Moderating effects of sex on the impact of diagnosis and amyloid positivity on verbal memory and hippocampal volume
Caldwell et al. Alzheimer's Research & Therapy
Moderating effects of sex on the impact of diagnosis and amyloid positivity on verbal memory and hippocampal volume
Jessica Z. K. Caldwell 0 1
Jody-Lynn Berg 0 1
Jeffrey L. Cummings 0 1
Sarah J. Banks 0 1
0 Cleveland Clinic Lou Ruvo Center for Brain Health , 888 West Bonneville Avenue, Las Vegas, NV 89106 , USA
1 Competing interests JZKC, JLB, and SJB declare that they have no competing interests. JLC Radiopharmaceuticals, Teva Pharmaceuticals, and CogState; having done consultation for AbbVie, ACADIA Pharmaceuticals, Accera, Actinogen Medical, Adamas Pharmaceuticals , Alkahest, Alzheon , Anavex Life Sciences, Astellas Pharma, AstraZeneca, Avanir Pharmaceuticals, Axovant Sciences , Biogen Idec, Biotie Therapies, Boehinger Ingelheim, Chase Pharmaceuticals, Eisai, FORUM Pharmaceuticals, Genentech, Grifols , Intra-Cellular Therapies, Iris Pharma, Ionis Pharmaceuticals, Eli Lilly and Company , Lundbeck, Merck, Neurotrope BioScience, Novartis, Nutricia, Otsuka, Pfizer, Probiodrug , QR Pharma , Resverlogix, Roche, Servier , Sunovion Pharmaceuticals, Suven Life Sciences, Takeda, Taisho Toyama Pharmaceutical Co., Transition Therapeutics, United Neuroscience, GE Healthcare, and MedAvante; owning stock in Adamas Pharmaceuticals , Prana Biotechnology, Sonexa Therapeutics, MedAvante , NeuroTrax, and Neurokos; and owning the copyright of the Neuropsychiatric Inventory. In addition, JLC has provided expert witness/legal consultation regarding olanzapine and ropinerole
Background: Alzheimer's disease (AD) impacts men and women differently, but the effect of sex on predementia stages is unclear. The objective of this study was to examine whether sex moderates the impact of florbetapir positron emission tomography (PET) amyloid positivity (A+) on verbal learning and memory performance and hippocampal volume (HV) in normal cognition (NC) and early mild cognitive impairment (eMCI). Methods: Seven hundred forty-two participants with NC and participants with eMCI from the Alzheimer's Disease Neuroimaging Initiative (second cohort [ADNI2] and Grand Opportunity Cohort [ADNI-GO]) were included. All had baseline florbetapir PET measured, and 526 had screening visit HV measured. Regression moderation models were used to examine whether A+ effects on Rey Auditory Verbal Learning Test learning and delayed recall and right and left HV (adjusted for total intracranial volume) were moderated by diagnosis and sex. Age, cognition at screening, education, and apolipoprotein E ε4 carrier status were controlled. Results: Women with A+, but not those with florbetapir PET amyloid negative (A-),eMCI showed poorer learning. For women with NC, there was no relationship of A+ with learning. In contrast, A+ men trended toward poorer learning regardless of diagnosis. A similar trend was found for verbal delayed recall: Women with A+, but not A-, eMCI trended toward reduced delayed recall; no effects were observed for women with NC or for men. Hippocampal analyses indicated that women with A+, but not those with A−, eMCI, trended toward smaller right HV; no significant A+ effects were observed for women with NC. Men showed similar, though nonsignificant, patterns of smaller right HV in A+ eMCI, but not in men with A− eMCI or NC. No interactive effects of sex were noted for left HV. Conclusions: Women with NC showed verbal learning and memory scores robust to A+, and women with A+ eMCI lost this advantage. In contrast, A+ impacted men's scores less significantly or not at all, and comparably across those with NC and eMCI. Sex marginally moderated the relationship of A+ and diagnosis with right HV, such that women with NC showed no A+ effect and women with A+ eMCI lost that advantage in neural integrity; the pattern in men was less clear. These findings show that women with A+ eMCI (i.e., prodromal AD) have differential neural and cognitive decline, which has implications for considering sex in early detection of AD and development of therapeutics.
