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 J_ID: ZAY Customer A_ID: 10-0865.R1 Cadmus Art: ANA22333 Date: 1-December-10 Stage: Page: 1

RESEARCH ARTICLE

Amyloid-b Associated Cortical Thinning in

Clinically Normal Elderly
J. Alex Becker, PhD,1 Trey Hedden, PhD,2,8 Jeremy Carmasin, BS,1 Jacqueline Maye, BS,1
Dorene M. Rentz, PsyD,3,4 Deepti Putcha, BA,2 Bruce Fischl, PhD,1,2 Douglas Greve, PhD,1,2
Gad Marshall, MD,3,4 Stephen Salloway, MD,5,6 Donald Marks, MD,7
AQ1 Randy L. Buckner, PhD,1,2,8,9,10 Reisa A. Sperling, MD,3,4 and Keith A. Johnson, MD1,3,4

Objective: Both amyloid-b (Ab) deposition and brain atrophy are invariably associated with Alzheimer’s disease (AD)
and the disease process likely begins many years before symptoms appear. We sought to determine whether
clinically normal (CN) older individuals with Ab deposition revealed by positron emission tomography (PET) imaging
using Pittsburgh Compound B (PiB) also have evidence of both cortical thickness and hippocampal volume
reductions in a pattern similar to that seen in AD.
Methods: A total of 119 older individuals (87 CN subjects and 32 patients with mild AD) underwent PiB PET and
high-resolution structural magnetic resonance imaging (MRI). Regression models were used to relate PiB retention to
cortical thickness and hippocampal volume.
Results: We found that PiB retention in CN subjects was (1) age-related and (2) associated with cortical thickness
reductions, particularly in parietal and posterior cingulate regions extending into the precuneus, in a pattern similar
to that observed in mild AD. Hippocampal volume reduction was variably related to Ab deposition.
Interpretation: We conclude that Ab deposition is associated with a pattern of cortical thickness reduction
consistent with AD prior to the development of cognitive impairment.
ANN NEUROL 2010;000:000–000

T he possibility of disease-modifying therapies for Alz-

heimer’s disease (AD) has motivated the development
of biomarkers that reflect underlying pathologic proc-
esses. The sequence of pathologic events in AD likely begins
many years, perhaps decades, prior to the development of
symptoms.1,2 Amyloid-b (Ab) deposition appears early in the
disease, prior to symptoms, and then plateaus as clinical de-
mentia emerges.3–6 In contrast, neurodegeneration, including
loss of synapses, neurons, and arborization, results in brain at-
rophy that worsens inexorably in parallel with cognitive
decline.2,6,7 The principal early sites of Ab deposition are neo-
cortical, typically in the parietal and frontal regions,4,8,9
whereas the sites of early atrophy include the medial temporal
regions.2,6,10,11 Here we relate these 2 phenomena in vivo in
clinically normal (CN) older individuals and in clinically
established AD patients, in order to determine the correspon-
dence between levels of Ab deposition and of atrophy.
It is now possible to observe the relation between
Ab deposition and atrophy in vivo with positron emission
tomography (PET) imaging using Pittsburgh Compound
B (PiB)9 and high-resolution volumetric magnetic reso-
nance imaging (MRI) data.2,12 PiB studies have confirmed
what was predicted by earlier postmortem studies,13–15
that a substantial fraction (25–50%) of CN older individ-
uals exhibit Ab deposition.16–21 While still in an early
phase, PET studies of Ab deposition in these otherwise nor-
mal individuals suggest evidence of early brain dysfunction
including disrupted default network functional connectiv-
ity,19,21 aberrant default network activity during memory
encoding,18 and even subtle cognitive impairment22,23 that

View this article online at wileyonlinelibrary.com. DOI: 10.1002/ana.22333

Received Jul 6, 2010, and in revised form Oct 6, 2010. Accepted for publication Nov 8, 2010.

Address correspondence to Dr Johnson, Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital, Bartlett 507,
33 Fruit Street, Boston, MA 02114. E-mail: kajohnson@partners.org

From the Departments of 1Radiology, 4Neurology, and 9Psychiatry, and the 2Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General
Hospital, Harvard Medical School, Boston, MA; 3Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School; 5Department of
Neurology, Warren Alpert Medical School, Brown University; 6Memory and Aging Program, Butler University; 7Tufts School of Medicine; 8Department of
AQ1 Psychology and Center for Brain Science, Harvard University; and 10Howard Hughes Medical Institute, Chevy Chase, MD.

Additional Supporting Information can be found in the online version of this article.

