Journal of Alzheimer’s Disease 65 (2018) 977–988 977

DOI 10.3233/JAD-180344
IOS Press

Episodic Memory and Learning

Dysfunction Over an 18-Month
Period in Preclinical and Prodromal
Alzheimer’s Disease
Jenalle E. Bakera,b,∗ , Yen Ying Lima, # , Judith Jaegerc,d , David Amese,f , Nicola T. Lautenschlagerf ,
Joanne Robertsona , Robert H. Pietrzakg,h , Peter J. Snyderi , Victor L. Villemagnea,j,k ,
Christopher C. Rowej,k , Colin L. Mastersa and Paul Maruff a,l, #
a The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia
b Cooperative Research Centre for Mental Health, Carlton, Victoria, Australia
c CognitionMetrics, LLC., Wilmington, DE, USA
d Albert Einstein College of Medicine, Bronx, NY, USA
e National Ageing Research Institute, Parkville, VIC, Australia
f Department of Psychiatry, Academic Unit for Psychiatry of Old Age, The University of Melbourne,

St. George’s Hospital, Kew, VIC, Australia

g U.S. Department of Veterans Affairs National Center for Posttraumatic Stress Disorder,

Clinical Neurosciences Division, VA Connecticut Healthcare System, West Haven, CT, USA
h Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
i Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI, USA
j Department of Nuclear Medicine and Centre for PET, Austin Health, Heidelberg, VIC, Australia
k Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, VIC, Australia
l Cogstate Ltd., Melbourne, VIC, Australia

Handling Associate Editor: Alden Gross

Accepted 10 July 2018

Abstract. Recent meta-analyses suggest that episodic memory impairment associated with preclinical Alzheimer’s disease
(AD) equates to 0.15–0.24 standard deviations below that of cognitively healthy older adults. The current study aimed to
characterize impairments in verbal acquisition and recall detectable at a single assessment, and investigate how verbal learning
and episodic memory deteriorates in preclinical AD. A verbal list-learning task, the International Shopping List Test (ISLT),
was administered multiple times over an 18-month period, to three groups of participants: amyloid-beta negative healthy
older adults (A␤– CN; n = 50); A␤+ positive healthy older adults (preclinical AD; n = 25); and A␤+ positive individuals
diagnosed with mild cognitive impairment (prodromal AD; n = 22). At baseline, there was no significant difference between
the preclinical AD and control groups rate of acquisition, or total and delayed recall, however all indices were impaired in
prodromal AD. Performance on ISLT total score improved in the control group over the 18-month period, but showed a
moderate magnitude decline in the preclinical AD group (Cohen’s d = –0.63, [–1.12, –0.14]) and the prodromal AD group
(Cohen’s d = –0.36, [–0.94, 0.22]). No significant impairment in acquisition associated with preclinical AD was seen at

# Co-senior
authors.
∗ Correspondence to: Jenalle Baker, 30 Royal Parade, Parkville,
VIC 3052, Australia. Tel.: +61 614 23 271 223; E-mail: jenalle.
baker@florey.edu.au.