Alzheimer's disease; Amyloid; Mild cognitive impairment (MCI); PET; Volumetric magnetic resonance imaging (MRI); Memory
Florbetapir positron emission tomography (PET) amyloid
positivity (A+) is a biomarker for fibrillar amyloid
associated with a high likelihood of progression to Alzheimer’s
disease (AD) dementia [
]. β-Amyloid (Aβ) accumulation
has been linked to brain atrophy [
] and cognitive
decline in AD [
]. However, findings have been mixed
regarding whether and how A+ relates to cognitive
dysfunction or hippocampal volume (HV) across the
spectrum of normal cognition (NC), early mild cognitive
impairment (eMCI), and AD [
Some inconsistencies in the extant literature relate to
disease stage included and concurrent versus
longitudinal assessment of outcomes. For example, on one
hand, although A+ may be detectable in NC, it may not
be meaningfully related to concurrent cognition until
development of eMCI [
]. On the other hand, A+
may be strongly linked to retrospective longitudinal
decline in NC but less predictive of future decline as the
disease progresses to eMCI . Other potentially
explanatory factors include differences in sample size, type of Aβ
measurement (e.g., binary positivity versus continuous
measures of Aβ load), hippocampal segmentation and
correction methodology [
], and type of outcome
measure employed (e.g., screening measures such as
overall scores on the Mini Mental State Examination [MMSE]
versus more specific memory measures).
Although traditionally treated as a confound, sex
differences in the relationship of A+ to cognition and
HV may also explain conflicting findings. Recent
investigations have revealed sex effects on hippocampal atrophy
in normal aging, eMCI, and AD, though one study showed
this only before controlling for Aβ levels [
Researchers have also shown that women’s established verbal
memory advantage over men [
] appears to function
as a form of sex-specific cognitive reserve, affording
women equal or better cognitive performance compared
with men via compensation despite positive biomarkers
for AD, including mild to moderate levels of hippocampal
atrophy  or fluorodeoxyglucose (18F-FDG)-PET
]. Mechanisms of sex effects on
hippocampal atrophy and cognition remain unclear, but as recent
reviews and studies suggest, the etiology may include a
complex interaction of effects of sex hormones; genetics
(e.g., apolipoprotein E ε4 [APOEε4] carrier status); and
psychosocial (e.g., differences in stress or coping),
demographic (e.g., education), and lifestyle (e.g.,
exercise, smoking, and alcohol use) factors [
Whether sex-specific reserve in cognition is seen in the
face of A+ remains unclear. It is also unknown whether
sex-specific hippocampal reserve exists for women with A+.
We examined whether sex moderates the effect of A+
on verbal learning and memory and HV in individuals
with NC and eMCI. We hypothesized that sex would
moderate the relationship of A+ and diagnosis with
cognition such that women with NC would show a
memoryrelated advantage over men that persists despite A+ and
that women with eMCI would lose that advantage. We
further hypothesized that sex would moderate the
relationship of A+ and diagnosis with HV such that women
with women with A+ and NC would show a neural
robustness in hippocampal integrity but that women with eMCI
would lose that advantage.