C 2010 American Neurological Association

V 1

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 J_ID: ZAY Customer A_ID: 10-0865.R1 Cadmus Art: ANA22333 Date: 1-December-10
ANNALS of Neurology
is offset by cognitive reserve.23 Here we relate the presence
and pattern of Ab-related atrophy observed in AD patients
to the pattern seen in CN older individuals.
Atrophy can be quantified by automated measure-
ment of brain MRI images, which yields estimated thick-
ness measures of anatomically parcellated cortical regions
as well as subcortical volumes.24–27 Such measurements
have revealed a characteristic pattern of cortical thickness
reductions and subcortical volume loss in clinically diag-
nosed AD patients.25,27–29 The AD-like pattern of atro-
phy has also been reported in presymptomatic autosomal
dominant AD,28 and in those with mild cognitive
impairment who go on to develop the clinical diagnosis
of AD.30 More recently, Desikan and colleagues11 identi-
fied a pattern of atrophy in the supramarginal cortex,
entorhinal cortex, and hippocampus with which mild cog-
nitive impairment (MCI) and AD could be distinguished
from normal aging, and Davatsikos and colleagues31 iden-
tified a similar pattern of volume loss that related to cog-
nitive decline among MCI as well as normal control sub-
jects.32 However, these studies used control groups of
older individuals in which amyloid was likely present, but
the impact was not assessed. Studies directly relating struc-
tural data to Ab deposition in CN subjects have yielded
inconsistent results; while some have reported reduced hip-
pocampal volume33,34 or cortical thickness29,34 in CN sub-
jects with greater Ab deposition, others have found this only
among Ab-positive CN35 or in normal individuals with
subjective cognitive impairment.36 Similarly, the impact of
age on amyloid and atrophy has not been consistently con-
trolled. We sought to relate both hippocampal volume and
cortical thickness reductions to a continuous measure of Ab
deposition adjusting for age in a large sample of both Ab-
positive and Ab-negative CN subjects and in AD patients.
We first determined the pattern of cortical thickness
reductions and hippocampal volume loss in mild AD
patients compared to CN subjects, and then investigated
whether a similar pattern of Ab-associated volume loss was
present in CN subjects. We also investigated the age-
dependence of Ab deposition and of Ab-associated thickness
reductions in both CN and AD, and quantified the extent
and anatomic specificity of Ab-related volume loss within
each group. We hypothesized that Ab deposition would be
associated with local cortical thickness reductions in regions
associated with the default network37 at early stages of the
pathophysiological process, prior to cognitive impairment.
Patients and Methods
Subjects
Participants were recruited from ongoing longitudinal studies in
aging and during screening for dementia clinical trials at the
2 Volume 000, No. 000
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Stage: Page: 2
Massachusetts General and Brigham and Women’s Hospitals,
and from several local referring tertiary memory clinics (S.S.,
G.M., and D.M.). All participants were studied using protocols
and informed consent procedures approved by the Partners
Human Research Committee. All subjects underwent at least 1
comprehensive medical and psychiatric interview, as well as a
neurological evaluation, to rule out any major medical or neu-
rological disorders that might contribute to cognitive dysfunc-
tion. None of the participants had any notable medical or neu-
rological illness, and none had a history of alcoholism, drug
abuse, or head trauma, or a family history of autosomal domi-
nant AD. None were clinically depressed (Geriatric Depression
Scale <11; Yesavage and colleagues38) or had other psychiatric AQ2
illnesses. Each participant was scored on the Mini-Mental State
Examination (MMSE),39 and also underwent a standard battery
of neuropsychological (NP) tests, as reported.23 The mean
(standard deviation [SD]) time between PET imaging and test-
ing was 0.90 (1.9) months.
Subjects were classified into 2 groups, CN (n ¼ 87) and
AD (n ¼ 32). All CN subjects had a Clinical Dementia Rating
(CDR) score of 0,40 MMSE > 27, and performance within 1.5
SD on age-and-education–adjusted norms on cognitive testing
as detailed.23 AD subjects were CDR ¼ 1 and satisfied criteria
for a clinical diagnosis of probable AD according to National
Institute of Neurological and Communication Disorders and
Stroke/Alzheimer’s Disease and Related Disorders Association
criteria.41 Of the 87 CN subjects, 60 had apolipoprotein E
(APOE) genotype data available: 47 were classified as e4-nega-
tive (no 4-alleles) and 13 as e4-positive (one or two 4-alleles).
PET Acquisition and Processing
Carbon-11 PiB PET was acquired and processed as described,
using the distribution volume ratio (DVR) with cerebellar cor-
tex as reference tissue.18,42 Detailed PET methods are discussed
in the Supporting Information.
MR Acquisition and Freesurfer Processing
High-resolution MRI images were acquired using magnetiza-
tion-prepared rapid gradient-echo (MP RAGE) and processed
with Freesurfer (FS) to measure cortical thickness and hippo-
campal volume, as described.18,19 The FS-generated cortical
parcellation defines a large precuneus region of interest (ROI)
that overlaps areas of the posterior cingulate, including Brod-
mann area 23 and 31 along the posterior midline43; we there-
fore denoted this cortical ROI as the posterior cingulate/precu-
neus (PCC) in the following. Further details of FS processing
are in the Supporting Information.
Choice of Proxy Region for Ab Deposition
As proxy ROI for Ab deposition, we chose the PCC because it
is a highly vulnerable, common site of early involvement. In
addition, however, we evaluated 9 other ROIs that are also vul-
nerable to Ab deposition to determine whether Ab-associated
volume/thickness changes differed when the proxy measure of
PiB retention was from these alternative ROIs: rostral anterior
cingulate, medial orbitofrontal, rostral middle frontal, caudal
