed, AAPs
that lack degenerating tau-positive neurites may have dystro-
phic neurites that are detected using other methods, including
the Bielschowsky silver method, thioflavine S, or immuno-
histochemistry that detects p62, ubiquitin, phosphorylated
neurofilament proteins, or amyloid precursor protein (APP).
Some of the variability may be due to the evolution of the
NP as part of the disease process (52Y54). Because non-AD
TABLE 2. Sources of Potential Bias for Clinicopathologic Correlation Studies of Alzheimer Disease
Sources of Potential Bias in AD CPC Studies
Patient Characteristics Clinical Workup Study Design Disease Heterogeneity Pathologic Workup
9Baseline ‘‘cognitive reserve’’
and education-linked factors
9Quantification of ‘‘cognition’’:
nonparametric cognitive
changes
9Recruitment, inclusion,
and exclusion criteria
9Different genetic risk
factors at play
9Evaluation and quantification
of other pathologies
9Varied access to high-quality
health care (diagnostics
and therapeutics)
9Quantification of non-AD
changes such as
cerebrovascular disease
9Cross-sectional vs
longitudinal assessments
9Some ‘‘atypical’’ forms
of disease
9Focus on complete
brain or mainly
hippocampus
9Non-AD structural
brain comorbidities
(cerebrovascular,
neurotrauma, etc)
9Cognitive assessment
instruments used
9Focus on rare cases or
attempting to understand
‘‘epidemiological’’
perspective
9Unknown effects of
environmental factors
9Multiple methods to
detect AAPs and NFTs
9Emotional and mood
disorders
9Individual clinician
‘‘thresholds’’
9Bias in terms of
autopsy rates
9Overlap and interplay
between different diseases
9Skew toward end-stage
disease at autopsy
9Systemic diseases that
affect cognition (metabolic,
hormonal, neoplastic, etc.)
9Variation among
clinician practices
9Age of individuals in
cohort at death
9Specificity of clinical,
biomarker, and pathologic
features
9Individual pathologist
‘‘thresholds’’?
9Environmental and
behavioral (substance
abuse)
9Evolution in assessment
methodology over time
9Definitions: ‘‘case’’
and ‘‘control’’ and
other terms
9Variation among
pathologist practices
9Cohort effects 9Use of biomarkers 9Interval between final
clinic evaluation
and death
9Accentuation nonhallmark
lesions (acetylcholine,
synapses)
9Use of semiquantitative
or ordinal variables
9Biostatistical methodology 9Quantitative or ordinal
variables
AAP, amyloid AYcontaining plaque; AD, Alzheimer disease; CPC, clinicopathologic correlations; NFT, neurofibrillary tangle.
J Neuropathol Exp Neurol
Volume 71, Number 5, May 2012 Alzheimer Disease Clinicopathologic Correlations
Ó 2012 American Association of Neuropathologists, Inc.
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tauopathies usually lack NPs, they are not an inevitable cel-
lular response to tau pathology (Table 2).
AAPs alone do not seem to be a sufficient substrate for
advanced clinical AD dementia (ADD). However, in contrast
to neurofibrillary (tau) pathology, there seems to be a strong
association between AD genetics and AA plaque formation.
All high-penetrance AD genetic risk alleles (i.e. APOE ?4
allele, Down syndrome, APP mutations and duplications,
PSEN1 and PSEN2 mutations) have been linked in various
experimental systems with increased AA deposition and
increased formation of putative toxic AA peptide species
(46, 55Y57). These data have strong mechanistic implications
with an epidemiological scope because genetic factors confer
approximately 70% of an individual’s risk for AD (58, 59).
The concordance of genetics and AA deposition is
aligned with CPC studies that indicate that AAPs may be a
temporally ‘‘upstream’’ feature of the neocortical disease, with
the caveats that brainstem and medial temporal lobe pretangles
and NFTs are seen in subjects without AA deposition in all age
categories (33, 39, 44). Thus, AAPs and NFTs are the hall-
mark features of AD but do not develop in the human brain
according to the same temporal or anatomic pattern (60, 61).
These nuanced observations, which have been gathered and
analyzed by many researchers, provide the bases to address
some of the controversies that have existed in the field for
decades.
CONTROVERSIES IN AD CPC RESEARCH
A basic goal of AD CPC research has been to assess
critically whether CPC data support the hypothesis that AD
neuropathologic changes (AAPs and NFTs) correlate with
clinical dementia. We note that there are publications con-
tending that CPC data argue against a deleterious role for AD
pathologic changes (i.e. that they may be an ‘‘epiphenomenon’
of aging) and that the disease should not necessarily be defined
by their presence (62Y68). This controversy has been ongoing
for many decades (38). There are 4 separate assertions that
seem to have gained traction in the field, thereby resulting in
uncertainty:
Assertion 1. One sometimes observes persons without dementia
with advanced AD pathologic changes at autopsy.
Assertion 2. One sometimes observes persons with cognitive
impairment who clinically to have AD, but who lack
AD pathologic changes at autopsy.
Assertion 3. Clinical trials aimed at reducing AD pathologic
changes have failed.
Assertion 4. AAPs and NFTs may be neuroprotective rather
than neurotoxic.