The Alzheimer’s Disease Neuroimaging Initiative (ADNI)
is a longitudinal, multisite AD biomarker study
(www.adniinfo.org). The present investigation includes participants
enrolled in the Alzheimer’s Disease Neuroimaging
Initiative second cohort (ADNI2) and the Alzheimer’s Disease
Neuroimaging Initiative Grand Opportunity Cohort
(ADNI-GO) who had amyloid PET imaging at baseline
and cognitive testing at screening (n = 742). Of
included participants, 526 had screening visit HVs that
met University of California, San Francisco (UCSF),
quality control standards (UCSF Freesurfer Methods
Quality Control [http://adni.loni.usc.edu/]). Participants
were NC ADNI2 participants (n = 285) and participants
with eMCI (ADNI2, n = 329; ADNI-GO, n = 128). ADNI
required participants with NC to have MMSE scores of
24–30, a Clinical Dementia Rating (CDR) of 0, and no
memory complaints. ADNI defined early eMCI as
including MMSE [
] scores of 24–30, CDR [
] of 0.5, CDR
Memory box score of 0.5 or greater, objective memory
loss as assessed by education-adjusted scores on the
Wechsler Memory Scale Logical Memory II test (raw
scores 9–11 for >16 years of education, 8–15 for 5–9
years of education, 0–7 for 3–6 years of education),
subjective memory complaint, and not meeting criteria
for dementia [
Hippocampal image processing
Fully processed HV and total intracranial volume (TIV)
numerical values were downloaded from ADNI, with
methods described in the UCSF Freesurfer Methods
Quality Control document (www.adni.loni.usc.edu). In
brief, magnetic resonance imaging (MRI) scans were
obtained at baseline according to a standardized protocol
(http://adni.loni.usc.edu/methods/mri-analysis/mri-acquisition/). Nonaccelerated T1-weighted images
(multiplanar reconstruction or inversion recovery-spoiled
gradient recalled acquisition in steady state) in
Neuroimaging Informatics Technology Initiative format were
preprocessed by the Mayo Clinic (gradient warping, scaling,
B1 correction, and N3 inhomogeneity correction).
Freesurfer (version 5.1; documented and freely available for
download online [http://surfer.nmr.mgh.harvard.edu/])
was employed for motion correction and averaging [
of multiple volumetric T1-weighted images (when more
than one was available), removal of nonbrain tissue
using a hybrid watershed/surface deformation procedure
], automated Talairach transformation, segmentation
of the subcortical white matter and deep gray matter
volumetric structures (including hippocampus) [
intensity normalization , tessellation of the gray
matter-white matter boundary, automated topology
], and surface deformation following
intensity gradients to optimally place the gray/white and
gray/cerebrospinal fluid borders at the location
where the greatest shift in intensity defines the
transition to the other tissue class [
quality control assessment of images was performed at
UCSF (see www.adni.loni.usc.edu).
In the present analyses, we employed HV that passed
UCSF-established quality control thresholds. We
examined left and right HVs rather than a mean volume across
hemispheres. This was based on significant testing for
effect of hemisphere conducted prior to primary analyses
described in the Statistical methods section (i.e., analysis
of variance with sex, A+, and their interaction as
betweensubjects factors and hemisphere as a within-subject factor,
predicting left and right hemisphere volumes). The
results revealed significant effects of hemisphere on
volume in NC [F(4,179) = 12.30, p = 0.001] and eMCI
[F(4,347) = 25.87, p < 0.001] as well as a significant
sexby-A+-by-hemisphere interaction in eMCI [F(4,347) =
4.12, p = 0.043]. We adjusted left and right HVs for TIV
according to procedures set forth by Mormino and
]. In brief, adjusted hippocampal volume (aHV)
was calculated according to the formula [aHV = raw
HV − β(TIV − mean TIV)]. Mean TIV values were
defined separately for NC and eMCI; mean TIV for the
appropriate diagnostic group was subtracted from each
individual’s TIV. This value was multiplied by the
regression coefficient (β) obtained from a regression of
TIV predicting HV in the appropriate diagnostic group.
Finally, we calculated aHV by subtracting this value
from raw left and right HVs for each participant.
Florbetapir PET image processing
We downloaded fully processed 18F-FDG-PET binary
positivity/negativity values from ADNI, where full
protocols are also described (www.adni.loni.usc.edu).