I Path: N:/3b2/ANA#/Vol00000/100231/APPFile/JW-ANA#100231
 J_ID: ZAY Customer A_ID: 10-0865.R1 Cadmus Art: ANA22333 Date: 1-December-10
anterior cingulate, precuneus, superior frontal, pars opercularis,
caudal middle frontal, inferior parietal, lateral orbitofrontal, and
global.
Dichotomization of PiB Data
Like earlier studies,2,18,19,23,34 we chose a threshold of amyloid
positivity that is somewhat arbitrary, since a rigorous definition
will likely require longitudinal follow-up. As in a previous
report,18 we split the CN group based on partial-volume–
corrected (PVC) PCC PiB retention: subjects with PCC
DVR > 1.60 were classified as CNþ (PiB-positive CN), and
those with DVR # 1.60 as CN$. This is a conservative thresh-
old and classifies fewer CN as PiBþ relative to other criteria
(eg, Hedden and colleagues19). As described below, all analyses
were also performed without the use of a threshold.
Statistical Analyses
We evaluated the relation of hippocampal volume and cortical
thickness to PiB primarily by treating PiB DVR as a continu-
ous variable. Regression models were used to examine the rela-
tionship of hippocampal volume and cortical thickness to Ab
burden in CN and AD groups; regression coefficients for all
models were estimated by ordinary least squares. At each corti-
cal vertex thickness was taken as the dependent variable, and
PVC PCC PiB DVR and age were taken as independent varia-
bles. Clusters of vertices with thickness-DVR regression coeffi-
cient p-values exceeding a predetermined threshold (p ¼ 0.05)
were identified, and cluster-wise statistical significances were
calculated via 5000 instances of a Monte Carlo simulation,
based on the noise distribution of the baseline analysis.44 We
evaluated the relationship of hippocampal volume to PiB reten-
tion using similar regression models, with gender added as a
covariate.11,45–47 Hippocampal volumes (sum of volumes in left
and right hemisphere) were covariance adjusted for total intra-
cranial volume as measured by estimated total intracranial vol-
ume (eTIV) over the full sample prior to inclusion in the
regression equation as the dependent variable.48
Parallel analyses were performed with regional average corti-
cal thicknesses (average of left and right hemisphere thicknesses)
from a set of anatomically defined cortical ROI: global (average
over all cortical ROI), inferior parietal, PCC, parahippocampal,
and entorhinal.26 ROI thickness was taken as the dependent vari-
able, and PiB DVR and age as independent variables.
A hypothetical model of the relationship of cortical thick-
ness and PiB retention was assessed under the assumption that
both followed sigmoid curves, parameterized by a common
time-like parameter (Supporting Information).
The age dependence of cortical thickness or hippocampal
volume was investigated by regressing thickness on age, or volume
on age and gender, in both the CN and AD diagnostic groups.
Volume or thickness contrasts between diagnostic groups (CN and
AD, or CN$ and CNþ) were assessed by analysis of covariance
(ANCOVA) implemented as a general linear model, with age and
gender covariates for volume, or age covariate for thickness.
Differences in eTIV-adjusted hippocampal volume between
diagnostic groups were assessed by ANCOVA implemented as a
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Becker et al: Ab and Cortical Thinning in Normal Aging
general linear model, with age and gender covariates; similar
models excluding the gender covariate were used to assess corti-
cal thickness differences between the same groups.
In order to test whether age differences of cortical thick-
ness or PiB uptake depended on APOE carrier status in the CN
group, e4 status (positive if one or two 4-alleles, negative other-
wise) was added to the model as a factor and allowed to interact
with the regression term. Similarly, the differential effect of
APOE status on the relationship of cortical thickness and PiB
uptake in the CN group was assessed by including carrier status
as a factor interacting with the thickness-PiB regression term.
The capacity of regional cortical average thickness to dis-
criminate between the CN$ and CNþ groups was assessed by
logistic regression followed by receiving operating characteristic
(ROC) curve analysis. Group membership probabilities pre-
dicted by the logistic regression model with thickness and age
regressors were used to construct a ROC curve, and the area
under the curve (AUC) and its statistical significance were com-
puted (Wilcoxon rank-sum test with continuity correction).
Results
Subject Characteristics
The AD and CN groups differed in MMSE scores and PCC
PiB retention, but not in age, gender, or education (Table 1). T1
Hippocampal volumes were slightly greater in men compared
to women even after residualization by intracranial volume
(data not shown). Gender was therefore included as a factor
in regression models involving hippocampal volume. Gender
effects were not detected in PiB or cortical thickness data.
Thickness/Volume Contrasts in AD vs CN
Reduced temporoparietal cortical thickness, controlling
for age, was seen in AD compared to CN (Supporting
Information Fig S1). Thickness decreases in AD relative
to CN ranged up to 0.20mm (first/second/third quartiles
¼ 0.10/0.13/0.15mm for vertices in the PCC). The ana-
tomic pattern included posterior cingulate extending into
the precuneus; inferior and superior parietal lobules;
superior, middle, and inferior temporal; fusiform; ento-
rhinal; parahippocampal, perirolandic, and posterior pre-
frontal regions. Anterior and medial prefrontal regions
were less involved (Supporting Information Fig S1). In
ROI contrasts, AD subjects had lower hippocampal vol-
ume (p < 1 % 10$5) and decreased entorhinal, parahip-
pocampal, PCC, inferior parietal, and global thickness
(p < 1 % 10$5), compared to the CN group (Support-
ing Information Fig S2).
Ab-Associated Cortical Thickness/Volume
Reductions in AD and CN
CONTINUOUS Ab (VERTEX-LEVEL ANALYSES). Treat-
ing PCC PiB retention as a continuous measure and
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TABLE 1: Demographics