Assertions 1 and 2 are addressed directly by extensive
data from AD CPC studies that support 3 points. The defini-
tion of ‘‘advanced AD pathologic changes’’ is critical. Some
groups may consider widespread diffuse and/or NPs as ad-
vanced AD pathologic diagnosis regardless of the numbers
and distributions of NFTs. It is clear, as mentioned previously,
that AAPs, in the absence of any other neurodegenerative dis-
ease lesions or other pathologies, are not a sufficient sub-
strate for severe dementia and thus do not constitute ‘‘advanced
AD pathologic changes.’’ In contrast, dense and extensive
neocortical NFTs are very consistently associated with de-
mentia and thus, according to new diagnostic criteria, these are
required to constitute high burden of AD neuropathologic
change (3). As for Assertion 2, it is true that dementia, even
one that may be clinically similar to probable AD, may be
present without AD pathologic changes; this is simply not AD,
but presumably one among many other diseases that cause
dementia (e.g. hippocampal sclerosis or vascular dementia).
These points will be considered in the context of the AD CPC
literature.
Assertion 3 relates to what clinical trials data tell us
about the impact of AD pathologic changes. There have been
cases in which individuals with mid- to late-stage clinical
Fig 1 4/C
FIGURE 1. Photomicrograph of a section from the cerebral
neocortex of an Alzheimer disease brain stained using double-
label immunohistochemistry for A-amyloid (AA, reddish brown)
and microtubule-associated protein (MAP) tau (black). AA
plaques (AAPs; blue arrows) are roughly spherical and extra-
cellular, whereas neurofibrillary tangles (NFTs; green arrows)
develop within neurons. Note that some of the dystrophic
neurites in the AAPs contain aberrant tau protein pathology
(black), which is biochemically identical to that seen in intra-
cellular NFTs. These AAPs have been described to be ‘‘neuritic
plaques.’’ Scale bar = 50 Km.
Nelson et al J Neuropathol Exp Neurol
Volume 71, Number 5, May 2012
Ó 2012 American Association of Neuropathologists, Inc.
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Page 5
AD were administered anti-AA immunotherapy that partially
cleared AAPs, but this clearance did not seem to mitigate NFT
formation or the inexorable disease course (69Y71). There are
multiple reasons why these trials may have failed, including
the late timing of the therapy. Thus, conclu sions drawn from
these trials may be premature (72, 73). In fact, there have been
hints of some beneficial effects (clinical and biochemical)
linked to human anti-AA immunotherapies (74Y79). As yet,
there are no agents that are capable of reducing tangle density.
In sum, clinical trials have not provided definitive answers as
to the direct role of AAPs or tangles in the cognitive impair-
ment associated with AD pathologic diagnosis (80, 81).
Assertion 4 is that AAPs and NFTs are actually neuro-
protective rather than toxic. Because autopsies provide only
cross-sectional data, they cannot prove mechanism. Because
both tau phosphorylation and AA peptide generation are seen
in ‘‘normal’’ brains, some contend that there are probably
beneficial and adaptive aspects to these molecular processes.
This is important to consider when developing therapies that
seek to inhibit those pathways (62). Yet, there are strong
arguments in favor of the hypotheses that the molecular pro-
cesses that underlie tau and AA deposition in NFTs and AAPs
are indeed pathologic. Abundant evidence from many inde-
pendent studies indicates that AA peptides and other plaque
substances (in their various molecular forms) may be neuro-
toxic, both directly and through secondary responses to stress,
injury, and inflammation (46, 82, 83). Both gain-of-toxic-
function and loss-of-normal-function deleterious effects also
have been described for phospho-tau (84Y89). The toxicity of
oligomeric forms of tau and AA peptides could be connected
with biochemical changes that also produce NPs and NFTs;
thus, the oligomeric species may be directly related to the
neuropathology, although they are not exactly correlated
(90Y95). It must be acknowledged that a simplistic concep-
tualization of ‘‘plaques and tangles’’ does not adequately
reflect the complexity of the biochemical changes in the
brains of patients with AD. Thu s, peptides and higher-order
aggregates derived from products of APP and MAPT genes
can potentially lead to combinations of neuroprotective and
toxic attributes. Here, we focus on data and analyses from
particular human autopsy studies to addres s the specific
question, ‘‘are there strong correlations between antemortem
cognitive impairment and the ‘defining’ hallmarks of the
disease?’’
We consider it to be an important clue that most brains
from elderly human subjects show abnormalities that fall
somewhere along particular continua of pathologic severity
(60, 96 Y100). These patterns of brain changes indicate spe-
cific features that can be correlated with clinical parameters,
modeled to understand disease mechanisms, and targeted for
therapeutics. Before addressing the ‘‘classic’’ AD pathologic
changes and their clinical correlates, we discuss in the fol-
lowing section some of the less common pathologic find-
ings in human brains, that is, the ‘‘exceptions that help test
the rules.’’