ISSN 1387-2877/18/$35.00 © 2018 – IOS Press and the authors. All rights reserved
978 J.E. Baker et al. / Impaired Learning in Early Alzheimer’s Disease
baseline. Individuals with preclinical AD showed a significantly different performance on the ISLT total score over an 18-
month period, compared to those without abnormal A␤. Individuals with prodromal AD showed substantial impairment on
the ISLT at baseline and declined to a greater extent over time.
Keywords: Alzheimer’s disease, amyloid-␤ protein, cognitive decline, learning curve, memory and learning tests, mild
cognitive impairment, neuropsychology, transfer of learning
INTRODUCTION
Neuropsychological models of Alzheimer’s dis-
ease (AD) emphasize episodic memory dysfunction
as a core clinical manifestation of both dementia and
its preclinical and prodromal stages. Consequently,
assessment of episodic memory is central to the detec-
tion of the disease clinically, as well as for monitoring
its progression. In non-demented older adults, accu-
mulation of amyloid-␤ (A␤) plaques and aggregation
of hyperphosphorylated tau are pathological hall-
marks of AD that are associated with brain volume
loss and subtle cognitive decline that can begin up to
30 years before dementia [1, 2]. This long preclinical
period provides an opportunity for understanding the
clinical development of AD. As such, understanding
how and when elevated A␤ disrupts episodic memory
is a central question to understanding the pathogene-
sis of AD.
In preclinical AD, where abnormally high lev-
els of A␤ (A␤+) occur in the absence of clinical
impairment, neuropsychological studies show that
while episodic memory is impaired, the magnitude is
relatively small (e.g., Cohen’s d of 0.15; [3]). By def-
inition, episodic memory impairment is much greater
in prodromal AD (A␤+ patients with mild cognitive
impairment [MCI]), typically 1.5 standard devia-
tions below age matched normative data [4]. In both
preclinical and prodromal AD, episodic memory dys-
function becomes clearer over time, with progressive
decline evident within prospective studies of preclin-
ical and prodromal AD (d’s 0.20–0.50). In contrast,
adults with low A␤ levels (A␤–) show no deteriora-
tion, or even some improvement, in performance on
episodic memory tests over the same periods [5–8].
The importance of time and of serial assessments
to detecting A␤+ related memory impairment in
non-demented older adults does raise the possibil-
ity that consideration of time-dependent learning
processes necessary for performance on episodic
memory tests in a single administration may increase
the sensitivity of those tests to early AD, compared to
summary scores derived from the same performance.
For example, verbal list learning tests require individ-
uals to learn a set of stimuli over multiple (typically
3–5) trials, with recall of these items required after
a brief delay [9]. By considering the rate of learn-
ing over trials as well as the related savings score,
impairments in episodic memory may become appar-
ent, which are not evident when summary scores
such as total and delayed recall are used. In older
adults with MCI, learning curves derived from ver-
bal list learning tests are flattened compared to those
from matched healthy controls [10–13]. In these MCI
groups, savings scores are typically 50% lower than
age-matched controls [14, 15]. Thus, consideration
of time-dependent learning curves and savings scores
may provide greater sensitivity to A␤+ related mem-
ory impairment than is currently seen when using
summary immediate and delayed recall scores.
Where appreciation of A␤+ related memory dis-
ruption requires verbal list learning tests be applied on
multiple occasions, the extent to which performance
on these tests change with the repeated assess-
ments in A␤– adults also becomes important. For
many standardized verbal list learning tests, repeated
administration in older adults is associated with some
improvement in performance (i.e., a practice effect),
with the magnitude of this varying as a function of the
number of administrations, time between administra-
tions, and number or equivalence of the alternative
forms [16–18]. Consequently, these practice effects
can obscure the presence and magnitude of A␤+
related memory decline [18]. Therefore, to detect
A␤+ related decline in episodic memory, it would
be optimal to use measures of episodic memory for
which repeated administration does not give rise to
practice effects, rather, resulting in stable and reliable
estimates of cognition [19].
Recently we developed a computerized verbal list
learning test with multiple parallel forms to enable
repeated administration over short periods of time
(International Shopping List Test; ISLT [19]). Unlike
other list learning tasks, for example, the Califor-
nia Verbal Learning Task (CVLT-second edition;
[20]), on each administration of the ISLT each word
 J.E. Baker et al. / Impaired Learning in Early Alzheimer’s Disease
in the list is generated pseudo-randomly and with-
out replacement from a library of validated stimuli
(n = 128). This means that at each assessment, partic-
ipants receive lists consisting of different words, and
any words used in an assessment are not repeated
upon subsequent assessments. This method allows
many alternate forms to be generated and controls
systematic error that can occur with different yet
static word lists [19, 21, 22]. This use of random
word lists allows the ISLT to be given repeatedly at
relatively short retest intervals without resulting in
practice effects, and to generate data with high relia-
bility (e.g., r’s for total score >0.80) in both healthy
younger and older adults and also in MCI and AD
patients [22, 23]. Further, ISLT outcome measures
can be separated into specific aspects of memory
(e.g., acquisition and retention; [22]). Quantitative
and qualitative analysis of ISLT performance may
therefore be useful to clarify the nature and magnitude
of episodic memory impairment in the earliest stages
of AD. However, the extent to which A␤+ disrupts
ISLT performance at baseline (over learning trials)
or over repeated assessments in both preclinical and
prodromal individuals remains unknown.
The first aim of this study was to determine whether
a greater focus on time dependent aspects of learn-
ing and memory could improve the sensitivity of
verbal list learning, over summary recall scores, to
A␤+ related memory impairment in early AD. The
second aim was to understand the nature and magni-
tude of A␤+ related disruption to verbal learning and
memory over 10 assessments of the ISLT over 18
months. We hypothesized that A␤+ would be asso-
ciated with disruption to the acquisition and delayed
recall of information in early AD, with this impair-
ment greater than that seen using summary scores.
We also hypothesized that A␤+ would be associated
with a deterioration in verbal learning and memory
over 18 months, while no change would be evident
in A␤– individuals over the same period.
METHODS
Participants
Participants in the current sample were recruited
from the Australian Imaging Biomarkers and
Lifestyle Rate of Change Sub-study (AIBL-ROCS),
a prospective cohort study of 196 older adults who
are cognitively normal or diagnosed with MCI or AD
979
where multiple assessments occur between routine
AIBL assessments. Recruitment, inclusion/exclusion
criteria, and measures used in the AIBL study
have been described previously [23, 24]. Briefly,
participants undergo neuropsychological, medical,
psychiatric and neurological examination at 18-
month intervals [24, 25]. Clinical classification has
been described previously [24]; briefly, consensus
diagnoses were assigned to participants based on
Winblad and Petersen criteria for MCI and NINCDS-
ADRDA criteria for AD [26, 27]. Clinical diagnoses
were made blind to A␤ neuroimaging results. For the
purposes of the current study, clinical groups were
based on combined clinical and neuroimaging results
of the AIBL ROCS sub-study, therefore 68 of the
total sample were removed, as they had no imaging
data. Also excluded were 12 individuals with a diag-
nosis of dementia, 12 individuals with a diagnosis
of MCI who were A␤–, and healthy participants who
scored outside the bounds of clinically normal (n = 7).
Therefore, the sample comprised 50 A␤– cognitively
normal (CN) older adults, 25 A␤+ CN older adults
(preclinical AD), and 22 A␤+ adults MCI (prodro-
mal AD). Demographic and clinical characteristics
of these groups are shown in Table 1.
Assessments
Demographic and clinical characteristics
Demographic information was collected at the
baseline assessment. Age, gender, and medical his-
tory were self-reported. The Wechsler Test of Adult
Reading (WTAR; [28]) was used to estimate the pre-
morbid intelligence of participants. Clinical disease
severity was rated using the Clinical Dementia Rating
scale (CDR; [29]). The Mini Mental State Exami-
nation (MMSE; [30]) was used to screen for global
cognitive function. APOE genotype was determined
from genotyping of blood. Assessment of depressive
and anxiety symptoms was conducted using Hospital
Anxiety and Depression Scale (HADS; [31]).
Neuroimaging
A␤ imaging with positron emission tomography
(PET) was conducted using one of three radioligands,
that is, Pittsburgh Compound B (PiB), florbetapir, or
flutemetamol. The acquisition protocol for each radi-
oligand has been detailed previously [25]. Briefly,
a 30-min acquisition was started 40 min after PiB-
injection, and 20-min acquisitions were performed
50 min after florbetapir injection and 90 min after
980 J.E. Baker et al. / Impaired Learning in Early Alzheimer’s Disease