CN All CN2 CN1 AD All

CDR 0 0 0 1 0 or 1
n (%F) 86 (66) 68 (65) 18 (67) 32 (44) 118 (60)
a
Age, yr 75 6 8 (55–90) 73 6 8 (55–89) 79 6 5 (69–90) 72 6 9 (57–84) 74 6 8 (55–90)
b
MMSE 29 6 1 (27–30) 29 6 1 (27–30) 29 6 1 (27–30) 22 6 4 (18–27) 27 6 4 (18–30)
Education, yr 16 6 3 (12–24) 16 6 3 (12–24) 16 6 3 (12–20) 18 6 1 (16–20) 16 6 3 (12–24)
PCC DVR 1.39 6 0.31 1.25 6 0.13 1.91 6 0.25 2.35 6 0.39 1.65 6 0.54
(0.98–2.40) (0.98–1.58) (1.61–2.40)c (1.36–2.97)d (0.98–2.97)
Values are mean 6 SD (range), except for n, which is number of patients (percentage female).
a
Differs from CN$ (p < 0.002).
b
Differs from CN$ and CNþ (p < 1 % 10$5).
c
Differs from CN$ (p < 1 % 10$5).
d
Differs from CN$ and CNþ (p < 1 % 10$5).
AD ¼ Alzheimer’s disease; CDR ¼ clinical dementia rating; CN ¼ cognitively normal; CN$ ¼ CN subjects with PCC PiB
DVR #1.60; CNþ ¼ CN subjects with PCC PiB DVR >1.60; DVR ¼ distribution volume ratio; F ¼ female; MMSE ¼
Mini-Mental State Examination; PCC ¼ posterior cingulate/precuneus; PiB ¼ Pittsburgh Compound B; SD ¼ standard deviation.

controlling for age, Ab-associated cortical thickness
reductions in both AD and CN subjects were seen in
the posterior cingulate, extending into the precuneus, in-
ferior parietal lobule, superior parietal, lateral temporal,
F1 and lateral prefrontal (Fig 1). In contrast to the AD vs.
CN thickness contrast maps in Supporting Information
Figure S1, medial temporal cortical Ab-associated thick-
ness reductions were not observed. No regions exhibited
significant cortical thickness increases with increasing
PiB retention.
In the CN group, cluster-wise statistical significance
of vertex-level regression coefficients was assessed by
Monte Carlo simulation to correct for capitalization on
multiple comparisons. We identified 7 clusters of vertices
as exhibiting significant thickness reductions with increas-
ing Ab at p < 0.05 (corrected): right posterior cingulate/

C
O
L
O
R
FIGURE 1: Ab-associated reduction in cortical thickness in CN subjects and AD patients. Regression coefficients expressing
reduction in thickness at each vertex per unit increase in PCC DVR controlling for age (bottom row), and corresponding
statistical significance as p value (top row) in CN or AD groups (left or right column, respectively). Only clusters of 3000 or
more contiguous vertices with regression coefficients exceeding 0.12mm/DVR are shown on the bottom row of surfaces.

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Becker et al: Ab and Cortical Thinning in Normal Aging

TABLE 2: Reduction of Vertex Cortical Thickness with Increasing PCC PiB Retention,
Controlling for Age in CN Subjects

Cortex Xa Y Z Max p Area (mm2)b CWP

Middle temporal, left $58 $12 $20 0.00002 1739 0.075
Inferior parietal, left $30 $65 40 0.00037 3617 0.0002
Supra marginal, left $42 $46 38 0.00032 3627 0.0002
Rostral middle frontal, left $41 35 19 0.0060 2850 0.0028
Precuneus, right 5 $57 22 0.000026 8256 0.00020
Supramarginal, right 42 $36 36 0.000013 2106 0.031
Rostral middle frontal, right 24 45 27 0.0019 3634 0.0012
Superior temporal, right 46 $36 8 0.0021 3146 0.0024
Vertex cluster-wise statistics determined by Monte Carlo simulation.
a
Talairach coordinates (X, Y, Z) of vertex in cluster with maximum p value.
b
Surface area of cluster in standardized cortical surface.
CN ¼ cognitively normal; CWP ¼ cluster-wise p value; DVR ¼ distribution volume ratio; PCC ¼ posterior cingulate/precuneus;
PiB ¼ Pittsburgh Compound B.