LESS-PREVALENT PATTERNS OF CLINICAL
AND PATHOLOGIC FEATURES FOUND
IN HUMAN BRAINS
‘‘Plaque-Only’’ Dementia
In 1987, Terry et al (101) described what has become
known as ‘‘plaque-only dementia.’’ There were 58 subjects
with dementia and AD changes, of which 40 had 2 or more
neocortical tangles per high-magnification field in frontal,
temporal, and parietal lobes; 18 had no neocortical NFTs. The
cases did not differ in hippocampal tangle densities and had
no significant differences in brain weights, neocortical thick-
ness, or neocortical neuron counts. Despite this, both groups
were demented and did not differ significantly on the Blessed
Dementia Scale. The existence of this ‘‘plaque-only’’ dementia
category has been controversial because some subjects with
pathologic findings similar to the plaque-only group described
by Terry et al have dementia and some do not. The current
revision of the National Institute on AgingYAlzheimer’s Asso-
ciation guidelines for the neuropathologic assessment of AD
stipulate that subjects with moderately dense neuritic AAPs
may be regarded as having an intermediate level of AD
TABLE 3. Alzheimer DiseaseYLinked Pathologic Features and Their Presence in Conditions That Have Pathologic Overlap With
Alzheimer Disease
Neuropathologic Observation
Clinical Condition
Diffuse
AAPs
AAPs With Tau
Neurites
Hippocampal
NFTs
Neocortical
NFTs References
Alzheimer disease +++ +++ +++ +++ This review
‘‘Oldest old’’ without dementia T jj +j++ jj (172, 324, 325)
Tangle-only dementia +++ + (116, 326)
Dementia with Lewy bodies +j++ jj + jj (327, 328)
Chronic traumatic encephalopathy +j+++ T +/++ +j+++ (329Y331)
Niemann-Pick Type C TT + + (332, 333)
Guamanian amyotrophic lateral sclerosisYParkinson
dementia syndrome
++ jj ++ ++ (334Y338)
Tauopathies: PSP, CBD, Pick disease, FTLD-MAPT jj jj ++ ++ (37, 339, 340)
AAP, neuritic and diffuse amyloid plaques containing AA peptide; FTLD-MAPT, frontotemporal lobar degeneration with mutation in MAPT; CBD, corticobasal degeneration;
NFT, neurofibrillary tangle; PSP, progressive supranuclear palsy.
jj, no disease-specific pathologic feature; T, scattered or inconsistent pathologic features; +, low level of pathologic features; ++, moderate level of pathologic features; +++, high
level of pathologic features.
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neuropathologic change and that other potential contributors to
cognitive impairment and dementia should be sought (3).
Notably, prior studies necessarily included brains from persons
with diseases (e.g. neocortical >-synucleinopathy or TDP-43
pathology) that were not at that time well characterized, but
which can coexist with variable neocortical amyloid loads.
Indeed, Hansen et al subsequently published an article titled
‘‘Plaque-only Alzheimer disease is usually the Lewy body
variant, and vice versa’’ (102). When modern pathologic
methods are used, severe cognitive impairment associated only
with diffuse AAPs in the brain at autopsy is rare and has an
unknown relationship to AD. Subtle cognitive impairment may
be associated with diffuse AAPs, indicating that these lesions
may play a direct role in incipient AD (54), although a direct
role of diffuse AA plaques without tau pathology has not been
proven. Furthermore, diffuse AAPsmaybeassociatedwith
cerebral amyloid angiopathy, which could produce impair-
ments separately (103, 104), although see Nelson et al (105).
As the field moves toward identifying subtle (i.e. early) cog-
nitive impairment, more work will be required to characterize
any deleterious influence of diffuse AAPs on cognition and
clinical manifestations in cases of presumed incipient AD. On
the other hand, the density of tau-positive NPs does correlate
directly and statistically independently with some degree of
cognitive impairment (105Y107) (
F2 Fig. 2).
‘‘Tangle-Only’’ or ‘‘Tangle-Predominant’’
Dementia and Other Non-AD Tauopathies
In most community-based autopsy series, non-AD
tauopathies constitute approximately 1% of dementia cases
(108Y115) (but see Noda et al [116]). In autopsy series asso-
ciated with dementia clinics, a higher propor tion of non-AD
tauopathies are seen, presumably due to recruitment bias
(111). Among well-recognized forms of tauopathies are
FTLD-MAPT, progressive supranuclear palsy, corticobasal
degeneration, Pick disease, argyrophilic grain disease, and
‘‘tangle-only dementia’’ (116Y125). There are also some
individuals with intact or subtly diminished cognitive abilities
whose brains harbor hippocampal and/or amygdala NFTs
(Braak stages IIIYIV) with few or no AAPs; these represent
approximately 5% of cases in some large autopsy series (41).
In this condition, the NFT s comprise tau isoforms similar to
those of classic AD, but these subjects do not have the same
distribution of APOE genoty pes as subjects with AD (118).
It rema ins to be determined whether these individuals died
early in the course of an idiosyncratic subtype of AD (12) or
instead reflect a completely different pathogenesis.
AAPs and NFTs But No Dementia
Confusion persists about individuals lacking docu-
mented cognitive impairment yet whose brains reveal neuro-
pathologic findings of AD at autopsy. This is an important
issue because it challenges the principle that the processes that
underlie AD neuropathologic changes are the sole cause of
cognitive impairment. To address this issue, longitudinal
studies of participants who are enrolled while cognitively
normal and followed for several decades can be used to study
the sequential clinical and corresponding molecular patho-
logic changes in AD. Rigorous analysis requires preliminary
modeling of what is expected at a population level based on
what is known about the disease.
The prevalence of dementia due to AD, as judged by
clinicians, doubles every half-decade after age 65; thus, ap-
proximately 30% to 40% of living 95-year-old patients receive
the diagnosis of ADD (126Y128). The interval between initial
ADD clinical diagnosis and death is approximately 8 years
(129), but AAPs and NFTs are present well over a decade
before death (130Y138). New terminology has been developed
to delineate stages of preclinical AD (48, 139, 140). The
Fig 2 4/C
FIGURE 2. (A, B) Correlations between antemortem cognitive
status (final Mini-Mental State Examination [MMSE] scores),
counted neocortical neurofibrillary tangles (NFTs; A), and
neuritic A-amyloid plaques (NPs; B) for 178 patients lacking
concomitant neuropathologic findings (189). Each circle rep-
resents data from a single individual. Neurofibrillary tangles
and NPs were counted and summed from 4 different portions
of cerebral neocortex: Brodmann areas 21/22, 18/19, 9, and
35, as described (189). Data are reprinted with permission
from the Journal of Neuropathology and Experimental Neurology
(2007;66:1136Y46). Copyright 2007, American Association of
Neuropathologists. The correlation between final MMSE scores
and neocortical NFT counts is greater than that between
MMSE scores and NP counts.