Florbetapir synthesis, image acquisition, and processing are
additionally described in prior publications [
4, 40, 41
brief, amyloid PET images were acquired at a variety of
sites (4 × 5-minute frames obtained 50–70 minutes
postinjection). Images were realigned; averaged; resliced to
1.5-mm3 voxel size; smoothed to 8-mm FWHM; and
coregistered to baseline native space structural MRI scans,
which were segmented and parcellated with Freesurfer
version 5.3.0 to define cortical gray matter regions of
interest (frontal, anterior/posterior cingulate, lateral
parietal, lateral temporal) [
]. A+ was determined by
extracting weighted cortical retention means (regional
standardized uptake value [SUVr]) from these regions,
calculating average SUVr, and dividing by the cerebellar
SUVr as a reference [
]. In the present analyses, we
used binary A+, employing the recommended 1.11 SUVr
ratio threshold for cross-sectional analyses [
Apolipoprotein E carrier status
We downloaded apolipoprotein E (APOE) genotype data
fully processed from ADNI (adni.loni.usc.edu). A binary
variable was created, coding all individuals as APOE ε4
carriers (heterozygotes, n = 251; homozygotes, n = 53) or
Clinical and cognitive measures
Cognitive outcome measures consisted of total learning
and delayed free recall performance scores on the Rey
Auditory Verbal Learning Test (RAVLT) [
calculated total RAVLT learning scores by adding the five
learning trial scores. We included modified total
performance score on the Montreal Cognitive Assessment
] as a measure of baseline cognitive status.
To create a MoCA score that did not include a measure
of memory performance, points earned for delayed list
word recall were excluded from the total score, resulting
in a maximum score of 25.
All analyses were performed using IBM SPSS Statistics
software (IBM, Armonk, NY, USA) and the PROCESS
]. Mann-Whitney U tests were performed
to examine group differences in demographic control
variables. Four separate moderation regression analyses
were performed to examine whether sex and diagnosis
moderated main effects of amyloid status on RAVLT
learning and delayed free recall scores as well as left and
right HVs. For all analyses, we treated A+ as an
independent variable, diagnosis as a moderator, and sex as a
secondary moderator. Modified MoCA scores, age at
screening visit, education, and APOE ε4 carrier status
were included as covariates. All continuous covariates
were mean-centered; dichotomous covariates were
For each of the four moderation analyses, outlying and
influential data points were defined as those that failed
two of the following three thresholds: (1) Cook’s D [D >
4/(n − k − 1)], where n = number of participants in the
analysis and k = number of predictors; (2) leverage as
defined by (2k + 2)/n, where n = number of participants in
the analysis and k = number of predictors; and/or (3)
Mahalanobis value greater than the chi-square cutoff at
p < 0.001 (df = 6). On the basis of these criteria, one
participant was excluded for the RAVLT learning analysis,
none were excluded for the RAVLT delay analysis, and two
were excluded for each of the HV analyses. We carefully
inspected data for all participants whose data failed a single
threshold measure in order to ensure no operator error
created outlying data points, as well as to ensure that data
points did not appear to belong to a different population.
Of 742 participants, 48.4% were women, 344 were A+,
304 were APOE ε4 allele carriers, and 457 were
diagnosed with eMCI. The average age of the sample was
71.59 years (SD 6.98) and ranged from 55 to 91 years.
Additional demographics by diagnosis, sex, and Aβ
status are displayed in Table 1.
Mann-Whitney U test results showed that, for NC,
men were significantly older (p = 0.01) and more
educated (p < 0.001) than women. For eMCI, men were
also significantly older (p = 0.02) and more educated
(p < 0.001) than women. There were no sex
differences in modified MoCA score or APOE ε4 carrier
status for NC or eMCI.