precuneus, left inferior parietal, left and right rostral
middle frontal, left and right supramarginal, and right
T2 superior temporal (Table 2; Supporting Information
Fig S3). There were no areas of significant interaction
between APOE carrier status and age-adjusted Ab-associ-
ated thickness variation in the CN group (n ¼ 60; data
not shown), indicating that thickness-PiB regression slopes
did not differ according to carrier status. To confirm that
the observed significant inverse relation of Ab and thick-
ness was not an artifact of the PET partial volume correc-
tion, we substituted non-PVC PiB DVR for PVC DVR in
the vertex-based regressions. Statistical significance of coef-
ficients in the non-PVC analyses were lower in the CN
group, as expected due to contraction of PET DVR ranges,
but the pattern of the effects did not change (Supporting
Information Fig S4).
CONTINUOUS Ab (ROI-LEVEL ANALYSES). Data in
ROI were expressed as age-adjusted structural change per
unit change in PiB retention for hippocampal volume
F2 (mm3/DVR) and cortical thickness (mm/DVR) (Fig 2).
Significant Ab-associated cortical thickness reduction (sig-
nificant negative regression coefficient expressing change
in thickness per unit increase in DVR) was confirmed in
PCC, inferior parietal, and global ROI, but entorhinal and
parahippocampal thickness and hippocampal volume var-
iations with Ab were not statistically significant.
CN GROUP DICHOTOMIZED INTO CN$/CNþ BY Ab
LEVEL. The vertex-level contrast of CN$ vs CNþ
groups revealed age-adjusted thickness reduction in the
CNþ group prominently in posterior cingulate/precuneus,
lateral parietal, and prefrontal cortices (Supporting Infor-
mation Fig S5). Thickness decreases in CNþ relative to
CN$ ranged up to 0.095mm (first/second/third quartiles
¼ 0.017/0.032/0.045mm for vertices in the PCC). In
ROI contrasts of CN$ vs CNþ groups, lower ROI aver-
age thicknesses were observed in the CNþ group but the
differences did not reach statistical significance possibly
because of lower sensitivity (Supporting Information Fig
S2). Using PCC thickness to discriminate CN$ and CNþ
subjects yielded a statistically significant (p < 0.05) logistic
regression model in which a 0.1mm decrease was associ-
ated with an odds ratio of 1.60. The corresponding AUC
¼ 0.70 (p < 0.01), holding age constant at its grand
mean. Other regions examined (parietal, frontal, or global
average) did not achieve a similar discriminative efficiency.
Thickness-Ab Sigmoid Modeling
While Ab-associated thinning was observed in CN sub-
jects as described above: (1) thinning was more anatomi-
cally extensive in the AD group; and (2) significantly
more thinning per unit DVR was observed in the AD
group (eg, 0.4mm/DVR in medial and lateral parietal
areas) than in the CN group (see Fig 1). A vertex-level
assessment of the difference revealed a significant interac-
tion of the thickness-vs-Ab coefficient and clinical status
factor (CN vs AD) in posterior midline and inferior pari-
etal regions (p < 1 % 10$4; data not shown). We related
these observations to candidate time courses along the
hypothetical CN–AD trajectory (see Supporting Informa-
tion), in which the data were evaluated using sigmoid
models to relate PCC cortical thickness and PiB reten-
tion. Assuming sigmoid time functions for PiB increase
and loss of cortical thickness, both with the same rate-of-