Nelson et al J Neuropathol Exp Neurol
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median life expectancy in Western countries is approximately
79 years (141). Thus, using these data, we can deduce con-
fidently that an ‘‘average’’ person dying at age 79 has an
approximately 15% likelihood of having been diagnosed
clinically with ADD, but an approximately 30% to 40%
chance of harboring significant AD neuropathologic changes
(otherwise, the prevalence of ADD could not reach approx-
imately 30%Y40% by age 95). Indeed, this is precisely the
observation reported by one of the largest autopsy series to
date (142) and is well supported by AD biomarker studies
(143Y145).
The existence of persons without dementia with some
AD neuropathologic changes is therefore not problematic. It
is expected that many persons die with brains that exhibit
AD neuropathologic change in the preclinical phase of AD;
indeed, data support the modeled expectations (44, 142). One
would exp ect a normally distributed population-based model
of AD to contain individuals with early or moderate AD who
are classified dichotomously (and falsely) as lacking demen-
tia. Pathologic changes that are present before clinical mani-
festations are a well-accepted notion in other chronic diseases
such as cancer, atherosclerosis, and others (146, 147) but are
equally relevant to discussions of AD. Significantly, the
severity and distribution of AD neuropathologic changes are
much lower in preclinical cases than in cases with clinically
severe ADD (48, 108, 148Y150). We are aware of no reported
case of truly intact cognition despite extremely severe AD
pathologic changes (i.e. widespread neocortical NFTs) mea-
sured with quantitative pathologic analysis, although many
persons with intact cognition have been assessed in autopsy
series (33, 42, 54, 133, 142, 148, 151Y166).
Dementia Cases Lacking AAPs, NFTs, or Other
Pathologic Substrates
The literature does not indicate large numbe rs of
patients with advanced dementia whose brains lack any
pathologic changes when u p-to-date neuropathologic methods
have been applied to their brains. Older studies that reported
cases with dementia and no other known pathologic substrate
lacked insights into more recently defined pathologies, such as
those with aberrant TDP-43, valosin-contai ning protein, and
fused in sarcoma inclusions (37, 167). Moreover, some prior
methods (e. g. Bielschowsky impr egn ation ) w ere l ess sensi-
tive to some tauopathies than Gallyas for NFTs, Campbell-
Switzer for AAPs, and immunohistochemistry. On the basis
of the discovery of these and other novel neurodegenerative
disease lesions in the past 20 years, we view reports that
some individuals in old age may have m oderate cognit ive
impairment without advanced AD pathologic diagnosis as a
challenge to the research community t o elucidate the novel
mechanisms underlying cognitive impairments in those sub-
jects (168Y173). A notable example of this is schizophrenia,
which, in elderly patients, is associated with dementia, al-
though the underlying basis of this dementia is enigmatic
(174Y176). Normal pressure hydrocephalus is another poorly
understood cause of dementia that may lack AD pathologic
changes (177, 178). Understanding these phenomena and how
they may contribute to cognitive impairment in a broader
population will require more thorough study of non-AD brain
diseases.
AD-Related Brain Pathology in Individuals
Older Than 90 Years
There have been reports of dissociat ion between AD
neuropathologic changes and cognitive status in extreme old
age, but these data merit careful analysis. The incidence of
dementia increases continually up to (179Y183) and above
(139, 184) 90 years of age. In contrast to the increased prev-
alence of clinical dementia with advanced age, the prevalence
of cases with high NP and high NFT pathologic diagno sis at
autopsy seems to level off in the oldest old according to
multiple autopsy series (154, 168Y172). However, not all
studies are in agreement on this point (185, 186); these
‘‘survivors’’ represent a small fraction of the human pop-
ulation with underrepresentation of APOE ?4 allele (187).
Even in extreme old age, the presence of many neocortical
NFTs correlates with antemortem cognitive decline (105,
188Y191). Thus, no ‘‘dissociation’’ exists between the AD
neuropathologic change and cognitive impairment. The enigma
relates to cognitively impaired individuals of advanced age
whose brains lack substantial AD pathologic diagnosis at
autopsy.
Cognitive impairment is associated with many diseases.
Cerebrovascular disease (CVD) is the most prevalent non-AD
pathologic diagnosis in the brains of the advanced aged and is
directly relevant to any CPC study related to dementia. The
difficulties introduced by this multifaceted and unpredictable
disease catego ry in aged individuals have been discussed
previously (17, 192Y204); 75% to 90% of patients older than
90 years have some degree of CVD pathologic diagnosis
(189, 205Y207). There is no universally applied rubric for
CVD pathologic diagnosis, although the recent National
Institute on AgingYAlzheimer’s Association criteria attempted
to systematize neuropa thologic assessment of this complex
form of brain injury (3). Nevertheless, the profound impact of
CVD on studies pertinent to cognition in the elderly seems to
be underappreciated in dementia research (208Y210).
In addition to AD and CVD, there are many widespread
contributors to cognitive impairment in the elderly. Examples
of these include hippocampal sclerosis (a prevalent disease
that plays a strong deleterious role in extreme old age and
is distinct from the disease linked to epilepsy in younger
individuals [211]), >-synucleinopathies, hematomas, argyr-
ophilic grain disease, neuropsychiatric disorders and their
therapies, failure of other organ systems, diabetes, hyper-
tension, chemotherapy, and other medication adverse effects
(157, 212Y220).