Table 1
Baseline demographic and clinical characteristics of each clinical group
A␤– CN (n = 50) Preclinical AD (n = 25) Prodromal AD (n = 22)
% Female 60% 52% 64%
% APOE ␧4 10% 24% 55%∗∗
Age 70.72 (5.81) 75.24 (9.47)∗ 79.45 (6.13)∗∗
Premorbid IQ 109.48 (5.02) 109.04 (7.50) 109.41 (5.84)
MMSE 29.44 (0.73) 28.96 (1.31) 27.36 (1.59)∗∗
CDR Sum of boxes 0 (0.5) 0 (0) 0.5 (3)∗∗
HADS Depression 2.44 (2.43) 1.55 (1.34) 3.95 (2.95)∗
HADS Anxiety 4.38 (2.42) 3.00 (2.56) 4.05 (2.28)
CVLT-II Total 55.30 (11.03) 53.38 (9.75) 36.34 (9.80)∗∗
CVLT-II Delayed 12.65 (4.31) 12.14 (3.80) 5.06 (3.85)∗∗
LM Immediate 13.71 (5.02) 13.81 (4.50) 8.97 (4.50)∗∗
LM Delay 12.44 (5.67) 12.44 (5.00) 6.07 (5.02)∗∗
Note. Means (SD). CDR-SB reported as median and range. Reference group for all pairwise comparisons
was the A␤– CN group. MMSE, Mini-Mental Status Examination; CDR-SB, Clinical dementia rating scale,
sum of boxes; HADS, Hospital anxiety and depression scale; CVLT-II, California Verbal Learning Test,
Second edition; LM, Wechsler Logical memory. ∗ p < 0.05; ∗∗ p < 0.001.