Mann-Whitney U tests showed that, for NC, those
with A+ were significantly older (p < 0.001), less
educated (p = 0.03), and less frequently APOE ε4 carriers
(p < 0.001) than those with florbetapir positron
emission tomography amyloid negativity (A−). No
differences based on A+ were observed in modified MoCA
scores (p < 0.001) for those with NC. For eMCI, those
with A+ were significantly older (p < 0.001), had lower
modified MoCA scores (p = 0.001), and were more often
APOE ε4 carriers (p < 0.001) than those with A−. No
differences were observed for education.
Sex moderation of amyloid status and diagnosis effects on verbal learning and free recall
The overall model with A+, diagnosis, sex, and their
interactions predicting verbal learning was significant
[F(11,727) = 48.26, p < 0.001, R2 = 0.39]. A three-way
interaction showed that sex significantly moderated
the effects of diagnosis and A+ on verbal learning
[t(727) = −2.25, p = 0.02]. Parsing this interactive effect
indicated that women were impacted differently by A+,
depending on diagnosis. In particular, women with A+ eMCI,
but not those with A− eMCI, showed poorer learning [A+
eMCI, t(727) = −3.65, p < 0.01]. Similar A+ effects were
not seen in women with NC [t(727) = −0.18, p = 0.85]. In
contrast, A+ impacted men similarly regardless of
diagnosis, with A+ showing trends toward poorer learning [NC,
t(727) = −1.94, p = 0.05; eMCI, t(727) = −1.66, p < 0.01].
All findings were significant after controlling for age,
education, modified MoCA score, and APOE ε4 carrier
status. See Table 2 and Fig. 1a.
The overall model with A+, diagnosis, sex, and their
interactions predicting verbal delayed recall was also
significant [F(11,729) = 32.94, p < 0.001, R2 = 0.27].
Analyses showed trends toward a three-way interaction,
suggesting that sex marginally moderated the effects
of diagnosis and A+ on verbal delayed recall [t(729) = −1.18,
p = 0.07]. Again, women with A+ eMCI, but not those with
A− eMCI, showed poorer delayed recall [t(729) = −3.64, p <
0.01], and no A+ effect was seen in women with NC
[t(729) = −0.96, p = 0.34]. There was no effect of A+ on
delayed recall for men with NC or eMCI [NC, t(729) = −1.36,
p = 0.17; eMCI, t(729) = −1.08, p = 0.28]. Findings are
controlled for age, education, modified MoCA score, and
APOE ε4 carrier status. See Table 2 and Fig. 1b.
Sex moderation of amyloid status and diagnosis effects on hippocampal volume
The overall model with A+, diagnosis, sex, and their
interactions predicting left HV was significant
[F(11,512) = 14.55, p < 0.001, R2 = 0.25]. However, the
three-way interaction of A+, diagnosis, and sex was
not significant [t(512) = −0.35, p = 0.73], indicating no
moderating effects of sex or diagnosis on A+ effects
for the left HV. Main effects indicated that diagnosis
related to smaller left HV across sexes, with men and
women with eMCI showing smaller left HV than men
and women with NC [t(512) = −5.88, p < 0.001]. Main
effects of A+ on left HV showed a trend toward
smaller left HV in men and women with A+ NC and
eMCI [t(512) = −1.69, p = 0.09]. There was not a
significant main effect of sex on left HV [t(512) = −1.30,
p = 0.19]. See Table 3 and Fig. 1c.
The overall model with A+, diagnosis, sex, and their
interactions predicting right HV was significant
[F(11,511) = 18.00, p < 0.001; R2 = 0.28]. The three-way
interaction of A+, diagnosis, and sex was a trend,
suggesting that sex marginally moderated the effects of
diagnosis and A+ on right HV [t(511) = −1.17, p = 0.09].
Parsing this interactive effect indicated that women were
again impacted differently by A+ depending on diagnosis,
with women with A+ eMCI, but not those with A− eMCI,
showing smaller right HV [t(511) = −2.71, p < 0.01]. There
was no association of A+ with right HV in NC
[t(511) = −0.77, p = 0.44]. For men, there was a trend
toward A+ relating to smaller right HV in A+ eMCI
and not A− eMCI [t(511) = −1.75, p = 0.08]. No
relationship was observed between A+ and right HV in NC men
[t(511) = −1.58, p = 0.11]. See Table 3 and Fig. 1d.