Thus, in the oldest old, the prevalen ce of concomitant
non-AD brain diseases, including CVD and hippocampal
sclerosis, begins to mimic the effects of AD pathologic diag-
nosis (154, 221, 222). Together, these and perhaps other
uncharacterized changes may weak en the apparent association
between AD pathologic diagnosis and cognit ive status (189,
195, 198). An analogy can be made to heart disease: it would
be difficult to study the clinicopathologic correlation between
coronary atherosclerosis and cardiac function if two thirds
of cases had alular dysfunction, infectious endocarditis, or
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severe arrhythmias. Despite all the potential pitfalls, many
high-quality studies related to the correlations between cog-
nitive status near the time of d eath and AD-type pathologic
burden at autopsy have been performed.
CLINICOPATHOLOGIC CORRELATION IN AD
Correlation Between AAPs and Cognitive Status
More than 40 CPC studies have assessed the correlation
between AAPs and severity of antemortem cognitive impair-
ment (38, 98, 103, 105Y108, 158, 162, 171, 185, 189, 191,
223Y260). These studies vary with respect to many factors
including the research cohort characteristics, anatomic areas
examined, pathologic methods, AAP subcategories and count-
ing techniques, metrics for cognition, the range and domains of
cognitive decline tested, and the rigor with which concomitant
pathologic findings were evaluated and factored into the study.
Although the study designs were diverse in CPC studies
involving AAPs, most studies confirm a significant correlation
between antemortem cognitive impairment and neocortical
AAPs, as demonstrated by Blessed et al (254) (
F3 Fig. 3). These
workers used the von Braunmu
¨
hl silver stain, which could not
differentiate between diffuse and neuritic AAPs. This, and
some other earlier studies, incorporated a bias related to the
inclusion of many individuals at opposite ends of the AD con-
tinuum thereby masking the poorer correlation between plaque
load and dementia severity among the impaired subjects. Sub-
sequent studies have established that the densities of NPs cor-
relate with antemortem cognitive impairment better than the
densities of diffuse AAPs (45, 98, 106, 154, 189, 261).
It is important to note, however, that many prior studies
have only considered limbic and neocortical plaques. The
distribution of A AP pathology may occur throughout the
entire neuraxis in advanced disease. Elderly without dementia
show early stages of this hierarchical process. The progression
of AAP pathology seems to begin in the neocortex with a few
diffuse plaques and then sequentially progress to also include
1) the hippocampus, entorhinal cortex, cingulate cortex, and
amygdala; 2) basal ganglia and diencephalon; 3) midbrain and
medulla oblongata; and 4) pons and cerebellum (262). A
recent study with large numbe rs of subjects assessed with
standardized antemortem cognitive testing found that the
amyloid stage that has progressed to involve the striatum is
highly predictive of dementia (263). Correlations between
amyloid stages (Thal phases), NFT burden, and cognitive
impairment are shown in
F4Figure 4.
A c ritical point supporting the importance of plaques is
that widespread neocortical NFTs are virtually nonexistent
without the presence of widespread AAPs, except in the
minority of cases that show a clear-cut non-AD tauopathy
(e.g. progressive supranuclear palsy). Owing in part to the
scarcity of neocortical NFTs in the absence of AAPs, and the
relatively modest apparent direct impact of AAPs on cogni-
tion, it has been suggested that the pathogenetic effect of
AAP-related substances may be mediated by ‘‘seeding’
neurofibrillary p athology (46, 88, 189, 264, 265). The current
clinical trial literature is compatible with the idea that AAP-
related substances kindle a self-propagating process related
to neocortical NFTs, as has been hypothesized (266Y269).
Regarding AAPs in AD, an analogy can be made to the
established role of high blood cholesterol in heart disease.
Hypercholesterolemia promotes atherosclerosis that over time
can cause myocardial infarction. Therefore, high blood cho-
lesterol is considered a causative risk factor for heart disease,
although it does not correlate with clinical heart disease in
all groups (many people live with hypercholesterolemia for
years without experiencing myocardial infarction). In the
same way, AAPs may be a key pathologic factor in AD
without equating with the clinical features of ADD.
Often neglected is the quest ion of lesion turnover (i.e.
AAPs being possibly reabsorbed during life so that they
would not be ‘‘counted’’ at autops y), which seems to occur in
some subjects (70, 270). For this reason, the number of AAPs
might plat eau (or at least the rate of increase flatten out),
leading to a ‘‘ceiling effect’’ relatively early in disea se pro-
cess that confounds linear correlations between plaque num-
ber and severity of cognitive change (253). AA vaccine trials
also attest to the ability of the immune system to clear diffuse
AAPs (69, 70, 271), but it is not known whether toxic APP
metabolites or other plaque components remain after clearance
of fibrillar AA-peptides (73, 272). The active ‘‘turnover’’ dur-
ing life could reduce the correlation between the lesion num-
bers observed at autopsy and clinical features of the disease.
Neuritic AAP (NP): A Pathologic Entity With
Mechanistic Implications
AAPs ringed by degenerating neurites that usually con-
tain abundant PHF-tau, that is, NPs (Table 1), deserve special
consideration. In histologic sections, NPs are characterized by
FIGURE 3.
AQ2
Correlations between antemortem cognitive status
(‘‘dementia scores’’) and counted amyloid plaques from the
1968 article by Blessed et al (254). Dementia scores were derived
from ‘‘psychological tests of orientation, remote memory, recent
memory, and concentration.’’ Amyloid plaques were visualized
using the von Braunmu
¨
hl silver stain. Each circle represents data
from a single individual. There is reasonable correlation between
the dementia scores and the number of plaques, although this
work antedated the era of neocortical synucleinopathy, TDP-43,
and other factors now known to both clinicians and neuro-
pathologists. This figure was reproduced with permission from
The British Journal of Psychiatry (1968;114:797Y811). Copyright
1968, The Royal College of Psychiatrists.