flutemetamol injection. For PiB acquisition, stan-
dardized uptake value (SUV) data for key regions of
interest were summed and normalized to the cerebel-
lar cortex SUV. This resulted in a region-to-cerebellar
ratio which was termed SUV ratio (SUVR). For
florbetapir, SUVR was generated using the whole
cerebellum as the reference region and for flutemeta-
mol, the pons was used as the reference region [32].
Consistent with previous studies, A␤ status was clas-
sified as either low (A␤–) or high (A␤+). For PiB, an
SUVR threshold ≥1.4 was used [32, 33]. For florbe-
tapir and flutemetamol, an SUVR threshold of ≥1.1
and ≥0.62 were employed to discriminate between
A␤– and A␤+, in accord with results of phase III
studies.
The International Shopping List Test (ISLT)
The ISLT is a 12-item verbal list-learning task con-
sisting of three learning trials and a delayed recall
trial [19]. Outcome measures include total number of
words recalled at each trial, delayed recall, and a sav-
ings score (delayed recall/trial 3), where higher scores
equal better performance [22]. For each administra-
tion of the ISLT the computer program draws 12
words pseudo-randomly (without replacement) from
a set of validated stimuli (n = 128). Thus, participants
receive lists consisting of different words, with words
used in one assessment, not repeated upon subse-
quent assessments for that individual. The reliability
of the total and delayed recall scores from the ISLT
in healthy populations, as well as those with MCI and
AD is uniformly high (rICC = 0.83–0.94), while trial
by trial reliability is slightly lower (rICC = 0.69–0.92)
[19]. Performance on the ISLT was not used in the
classification of clinical disease status for any partic-
ipant.
AIBL verbal learning and memory tests
Classification of verbal episodic memory impair-
ment in the AIBL cohort is based on performance
on the California Verbal Learning Test, Second Edi-
tion (CVLT-II) and on a modified administration of
the Logical Memory (LM) subtest of the Wechsler
Memory Scale – Revised (WMS -R). The CVLT-II is
a 16-item verbal list learning task consisting of five
learning trials, immediate free and cued recall trials,
and delayed recall and recognition trials [20]. For the
purposes of this study, the total of the five learning
trials and delayed free recall trial were used. Higher
scores indicate better performance. The LM subtest is
a paragraph story recall task in which participants are
read a short story and are required to repeat as much
information as they can remember, both immediately
after being read the story (LM-I) and after a 30-min
delay (LM-II; [28]). Both tests were administered in
the context of the entire AIBL neuropsychological
battery [24] and both are used for clinical disease
staging in the study.
Procedure
The procedure for the AIBL-ROCS has been
described previously [23]. Briefly, participants from
the AIBL study were recruited for a series of repeated
assessments over short test-retest intervals over an
18-month period. Participants were assessed once per
month for four months, then at six months, and then
every three months up to 18 months. This proce-
dure was utilized in part to mirror the designs used
 J.E. Baker et al. / Impaired Learning in Early Alzheimer’s Disease
in clinical trials of new medicines for AD, where
in some cases repeated assessments occur at shorter
retest intervals which then increase with time (e.g.,
[34, 35]). An initial training assessment was con-
ducted to prepare participants for regular home visits
and to familiarize them with the computerized ver-
sion of a list-learning task, and therefore the second
assessment was considered the baseline. Assessments
were conducted either at the participants’ home, a
location nearby, or at the Mental Health Research
Institute, in Parkville, Australia. During the time
between the initial list presentation of the ISLT and
the delayed recall trial (approximately 30 min), sev-
eral other non-verbal computerized cognitive tasks
were administered.
Data analysis
All analyses were conducted in RStudio [36] using
R version 3.3.1 [37]. Packages used included “afex”
for analysis of repeated measures [38], “lme4” for
linear mixed model analysis [39], and “ggplot2” for
data visualization [40].
Differences in demographic or clinical
characteristics
Differences between groups on relevant demo-
graphic and clinical characteristics were explored
using a series of one-way ANOVAs for continu-
ous variables and chi-square tests for non-continuous
and categorical variables (e.g., CDR, APOE status,
and sex). Characteristics for which group differences
were identified at the p < 0.05 threshold were then
added to subsequent analyses as covariates.
Group differences in episodic memory at baseline
To test the hypothesis that learning and recall in
preclinical AD would be qualitatively similar but
quantitatively different from prodromal AD, while
also different from A␤– CN adults, the analysis pro-
ceeded in two stages. First, learning curves on the
ISLT trials including the delayed recall trial were
compared between groups by submitting the num-
ber of words recalled on each trial to a 3 × 4 (group
[A␤– CN, preclinical AD, prodromal AD] × trial
[One, Two, Three, Delayed]) mixed design ANOVA
(formula = score ∼ group + age + apoe + hadsd +
Error(id/(trial)). Statistically significant group × trial
interactions were decomposed using interaction con-
trasts. Generalized eta-squared (␩2G ) was used to
represent the magnitude of the interaction. Second,
summary ISLT performance measures, derived from
981
those measures showing sensitivity to A␤+ in the
learning curve analyses were compared between
groups using a series of planned comparisons set
within a one-way ANOVA, i.e., between A␤– CN and
preclinical AD, and between preclinical and prodro-
mal AD. Measures of effect sizes (Cohen’s d) were
used to express the magnitude of difference from the
comparison group for each measure.