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FIGURE 2: Ab-associated hippocampal volume and regional
thickness changes in CN and AD groups. Regression
coefficients expressing change in hippocampal volume or
regional average thickness per unit increase in PCC DVR
controlling for age (age and gender for hippocampal
volume), and corresponding 95% confidence intervals and
statistical significances (right).
change achieved at the midpoint of the S-shaped portion
of the curves, we calculated how far apart in time these
midpoints would have to be in order to achieve the best
fit to our data. In fitting this model to the age-adjusted
F3 CN and AD group data (Fig 3; r2 ¼ 0.48; p < 1 %
10$4) we calculated this time lag parameter (see Supple-
mental Material) to be equal to 0.35 times the amyloid
saturation time (the time to go from zero to maximum
amyloid). For example, if a 10-year amyloid saturation
time were hypothesized, the time lag between the rapid
phases of PiB increase and cortical thinning would be
3.5 years.
Age Dependence of Thickness/Volume and of
PiB Retention in CN and AD
Vertex-level analyses revealed that greater age was associ-
ated with reduced thickness among CN subjects in peri-
rolandic, lateral and inferior temporal, superior parietal,
posterior cingulate, and precuneus cortices (p < 0.0001,
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uncorrected for multiple comparisons; see Supporting In-
formation Fig S6). The vertex-based findings were con-
firmed in cortical ROI, where age-related reductions were
also seen in parahippocampal, inferior parietal and global
cortical thickness, and marginally in entorhinal thickness in
the CN group. Age-associated hippocampal volume reduc-
tion was also significant in the CN group. In the AD
group, greater age was associated with decreased volume in
hippocampus and reduced thickness prominently in para-
hippocampal cortex (Supporting Information Fig S6).
Analyses of PiB data derived either from vertices or
from confirmatory ROI revealed that while higher PiB
retention in precuneus/posterior cingulate, anterior cin-
gulate, and prefrontal regions was associated with greater
age in the CN group, the inverse relation was seen in the
AD group (Supporting Information Fig S7). For example,
age was associated with increased PCC ROI PiB retention
in the CN group (p < 0.001), but with decreased PCC
retention in the AD group (p < 0.005). This corre-
sponded to a significant difference in the regression line
slopes between the 2 groups (p < 1 % 10$4). Prominently
FIGURE 3: Modeling of PCC thickness as a function of PiB
retention in CN and AD groups. Least squares fit (solid
curve) of thickness-PiB functional relationship based on
sigmoid time courses, with the maximum rate of thickness
decline later in time than the maximum rate of PiB increase;
compare solid (thickness) and dotted (PiB) sigmoids (inset
graph). Dashed curves correspond to shorter time lags,
long-dashed curves correspond to one-half the best-fit time
lag, and short-dashed curves correspond to no lag. The
inset shows the underlying sigmoid time courses for PiB
(dotted) and thickness at the 2 time lags. As the time lag
between thickness and PiB increases, the curvature of the
thickness-PiB curve increases. Binding potential (which is
equal to DVR 2 1) was used as the PiB measure in the
modeling since we assumed that PiB BP asymptotes to zero
prior to disease onset.
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reduced Ab deposition as a function of age was observed
in medial occipital regions in AD (Supporting Information
Fig S7). When non-PVC data were used, the age associa-
tions were similar but less robust possibly due to the nar-
rower ranges of uncorrected DVR (data not shown).
There were no areas of significant interaction
between APOE carrier status and variation with age of
cortical thickness or PiB retention in the CN group (n ¼
60; data not shown).
Differential Impact of Age and Ab Deposition
on Hippocampal Volume and Cortical Thickness
Maps of cortical thickness for the age regression coefficient
were computed with the Ab deposition term also included
in the model. These were nearly identical to the maps of
the simple age-dependence (Supporting Information Fig S6),
indicating that the age was inversely related to thickness in-
dependent of Ab deposition (data not shown).
Using ROI data we evaluated a regression model
that included age, gender, and PCC PiB retention as pre-
dictors of PCC ROI thickness or hippocampal ROI vol-
ume. PCC thickness was independently associated with
both age (p < 1 % 10$3) and Ab deposition (p <
0.004). In contrast, hippocampal volume was associated
with age (p < 1 % 10$5) but not with Ab deposition
(p ¼ 0.38). Gender was not related to either hippocampal
volume (preadjusted for eTIV; p < 0.07) or PCC thickness
(p < 0.45). When added to the models, the age-by-Ab
interaction term was not significant in either case. Thus,
covarying Ab deposition, greater age was associated with
reduced hippocampal volume and PCC thickness; however,
covarying age, Ab deposition was associated with reduced
PCC thickness but not with reduced hippocampal volume.
Choice of Proxy for PiB Retention
We tested the hypothesis that results using alternative,
non-PCC regions would differ from those in which the
PCC was used as the proxy for Ab deposition. We found
that using as proxy the rostral anterior cingulate, rostral
middle frontal, or inferior parietal cortices all yielded simi-
lar patterns of Ab-associated cortical thinning, which was
not surprising given the high correlation of PiB retention
in these regions with PiB retention in the PCC (Pearson
correlations ranged from 0.80 to 0.89) In contrast, hippo-
campus PiB retention was not significantly related to thin-
ning in any cortical region (data not shown).
Discussion
The major finding of this study is that significant Ab-
associated cortical thinning occurs among CN older indi-
viduals in a pattern consistent with early AD. While this
finding supports the possibility that Ab deposition in
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Becker et al: Ab and Cortical Thinning in Normal Aging
normal individuals represents preclinical AD, direct ob-