Nelson et al J Neuropathol Exp Neurol
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nearby abnormal nerve cell processes (Fig. 1). The abnormal
NP-contacting dendrites and axons contain pathologic tau
fibrils identical to those seen in NFTs (244, 273), with loss of
adjacent synapses (274, 275). Dystrophic axons from com-
pletely different afferent sources, expressing distinct neuro-
transmitters, have been shown to be present in particular NPs
(276, 277), which strongly implies that toxicity is directed from
the (extracellular) plaque to the radially arranged intracellular
neurites. The particular toxic substance(s) within NPs still have
not been completely characterized (90, 103, 278), but NPs
represent a nidus in which extracellular plaque substance(s)
seem to induce intracellular degenerative changes with tau
pathology (18, 50, 279Y281). This process may be synergistic
or identical to the stimuli that could promote NFTs in human
brains. Neuritic plaques seem to develop after diffuse AAPs
and NFTs (44). Using data from the National Alzheimer’s
Coordinating Center with inclusion and exclusion criteria, as
described previously (282), NPs and NFTs tend to coexist
(
T4 Table 4); this corroborates earlier observations (283). The
characteristic anatomic distribution of NPs and NFTs supports
additional hypotheses in relation to their formation that are
outside the scope of this review (33, 39, 284Y286).
Correlation Between NFTs and Cognitive Status
Numerous CPC studies have assessed the association
between NFTs and cognitive status (38, 98, 154, 158, 162,
185, 188, 189, 191, 223Y232, 235Y240, 244, 250Y252, 258,
261, 264, 287Y296). As with studies on AAPs, those of NFTs
have used diverse study designs. Regardless of methodology,
the correlation between neocortical NFTs (but not necessarily
allocortical or subcortical NFTs) and antem ortem cognitive
status is strong in studies that span the spectrum of cogni-
tive impairment (provided there is not a strong influence by
other diseases that can cause cognitive impairment). Result s
from the University of Kentucky Alzheimer’s Disease Center
(189) corroborate previous findings (Fig. 2). Duyckaerts et al
(287) and Sabbagh et al (252) independently arrived at the
conclusion that the density of NFTs in selected cerebral
cortical fields significantly (p G 0.01) correlated with Blessed
or Mini-Mental State Examination scores (297). Likewise,
Fig 4 4/C
FIGURE 4. A-Amyloid (AA) phase showing the relationship between cognition, as represented by the retrospectively determined
clinical dementia rating scale (CDR) score, and the phase of AA deposition determined in the medial temporal lobe (MTL) in 202 cases
(103, 262). NonYAlzheimer disease (AD) dementia cases were excluded from this analysis. (A) Almost all demented cases exhibited
end phases of the expansion of AA deposition without major differences; cases without dementia had early-phase AA pathology
(partial correlation controlled for age and sex for all cases: r = 0.582, p G 0.001; only for AD cases: r = 0.086, p = 0.605).
(B) Relationship between Braak neurofibrillary tangle (NFT) stage and AA phase in 201 AD and control cases. With increasing
Braak NFT stage, the distribution of AA plaque deposition expanded to end-phase AA deposition reached with Braak NTF stage IV
(partial correlation controlled for age and sex for all cases: r = 0.621, p G 0.001; only for AD cases: r = 0.07, p = 0.671).
TABLE 4. Distribution of Cases According to Braak Stages
and Neuritic Amyloid Plaque Densities
Neuritic AA Plaque Density
None Sparse Moderate Frequent
Braak staging (NFTs)
05214103
I7924317
II 68 59 48 17
III 48 59 108 64
IV 22 41 160 158
V 0 25 134 553
VI 3 14 72 1,035
Data are from the National Alzheimer’s Coordinating Center (n = 2,903 included,
as described previously [282]) to sh ow distribution of cases according to Braak stages
(0 to VI) of neurofibrillary tangles (NFTs) (60) and neuritic amyloid (AA) plaque den-
sities, graded according to Consortium to Establish A Registry for Alzheimer’s Disease
criteria (51).
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Dickson et al (251) described a strong correlation between
cortical NFT counts or phospho-tau ELISA measurements
and Blesse d Information, Concentration, and Memory test
scores. Similar results were obtained by Bennett et al (264)
who found a strong correlation between global cognitive sta-
tus and densities of neocortical tau-positive tangles.
On the basis of the review of an enormous sample of
cross-sectional autopsy data, the pattern of NFT development
across the clinical spectrum of disease has been integrated in
Braak neuropathologic staging (60, 298, 299). Neurofibrillary
pathology is observed in the human brain long before AA
plaques develop (39, 44, 300). At 40 years, all individuals
studied by Braak and Del Tredici (39) and Braak et al (44)
exhibited at least initial neurofibrillary pathology in the brain-
stem (
F5 Fig. 5). The relationship between the near-universal tau
pathology seen in the locus ceruleus of middle-aged individ-
uals and AD is not known. As AD progresses, the NFTs
become numerous in locus ceruleus, which may suggest the
same pathogenetic process is becoming more severe (301).