Change in episodic memory over time
To test the second hypothesis that assessing change
in memory over time using multiple repeated assess-
ments would allow characterization of A␤+ related
memory change in preclinical AD, the second anal-
yses proceeded in two stages. First, the three main
performance measures for the ISLT, identified from
the baseline analyses, were submitted to a series of
linear mixed model (LMM) analyses using maximum
likelihood estimation and an unstructured covariance
matrix. In the LMM, group, time, and group x time
interaction were entered as fixed factors; participant
entered as a random factor; age, APOE ␧4 status, and
depression subscale of the HADS as covariates (for-
mula = score ∼ group*time + age + apoe + hadsd +
(1|id)). From these analyses, the magnitude of dif-
ference between groups in the estimates of rate of
change for each summary ISLT were expressed as
Cohen’s d. Due to the possibility of distribution of
performance on verbal list learning tests to be biased
towards ceiling effects within healthy populations
and floor effects within those with objective mem-
ory impairment when using parametric statistical
methods, we repeated analyses using non-parametric
quantile regression. This allowed investigation of
the presence of distribution biases within the
ISLT performance measures (see Supplementary
Material).
RESULTS
Group differences in demographic and clinical
characteristics
Statistically significant group differences were
identified for proportion of APOE ␧4 carriers,
age, and the depression subscale of the HADS
(Table 1); thus, subsequent analyses included
these variables as covariates. As expected, groups
also differed significantly with respect to MMSE
and CDR scores. Comparison of the A␤– CN
group to the preclinical AD group indicated
no statistically significant differences in perfor-
982 J.E. Baker et al. / Impaired Learning in Early Alzheimer’s Disease
mance in CVLT-II total (d = –0.18[–0.66, 0.30]),
CVLT-II delayed (d = –0.12[–0.60, 0.36]), LM-I
(d = 0.02[–0.50, 0.46]) or LM-II (d = 0.00[–0.48,
0.48]) scores. As expected, compared to the
A␤– CN group, the prodromal AD group per-
formed significantly worse on all aspects of the
CVLT-II and LM tests (CVLT-total d = –1.78[–2.35,
–1.20], CVLT-delay d = –1.82[–2.40, –1.24]; LM-
I d = –0.97[–1.50, –0.45], LM-II d = –1.16[–1.70,
–0.63]). Similarly, compared to the preclinical AD
group, the prodromal AD group performed signif-
icantly worse on CVLT-II total (d = –1.74[–2.41,
–1.07]), CVLT-II delayed recall (d = –1.85[–2.53,
–1.17]), LM-I (d = –1.08[–1.69, –0.46]), and LM-II
(d = –1.27[–1.90, –0.65]).
Group differences in learning at baseline
Mean words recalled on each of the three ISLT
trials are shown in Fig. 1. The mixed ANOVA
revealed a statistically significant group × trial inter-
action, F(5.50, 231.16) = 6.71, p < 0.001, η2G = 0.04.
This effect was decomposed using two interaction
Fig. 1. Mean words recalled for each clinical group at each ISLT
learning trial and delayed recall at baseline. Error bars repre-
sent 95% confidence intervals. Analyses adjusted for age, HADS
depression, and APOE ␧4 carriage. No significant differences
between the performance of the A␤– CN and preclinical AD group.
Prodromal AD group significantly impaired across trials and at
delayed recall.
Table 2
Group mean performance on ISLT measures at baseline
Mean (SD)
Outcome A␤– CN Preclinical
AD
ISLT Total 26.92 (5.02) 26.78 (4. 55)
Delayed 9.47 (2.69) 8.78 (2.40)
Savings 90.88 (23.69) 85.40 (21.20)
Note. Means (SD) are adjusted for the covariates of age, HADS Depression, and APOE ␧4 status. ∗∗ p < 0.001.
contrasts. The first interaction contrast compared
learning across trials between the A␤– CN group and
the preclinical AD group. No significant group × trial
interaction was observed (p = 0.24, d = 0.16) and for
both groups, total words recalled improved across
the three learning trials, F(2.66, 186.25) = 4.65,
p = 0.005, d = 0.29. Savings for the A␤– CNs were
approximately 5% greater than in the preclinical AD
group, although the difference was not significant
(Table 2). The second interaction contrast compared
the rate of learning across trials between the pre-
clinical AD group to the prodromal AD group and
a significant group × trial interaction was observed,
F(3, 105) = 10.10, p < 0.001, d = 0.46. Compared to
the preclinical AD group, the prodromal AD group
recalled fewer words on each trial (Fig. 1). The
prodromal AD group had significantly less savings
(approximately –36%) compared to the preclinical
AD group (Table 2).
Table 2 summarizes the comparisons of the ISLT
learning trials, delayed recall, and savings scores
between groups. ANOVAs indicated significant dif-
ferences between groups on all three metrics, and
this effect was driven by the prodromal AD group
(Table 2). Cohen’s d effect sizes showed the magni-
tude of the difference between the preclinical AD and
A␤– CN groups were small for all summary metrics
(Cohen’s d’s < 0.25). In contrast, the magnitude of the
difference between the preclinical AD and prodromal
AD groups was very large (Cohen’s d’s > 1.50).
Group differences in rate of change in episodic
memory over 18 months
The results of the LMMs of ISLT performance
scores are summarized in Table 3 and shown graph-
ically in Figs. 2–4. Group mean slopes derived
from these models are also presented in Table 3.
A significant group × time interaction was observed
for ISLT total recall. Compared to the A␤– CN
group, the preclinical AD group showed significantly
less change over time with the difference moder-
Cohen’s d [95% Confidence intervals]
Prodromal A␤– CN versus Preclinical AD
AD Preclinical AD versus Prodromal AD
18.47 (4.55) –0.03 [–0.51, 0.45] –1.84 [–2.52, –1.16]∗∗
3.81 (2.44) –0.27 [–0.75, 0.22] –2.05 [–2.76, –1.35]∗∗
49.13 (21.53) –0.24 [–0.72, 0.24] –1.70 [–2.36, –1.03]∗∗
 J.E. Baker et al. / Impaired Learning in Early Alzheimer’s Disease 983