servation with longitudinal data will be required to evalu-
ate the strength and timing of this link. Our data suggest
that Ab-associated neurodegeneration manifests as corti-
cal thinning in regions vulnerable to early Ab deposition,
including association cortices along the posterior medial
wall and lateral parietal cortex. In particular, we observed
thinning in the inferior parietal lobule and the posterior
cingulate extending into the precuneus, which are regions
that form nodes of a large-scale cortical system known as
the default network.37,49,50 This system has been impli-
cated in both memory-related function and in amyloid-
related and AD-related memory dysfunction.18,37,50–53
Our findings are consistent with a pathophysiologic link
between Ab deposition and neurodegeneration in this
network, which may anticipate memory failure and pro-
gression to clinical dementia.18,19,21,37,54
Along the posterior midline, the posterior cingulate
and retrosplenial cortex are anatomically connected to
medial temporal structures, and we found that while the
hippocampus and medial temporal lobe (MTL) cortices
demonstrated significant age-associated atrophy, the asso-
ciation of MTL atrophy with Ab deposition was variable
in these asymptomatic older individuals. While our
results are consistent with the hypothesis that MTL atro-
phy coincides with the emergence of manifest cognitive
impairment,2,55,56 we did not observe a significant differ-
ence between MTL and cortical atrophy, and thus cannot
order the relative timing of effects with the present data.
While macroscopically-visible cortical atrophy is associ-
ated with dementia, it is not generally observed in non-
demented individuals at postmortem,57 perhaps because
of an inability to differentiate it from normal age-associ-
ated atrophy. Our data suggest that the Ab deposition
commonly detected in normal older individuals is associ-
ated with subtle posterior cingulate and parietal neurode-
generation that occurs prior to, and may be a harbinger
of, clinically significant impairment.29 It is possible that
further investigation will reveal evidence of subtle cogni-
tive alterations related to cortical thinning even within
CN individuals, particularly when the level of cognitive
reserve is considered.23
More broadly, our findings should be considered in
the context of a putative sequence of events in AD
pathology that can be observed with biomarkers. Using a
largely biphasic model of disease sequence, Ab deposition
has been hypothesized to occur early in the sequence of
AD pathology and to be followed later by neurodegener-
ation, which is then related to the symptomatic phases of
the disease, cognitive decline and dementia.58–60 Our
present findings and those of earlier studies29,33,34 that
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suggest PiB retention is correlated with cortical thinning
in normal individuals raise the possibility that the
hypothesized lag period between Ab deposition and neu-
rodegeneration may be shorter than previously thought.
A precise mechanism by which Ab deposition could be
linked to neurodegeneration has not been firmly estab-
lished. It is possible that toxic effects of Ab oligomeric
assemblies that surround fibrillar forms could be exerted
locally early in the process and result directly in synapse
and cell loss.61,62 Such a mechanism entails a direct rela-
tionship between the presence of Ab and neurodegenera-
tion, which could potentially be observed with sensitive
biomarkers. However, while the sensitivity of Ab imaging
may be improved in the future and permit better detec-
tion, individuals with predominantly prefibrillar or poly-
morphic forms of Ab that are refractory to PiB would
not be detectable with PiB or likely with other thioflavin
or Congo-red derivatives.63–65
We found that Ab and PCC thickness were more
strongly correlated in AD than in CN (see Fig 1) and we
evaluated these data according to a recently proposed
model59 in which Ab deposition and cortical thickness
follow sigmoid-shaped curves in time. We simultaneously
fit sigmoid models to PCC PiB and age-adjusted thick-
ness data for the combined CN and AD groups, and
determined the temporal lag between the dynamic phases
of amyloid accumulation and cortical thinning to be
approximately 35% of the total time required for amy-
loid to rise from its baseline to maximum. It should be
emphasized that the model in its particularities as pre-
sented here is tentative, and should be considered as a
schematic rather than definitive treatment of the prob-
lem. Such modeling will remain speculative as to accurate
parameters of the underlying sigmoid curves until longi-
tudinal data are available.
Whereas AD neurodegeneration is well established
to occur prominently in the MTL55,56,66 and to be corre-
lated with neurofibrillary pathology,67 our findings are
consistent with emerging evidence that thinning in poste-
rior association cortices is also a prominent feature of
MCI and AD.11,29,37,68 While the measured amount of
age-adjusted thickness reduction per unit of PiB reten-
tion (DVR) was approximately the same in the posterior
cingulate/precuneus and in MTL structures, the standard
errors were larger in the MTL (see Fig 1) and the regres-
sion coefficients did not reach significance. Future work
with a larger data sample will be required to order the rel-
ative emergence of effects between posterior cingulate and
MTL structures. Neurofibrillary tangle pathology may par-
tially explain this observation of greater variability in the
MTL, since it is common in MTL but rarely widespread
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in cortex of CN subjects.57,58,67,69 Our data are not con-
sistent with previous observations that Ab deposition is
only seen after significant neurofibrillary tangle deposition
and MTL atrophy,69 but instead suggest that the patho-
logic sequence of events in preclinical AD is one in which
Ab deposition is related to neurodegeneration in posterior
cingulate and distributed regions of association neocortex
that occurs along with or possibly even prior to hippocam-
pal and entorhinal neurodegeneration.
Previous reports of the relation of PiB retention and