In more advanced disease, the neuroanatomic distribu-
tion of NFTs correlates both with the location at which neurons
die (302Y305) and with the cognitive domains affected in
patients with ADD. For example, early AD symptoms tend to
relate to memory, when the anatomic substrates of memory in
the medial temporal lobe are selectively affected by NFTs
(Braak stages IIIYV). The cognitive domains affected in mid-
and late-stage ADD expand to include areas of executive
function, visuospatial capacities, and speech. These manifes-
tations occur in synchrony with the development of NFTs in
the neocortical areas responsible for those functions (Braak
stages VYVI). Braak staging provides a useful ordinal system
for describing the topographical distribution of pretangles and
NFTs in human brain. Nevertheless, Braak staging also masks
the fact that marked variability in pathologic lesion density
across cases exists within a given Braak stage (7, 12) and that
not all AD cases fall within the same spatial continuum with
regard to brain NFT distributions (12, 15, 151).
A key question in this regard is whether a heavy neo-
cortical NFT load is present in individuals with intact cog-
nition. In a review of 11 different studies comprising 555
subjects without dementia, a total of 12 brains were assessed
as Braak stage V (2.2%); 3 were assessed as Braak stage VI
(0.5%) (142). However, not all Braak stage VI brains were the
same; there was significant variation in NFT burden in these
cases (142, 151). In the Braak stage VI cases studied where
neocortical NFTs were most abundant, cognitive impairment
was found on testing (151). It is important to emphasize that,
among thousands of cases from dozens of CPC studies world-
wide, there never has been a report of a thoroughly docu-
mented individual with truly ‘‘end-stage’’ neocortical NFT
pathology who lacked antemortem cognitive impairment
proximal to death (142, 151). Even the single case report
‘‘outlier,’’ a Braak neuropathologic stage VI case without full-
blown dementia, had some degree of cognitive impairment
within expectations for late preclinical AD (306).
As with AAPs, NFTs are quantified with certainty only
at autopsy. Therefore, it is necessary to know whether some
NFTs are removed (or reabsorbed) from the brain before
death. Some, but not all, studies have indicated that more
neurons disappear in brains of demented subjects than can be
explained directly by the number of NFTs and ‘‘ghost tangles’’
observed at autopsy (285, 304, 307Y310) (but see [305]). Thus,
Fig 5 4/C
FIGURE 5. Development of phospho-tau (AT8)-immunoreactivity
(ir) versus A-amyloid (AA) pathologic findings. (A) White columns
indicate the relative frequency of 2,332 nonselected autopsy cases
devoid of any abnormal intraneuronal tau deposits. Columns in
shades of blue indicate the relative frequency of cases with all
types of intraneuronal lesions. (B) Development of extracellular
AA deposits. Purple areas within the columns indicate subgroups
of cases showing plaque-like AA-amyloid deposits in temporal
neocortex (Phase 1, light purple), allocortex and neocortical
association areas (Phases 2 and 3, middle purple and dark purple),
or in virtually all cerebral cortical regions (Phase 4, black). Note
the relatively late appearance of AA plaques in comparison to
subcortical neurofibrillary tangles. This figure is reproduced with
permission from the Journal of Neuropathology and Experimental
Neurology (2011;70:960Y99) (44). Copyright 2011, American
Association of Neuropathologists.
Nelson et al J Neuropathol Exp Neurol
Volume 71, Number 5, May 2012
Ó 2012 American Association of Neuropathologists, Inc.
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Page 11
some evidence exists for NFT ‘‘turnover,’’ neuronal shrinkage,
and/or non-NFT cell death mechanism(s).
Overview of Specific Large Autopsy Series
A subset of the CPC studies is highlighted inT5 Table 5.
These studies were chosen because they represent large au-
topsy series with detailed clinical and pathologic assessments.
The inclusion criteria for Table 5 were as follows: number
of patients more than 40, neuropathologic assessments that
included study of both NFTs and AAPs in the cerebral neo-
cortex (not just the hippocampus), subjects with a broad range
of pathologic severities, and nondichotomous correlation with
cognitive status (i.e. not demented vs nondemented). The se
inclusion criteria do not min imize the contributions of studies
with smaller samp le sizes, for example, the important CPC
study by Arriagada et al (293) that assessed 10 patients.
Nonetheless, a detailed description of all smaller autopsy
series would comprise many dozens of additional studies
along with a commentary regarding each of their specific
attributes. It should also be mentioned that some of the
important autopsy series of AD CPC are excluded from this
list because they only assessed AAPs and not NFTs, assessed
only the hippocampus, or viewed cognitive status as a
dichotomous variable. Studies not shown in Table 5 include
the seminal articles of Blessed et al (254), Roth et al (255),
and Tomlins on e t al ( 38, 256), which fou nd a c or rel atio n
between dementia severity and amyloid plaques counted
in cerebral cortex (with the caveat described previously),
andpreviousstudiesthathadalsohelpedtoestablishthe
TABLE 5. Large Clinicopathologic Studies of Alzheimer Disease
Study Institution References* Year* N*
Avg
Int*
Methodological
Considerations
Main Finding(s) Correlating
AD Pathology to CI
Harvard Medical School (261) 1991 56 NR C-S, QP NFT 9 total amyloid plaques correlate with
dementia severity
Oxford Project to Investigate
Memory and Aging
(296, 341) 1995 86 NR L, BP NFTs 9 NPs 9 total amyloid plaques
correlate with dementia severity
Mount Sinai ADRC (291, 342, 343) 1995 70 NR C-S, QP, cognitive status
based on chart review
NFTs d AAPs correlate strongly with CI