Table 3
Results of linear mixed model analyses examining the ISLT outcome measures over 18 months, and mean slopes (SD) for each group
Outcome Group Time Group × time A␤– CN Preclinical AD Prodromal AD
(df) F Slope (SD)
Total (122.32) 28.88∗∗ (596.53) 3.43 (596.14) 9.34∗∗ 0.07 (0.18)∗∗ –0.06 (0.19) –0.13 (0.19)∗∗
Delayed recall (112.23) 34.90∗∗ (595.22) 1.89 (594.89) 4.24∗ 0.02 (0.09) –0.01 (0.10) –0.05 (0.09)∗
Savings (138.52) 22.88∗∗ (597.17) 1.16 (596.69) 0.81 –0.04 (1.06) 0.02 (1.14) –0.39 (1.24)
Note. Analyses covaried for age, HADS Depression, and APOE ␧4 carriage. ∗ p < 0.05; ∗∗ p < 0.001.

Fig. 2. Mean words recalled on the ISLT total score for the A␤–
CN, preclinical AD, and prodromal AD groups from baseline to 18
months. Baseline is represented by the second assessment as the
first was an initial training assessment. Shading represents 95%
confidence intervals fitted via a linear smoothing function. Analy-
ses are adjusted for age, HADS depression, and APOE ␧4 carriage.
The preclinical and prodromal AD group slopes are significantly
different to the A␤– CN group slope. A significant increase in
performance is also seen in the A␤– CN group.
Fig. 4. Percentage of savings on the ISLT savings score for A␤–
CN, preclinical and prodromal AD groups from baseline to 18
months. Baseline is represented by the second assessment as the
first was an initial training assessment. The shading represents
95% confidence intervals fitted via a linear smoothing function.
Analyses are adjusted for age, HADS depression, and APOE ␧4
carriage. No change over the 18-month period was observed for
any of the groups.