hippocampal volume in CN subjects have been inconsis-
tent. Some reported an inverse relation (ie, decreased vol-
ume with increased PiB retention) in CN subjects,33,34
while others found such a relation only among the Ab-
positive CN group35 or only in CN subjects with subjec-
tive cognitive impairment.36 These studies have differed in AQ3
their treatment of the potentially confounding effect of
age on both Ab level and atrophy. We evaluated hippo-
campal volume, cortical thickness, and PiB retention for
evidence of age-dependence and found evidence for an age
effect in all domains. The age-dependence of volume/
thickness across a broad age range has been previously
reported,70 and although some investigators have not
found a significant impact of age within a more restricted
older age range,29 others have applied an age-adjustment
to thickness/volume data.11 The strong age-dependence of
Ab deposition we observed in CN subjects is consistent
with neuropathological studies that inferred from cross-
sectional data that Ab gradually accumulates with age.68
Several PiB studies9,16,71 did not report evidence of a sig-
nificant relationship with age, perhaps due to the small
sample sizes with limited age ranges, although a recent
study did demonstrate an age association.72 Morris and
colleagues73 found that the age-dependence of PiB data
was largely accounted for by the strong age association
with PiB retention among carriers of the APOE4 allele,34
likely a reflection of the sample enrichment for younger
CN subjects with positive family histories. We did not
find an interaction of the age-Ab relationship with
APOEe4 carrier status among the subset of subjects on
whom genotypes were available (data not shown).
Interestingly, the age-dependence of Ab deposition
among CN subjects was reversed in AD patients, such
that greater age was associated with lower levels of Ab
deposition. The reversal of the Ab-age coefficient in the
AD group compared to the CN group could be due to a
survivor effect, such that older subjects with greater
amounts of Ab were too impaired (eg, MMSE < 18) to
have been included in our study. Other potential factors,
including an age-related change in PiB binding sites or
affinity or a change in the production or clearance of
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Ab,74,75 will require further study. Moreover, longitudi-
nal observation over long intervals may be required to
determine whether individual AD patients’ levels of Ab
decline over time, which has not been observed in longi-
tudinal PiB data that has spanned 1 to 2 years.2,5,76
In summary, our findings provide support for the
hypothesis that Ab is associated with local neurodegenera-
tion in key nodes of a distributed network supporting mem-
ory processes, and that this process begins prior to clinically-
evident cognitive impairment, but continues into the stage
of clinical dementia. Longitudinal follow-up of these CN
older individuals is ongoing to determine if the combination
of Ab burden and volumetric loss is predictive of incipient
cognitive decline, and progression to AD dementia.
Acknowledgments
This research was supported by grants from the National
Institutes of Health (NIH) (National Institute on Aging
[NIA] R01-AG027435-S1 to R.A.S. and K.A.J.; P50-
AG00513421 to K.A.J. and R.A.S.; P01-AG036694 to
R.A.S., K.A.J, and R.L.B; R01-AG021910 to R.L.B.);
Massachusetts Alzheimer’s Disease Research Center
(ADRC); Howard Hughes Medical Institute (HHMI) (to
R.L.B.); Alzheimer Association (IIRG-06-32444 to R.A.S.
and K.A.J.; IIRG-08-90934 to D.M.R. and K.A.J.); Charles
H. Farnsworth Trust, Boston, MA (to D.M.R.); and an
AQ4 anonymous medical foundation.
We thank the investigators and staff of the Massachu-
setts Alzheimer’s Disease Research Center (ADRC), the indi-
vidual research participants, and their families and caregivers.
Potential Conflict of Interest
J.C., T.H., D.P., J.A.B., J.M., D.M.R., and R.L.B. have
none to report. B.F. has received one or more grants and
has a grant pending from the NIH. D.M. is involved with
an ongoing phase 3 clinical trial with Elan Pharmaceuticals
and Janssen Immunotherapy, and is on the speakers’
bureaus of Novartis and Pfizer. S.S. serves on the scientific
advisory boards of Elan Pharmaceuticals, Sanofi-Aventis,
Pfizer Inc., Eisai Inc., and Bristol-Myers Squibb; serves as
Associate Editor for the Journal of Neuropsychiatry and
Clinical Neurosciences; receives publishing royalties for The
Frontal Lobes and Neuropsychiatric Illness (American
Psychiatric Press, Inc., 2001), The Neuropsychiatry of
Limbic and Subcortical Disorders (American Psychiatric
Press, Inc., 1997), and Vascular Dementia (Humana Press,
2004); receives honoraria from Eisai Inc., Pfizer Inc,
Novartis, Forest Laboratories Inc., Elan Pharmaceuticals,
and Athena Diagnostics, Inc.; holds corporate appointments
with Merck Serono and Medivation, Inc.; receives research
support from Elan Pharmaceuticals, Wyeth, Bristol-Myers
Month, 2010
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Becker et al: Ab and Cortical Thinning in Normal Aging
Squibb, Janssen Immunotherapy, Pfizer Inc., Bayer, and Eisai
Inc.; received research support from Myriad Genetics, Inc.,
GlaxoSmithKline, Neurochem-Alzhemed, Cephalon, Inc.,
and Forest Laboratories Inc.; receives research support
from the Alzheimer’s Disease Neuroimaging Initiative,
Dominantly Inherited Alzheimer’s Network (NIA
1U01AG032438-01); received research support from
Aging Brain: DTI, Subcortical Ischemia and Behavior
(NIA 1 R03 AG023916-01A1); and receives research
support from The Norman and Rosalie Fain Family
Foundation, the Champlin Foundation, and the John and
Happy White Family Foundation. D.G. has a grant from
the NIH. K.A.J. has received grants and has grants pending
from the NIH/National Institute on Aging and The
Alzheimer Association. G.M. has grants pending from the
NIH and AFAR that are not in conflict with the current
work. R.A.S. has a grant pending from the NIH/National
Institute on Aging. AQ5
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AQ1: For all authors, please verify first or middle names added. Also, please provide city and state in all affiliations.

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