Albert Einstein (154, 155, 251) 1995 45 11.7 L, QP NFTs 9 AAPs correlate strongly with CI
Vienna Longitudinal Study
on Dementia
(98) 1996 122 6.8 L, QP NFTs 9 AAPs correlate strongly with
cognitive status
Washington University ADRC (225, 344) 1998 199 NR L, QP Correlation to CI: NFTS 9 ‘‘cored senile
plaques’’ 9 total senile plaques
Nun Study (109, 151, 288) 1999 495 9.6 L, CC, QP, only (female)
nuns
NFTs correlate best with CI; all cases
above threshold demented
Cambridge, UK Group (345) 2000 48 G12 L, BP NFTs È NPs 9total amyloid plaques
correlate with global ‘‘clinical severity’’
of AD
Mayo Clinic ADC (346) 2002 67 0.7 L, BP Significant correlation between Braak
stage and CI
Rush University (190, 264, 347, 348) 2004 652 8.2 L, CC, QP NFTs 9 NPS correlate with CI
University of California,
San Diego, ADRC
(106) 2004 131 8.5 L,QP NFTs correlate best with late AD CI, but NPs
correlate better in early disease
Honolulu-Asia Aging Study (349) 2005 333 16.0 L, CC, QP, only males NFTs and NPs far more dense in subjects
with than those without dementia
Caveat: many concomitant pathologies
Adult Changes in Thought (108, 350) 2007 211 G24 L, BP, CC NFTS (Braak stage) correlates with CI
much stronger than AAPs
University of Kentucky ADC (105, 189) 2007 334 13.1 L, QP NFTs correlate best with cognitive status;
all cases above threshold demented
Combined ADC project (54) 2009 97 0.7 Various, QP, Subjects
without dementia only
Presence of diffuse amyloid plaques
correlates with subtle CI
Banner-Sun Health Research
Institute
(252, 351) (258) 2010 150 12.5 L, QP, BP NFTs 9 AAPs correlate strongly with CI
Baltimore Longitudinal Study
on Aging
(161, 188) 2010 209 8.8 L, BP NFTs in neocortex the key correlate of CI
across the aging spectrum including
past 90 y
90+ Study (191) 2011 108 5 L, QP, BP Neocortical NFTs and hippocampal
sclerosis key CI correlates in aged group
*References refer to the most relevant articles. See text for inclusion and exclusion criteria.
Methodological considerations: AAP, neuritic and diffuse amyloid plaques containing AA peptide; AD, Alzheimer disease; ADC, Alzheimer Disease Center; ADRC, Alzheimer
Disease Research Center; Avg Int, average documented inte rval between death and autopsy in months; BP, pathology assessed using Braak stages (60); CC, community-based cohort;
C-S, cross-sectional; CI, cognitive impairment; L, longitudinal; N, number of subjects in most relevant and recent article; NFT, neurofibrillary tangle; NP, neuritic plaque; NR, not
recorded; QP, quantitative pathology (lesion counts).
J Neuropathol Exp Neurol
Volume 71, Number 5, May 2012 Alzheimer Disease Clinicopathologic Correlations
Ó 2012 American Association of Neuropathologists, Inc.
11
Page 12
connection between AAPs, NFTs, and antemortem cognitive
impairment (311Y320).
Diversely designed studies from at least 18 different
research centers have produced high-quality data with some
common conclusions, notably that the density of neocortical
NFTs is the pathologic feature that best correlates with ante-
mortem cognitive status (T able 5). The correlation is less
strong for neuritic AAPs, and less still for diffuse AAPs.
Hippocampal pathology is nearly universal in AD cases, yet
AD neuropathologic changes in hippoc ampus do not correlate
as well as neocortical pathology with cognitive status at any
stage of the disease due to floor and ceil ing effects. Finally, it
is critically important to take into account concomitant path-
ologies that contribute substantial ‘‘noise’’ to the system.
There are increasingly detailed and insightful assess-
ments of both clinical and neuropathologic parameters, com-
bined with more optimal subject recruitment, improved
testing for new disease entities, and well-powered sample
sizes. All of these factors help us to perform more valid
analyses and generate consistent data. The overwhelming
conclusion from many academic centers around the world is
that AD neuropathologic changes, especially in the advanced
stages of the disease (i.e. with abundant neocortical diffuse
and neuritic AAPs and NFTs), correlate with the severity of
antemortem cognitive impairment.
EVOLVING CONCEPTS AND UNANSWERED
QUESTIONS
The field of AD research has made progress with
respect to in vivo diagnostic methods to track the progression
of AD and to identify patients who may benefit from candi-
date therapies. For the most part, these methods, which
include neuroimaging, cerebrospinal fluid, and blood markers,
are beyond the scope of the current review. Nonetheless, the
strong focus on neuroimaging and biomarkers has raised
important issues about the basic concept and definition of AD.
There may be a future method that does not involve brain
autopsy and that is optimized for diagnosing specifically the
devastating illness that we refer to as AD. However, until such
a method becomes available, neuropathologic examination
remains the criterion standard for disease definition. Because
cognitive impairment in aging may be attributed to many
different conditions other than AD, current biomarkers for AD
are limited to predicting which patients may become cogni-
tively impaired with neocortical AAPs and NFTs, rather than
just predicting cognitive impairment alone. For example,
hippocampal atrophy is visualized on magnetic resonance
imaging in both AD and hippocampal sclerosis patients and is
therefore not a distinct AD biomarker. This is an important
consideration because up to 20% of individuals in advanced
age are affected by hippocampal sclerosis that correlates with
cognitive impairment is independent of AD pathologic diag-
nosis (105, 211, 321Y323). A patient lacking AD pathologic
diagnosis at autopsy, despite ‘‘biomarker positivity,’’ is not
an AD case and suggests the biomarker has imperfect spe-
cificity. Conversely, AD pathologic diagnosis at autopsy in a
biomarker-negative case implies imperfect sensitivity. More-
over, it is important to remember that AD is often mixed with