group the difference in slopes was not signif-

Fig. 3. Mean words recalled on ISLT delayed recall for A␤–
CN, preclinical, and prodromal AD groups from baseline to 18
months. Baseline is represented by the second assessment as the
first was an initial training assessment. Shading represents 95%
confidence intervals fitted via a linear smoothing function. Analy-
ses are adjusted for age, HADS depression, and APOE ␧4 carriage.
No significant difference in the slopes between the A␤– CN and
preclinical AD groups. The prodromal AD group significantly
declined over the 18 months.
ate in magnitude (Cohen’s d = –0.63[–1.12, –0.14]).
The prodromal AD group showed significant decline
over time, however, relative to the preclinical AD
icant, although moderate in magnitude (Cohen’s
d = –0.36[–0.94, 0.22]). A significant group x time
interaction was also observed for ISLT delayed recall.
Compared to the A␤– CN group, the preclinical
AD group did not show a significantly faster rate
of decline over time, but the effect size of differ-
ence in slopes was moderate in magnitude (Cohen’s
d = –0.37[–0.85, 0.11]). The prodromal AD group
showed significant decline over time, however, rel-
ative to the preclinical AD group the difference
in slopes was not significant, although of moder-
ate magnitude (Cohen’s d = –0.42[–1.00, 0.16]). No
significant group x time interaction was observed
for the ISLT savings score (Table 3, Fig. 2c). Re-
analysis of the prospective data for the ISLT using the
non-parametric quantile regression yielded a pattern
of outcomes consistent with the parametric meth-
ods (see Supplementary Table 1 and Supplementary
Figures 1–3). This indicates that outcomes of the
linear mixed models were not influenced by any
group-based biases in data distributions on the ISLT
outcome measures (see Supplementary Material).
984 J.E. Baker et al. / Impaired Learning in Early Alzheimer’s Disease
DISCUSSION
The first hypothesis that the acquisition and recall
of verbal information would be impaired in early
AD in the presence of A␤+ was partially supported.
At the baseline assessment, no differences in acqui-
sition, total recall, delayed recall, or the savings
scores on the ISLT were observed in the preclini-
cal AD group. Furthermore, effect sizes reflecting
differences in performance between the groups for
each of these measures were uniformly small (i.e.,
Cohen’s ds < 0.25), equivalent to estimates of mem-
ory performance detected using the CVLT-II and LM
tests (i.e., Cohen’s ds < 0.20), and consistent with the
magnitude of impairments in memory in preclinical
AD observed in previous reports [7, 41, 42]. This
indicates that when assessed on a single occasion,
preclinical AD is not characterized by impairment in
episodic memory even when the measures of mem-
ory are analyzed to consider both the acquisition
and retention of verbal information. In contrast, the
prodromal AD group showed substantial impairment
(i.e., Cohen’s ds > 1.50) on all measures of the ISLT,
equivalent to impairment evident on the CVLT-II and
LM tests (Cohen’s ds > 1). Thus, for the preclinical
and prodromal AD groups, analyses of acquisition
and retention did not provide estimates of memory
impairment that were greater than the ISLT summary
scores or the CVLT-II and LM scores.
The second hypothesis that with repeated assess-
ment, episodic memory would deteriorate in A␤+
individuals, but not change in those without A␤,
was also partially supported. The preclinical AD
group showed a decline in the ISLT total recall score
over the 18-months that, when compared to the A␤–
CN group, was moderate in magnitude (Cohen’s
d = –0.63). A decline of equivalent magnitude in ver-
bal list learning was evident in the prodromal AD
group on the ISLT measures of total and delayed
recall (Cohen’s ds –0.36 and –0.42, respectively).
This decline in performance on the ISLT is con-
sistent with the decline on other tests of verbal
episodic memory in both preclinical and prodromal
AD observed previously in other natural history sam-
ples [8, 43–45]. These data therefore indicate that
estimates of cognitive dysfunction in the preclinical
stage of AD are most obvious as change over time
based on repeated assessments, when compared to
individuals without A␤+.
The observation here, and elsewhere, that indi-
viduals with preclinical AD show no substantial
impairment in verbal learning and memory when
assessed on a single occasion, but do show decline
when assessed over time, indicates that while A␤+
related disruption to medial temporal lobe areas
begins very early in the AD process, this takes a long
time to manifest clinically [41, 42, 46–48]. Thus, this
preclinical phase of AD is agreed upon to provide
an opportunity to intervene so to prevent further neu-
ronal loss and forestall the development of AD [49].
These data also suggest that the slow course of A␤+
related memory loss continues through the preclini-
cal stage until it becomes severe enough to warrant
clinical classification of MCI, whereupon clinically
meaningful memory impairment becomes obvious at
a single assessment. The A␤+ related decline then
continues steadily throughout the prodromal phase.
Previous studies suggest that A␤+ related memory
decline is correlated with loss of volume in the MTL
[50–52]. However, even with this decline in memory,
individuals with MCI remain able to live indepen-
dently and by definition have difficulty only with the
most demanding of daily living tasks [4, 10, 53]. Stop-
ping AD in the prodromal or preclinical stages could
therefore provide enormous benefit to individuals.
Although the ISLT was designed to minimize
practice effects from repeated administration, using
multiple parallel forms gained from randomization of
word lists upon each assessment, the A␤– CN group
did show a slight improvement, of approximately one
word, over the eight assessments conducted in the 18-
months (Table 3). This slight improvement in ISLT
performance in A␤– CN adults was most likely a
consequence of the high frequency of ISLT admin-
istration in the study, as no improvements in ISLT
performance were observed in previous studies where
it was administered four times over three months in
CN older adults and three times in a single setting in
younger adults [19, 54]. Additionally, performance
on the ISLT has remained stable between two assess-
ments over a period of one month in participants with
clinically diagnosed AD [22]. While the results of this
study suggest that even with optimization for repeated
use, eight administrations within an 18-month period
still results in practice effects in healthy individu-
als, the magnitude of the practice effect on the ISLT
(d = 0.10) was much less than in previous reports. For
example, moderate improvements on the Neuropsy-
chological Assessment Battery (NAB) list learning
task and the Auditory Verbal Learning Test (RAVLT)
have been observed with fewer administrations, equal
to a 0.39 standard deviation annual increase [55], and
an improvement of d = 0.51 after three assessments
in 30 months, respectively [56]. Indeed, the absence
 J.E. Baker et al. / Impaired Learning in Early Alzheimer’s Disease
of practice effects from repeated administration of
memory tests has been proposed to be characteristic
of early AD. While the current study aimed to mini-
mize practice effects through the use of the ISLT in
order to gain reliable estimates of A␤+ associated
cognitive change, previous work has shown that the
degree of practice effects can provide an understand-
ing of disease progression. For example, reduced
practice effects were five times more likely in individ-
uals with A␤+ compared to those without A␤ [57].
Similarly, the magnitude of practice effects across
three consecutive memory assessments was signifi-
cantly less in those who progressed to clinical disease
than in those that did not (d = 0.07 and 0.33, respec-
tively) [58]. However, in each case, these estimates
of A␤+ related dysfunction were based on a reduc-
tion in the magnitude of practice effects, while still in
the presence of performance gains, rather than from
observation of a declining trajectory associated with
A␤+, as was shown in the current study (e.g., Fig. 2).
In the context of the hypothesis that memory dys-
function in preclinical AD is more evident upon
repeated assessment, it is worth considering that the
analysis of learning curves from the individual ISLT
trials on the first administration could be consid-
ered an index of practice, albeit over minutes rather
than over days, months, or years. As no difference
in learning curves was observed between A␤– CN
and preclinical AD groups at baseline (Fig. 1), it is
likely that information about memory dysfunction in
preclinical AD, here shown over 18 months, and in
previous studies over a period of one week [57] or sev-
eral years [58], requires a time interval longer than
minutes to become evident. The reduction in practice
effects from high-frequency assessment in preclini-
cal AD groups comparative to CN A␤– older adults
suggests that memory dysfunction could be concep-
tualized as a deficit in learning from repetition. As
such, the assessment of memory utilizing primarily
learning-based episodic memory paradigms may pro-
vide a more effective method for characterization of
this proposed deficit in preclinical AD.
There are some caveats to the generalization of the
current results. First, the AIBL-ROCS sample was
selected specifically to undergo high frequency test-
ing, and as such the repeated assessment schedule
employed in AIBL-ROCS does not reflect that typ-
ically used in clinical practice. Future research will
need to administer repeated assessments in a similar
context to that of clinical practice to provide greater
generalizability of results. Second, the AIBL sam-
ple is unlikely to be representative of the general
985
population, as the study utilizes detailed inclusion and
exclusion criteria to ensure minimal untreated comor-
bidities. Third, given that many AIBL participants
have had prior exposure to cognitive testing, replica-
tion in a sample naı̈ve to cognitive testing would help
to increase generalization to the broader population.
Fourth, due to the schedule of testing and necessary
home visits for the current study, the sample size was
small and as such, replication of the current results in
a larger sample is warranted.
Notwithstanding these limitations, our findings
highlight an issue with current models attempting
to understand subtle cognitive dysfunction in pre-
clinical AD populations using neuropsychological
methods created for the detection of impairment.
They underscore the importance of shifting from
examination of neuropsychological performance at
one timepoint to characterizing change in cognitive
processes over time. Ultimately, the ability to conduct
repeated assessments over shorter time periods will
need to become the standard assessment protocol for
individuals at risk of AD to demonstrate meaning-
ful change in cognitive function. Our results suggest
that even when using cognitive tasks with high test-
retest reliability, practice effects can be seen in A␤–
CN adults but not in those with preclinical AD. As
such, a potential way forward is to deliberately seek
to improve performance in order to separate individ-
uals who are able to improve from those who cannot,
potentially leading to an increase in the reliability of
prediction of disease progression.
ACKNOWLEDGMENTS
Funding for the study was provided by
AstraZeneca Pharmaceuticals LP, the CSIRO
Flagship Collaboration Fund and the Science and
Industry Endowment Fund (SIEF) in partnership
with Edith Cowan University (ECU), The Mental
Health Research Institute (MHRI), Alzheimer’s
Australia (AA), National Ageing Research Institute
(NARI), Austin Health, CogState Ltd, Hollywood
Private Hospital, Sir Charles Gairdner Hospital. The
study also receives funding from the National Health
and Medical Research Council (NHMRC), the
Dementia Collaborative Research Centres program
(DCRC), The McCusker Alzheimer’s Research
Foundation, and Operational Infrastructure Sup-
port from the Government of Victoria. The authors
acknowledge the financial support of the Cooperative
Research Centre (CRC) for Mental Health. The CRC
986 J.E. Baker et al. / Impaired Learning in Early Alzheimer’s Disease
programme is an Australian Government Initiative.
YYL reports grants from the National Health and
Medical Research Council (GNT1111603, GNT
1147465). The ROCS team wishes to thank the
participants in the ROCS study for their commitment
and dedication to helping advance research into
the early detection and causation of AD and the
clinicians who referred patients to the study.
Authors’ disclosures available online (https://
www.j-alz.com/manuscript-disclosures/18-0344r1).
SUPPLEMENTARY MATERIAL
The supplementary material is available in the
electronic version of this article: http://dx.doi.org/
10.3233/JAD-180344.
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