In the present study, we examined the moderating
effects of sex on the impact of diagnosis and A+ on verbal
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Abbreviations: A+ Florbetapir positron emission tomography amyloid positivity, APOE Apolipoprotein E, MoCA Montreal Cognitive Assessment, PET Positron
emission tomography, RAVLT Rey Auditory Verbal Learning
Age, education, and modified MoCA score were centered at their means. Dichotomous variables were centered on zero (RAVLT total learning score overall model,
R = 0.623, p < 0.0001; RAVLT Delayed Free Recall score overall model, R = 0.522, p < 0.0001)
a n = 739 after exclusions
b n = 741 after exclusions
Fig. 1 Sex moderation of diagnosis and amyloid status effects. Sex moderates effects of diagnosis and florbetapir positron emission tomography amyloid
positivity (A+) on verbal learning (a) and marginally moderates effects on verbal delayed recall (b) and right hippocampal volume (HV; d), but it does not
moderate effects on left HV (c). Specifically, learning and memory scores appear robust to A+ effects in women with normal cognition (NC; a, b). Women
with prodromal AD (A+ early mild cognitive impairment [eMCI]) lose this advantage (a, b). In contrast, A+ impacts men’s verbal learning and memory
scores comparably across NC and eMCI (a, b). Sex shows no moderating effect for left HV (c), but individuals of both sexes with eMCI show smaller left HV
than individuals with NC. Sex marginally moderates the relationship of A+ and diagnosis with right HV, such that women with NC showed no effect of A+
on HV and women with prodromal AD lost that advantage in neural integrity (d). A− Florbetapir positron emission tomography amyloid negativity, AVLT
Auditory Verbal Learning Test. Rey AVLT scores are group means. HV units are derived via correction for total intracranial volume
Abbreviations: A+ Florbetapir positron emission tomography amyloid positivity, APOE Apolipoprotein E, MoCA Montreal Cognitive Assessment, PET Positron
Age, education, and modified MoCA scores were centered at their means. Dichotomous variables were centered on zero. Left hippocampus overall model
(R = 0.495, p < 0.0001); right hippocampus overall model (R = 0.533, p < 0.0001)
a n = 524 after exclusions
learning and memory and HV. The main finding was
that sex moderated the effects of A+ and diagnosis on
verbal learning. In addition, we showed that sex
marginally moderated the effects of A+ and diagnosis on verbal
delayed recall and that sex marginally moderated the
effects of A+ and diagnosis on right HV. In contrast, no
sex moderation effects were observed for left HV.
With respect to cognition, our findings specifically
suggest that women’s advantage over men in verbal
learning—and to a lesser extent delayed recall—was robust
to A+ in NC. Moreover, in eMCI, only women with A+,
and not those with A−, showed poorer learning—and to
a lesser extent poorer delayed recall. These effects were
observed after accounting for baseline cognitive status, age,
education, and APOE ε4 carrier status. We conceptualize
these findings as consistent with A+ eMCI representing a
prodromal AD stage and A− eMCI as representing
suspected non-Alzheimer’s pathophysiology (SNAP). Our
findings are consistent with literature showing better
verbal memory performance in women [
] and positing a
cognitive or memory reserve advantage for women with
fewer prodromal AD traits (i.e., amnestic eMCI but
moderate to large HV), but not with more prodromal AD traits
(i.e., amnestic eMCI, dementia diagnosis, and small HV)
25, 26, 46
]. Our findings are also partially consistent with
a very recent study showing that women with low to
moderate Aβ burden (but not high Aβ burden) had better
verbal delayed recall than men and that this effect was specific
to MCI versus NC or AD. A moderating effect of sex
shown in the present study may help to explain some
conflicting findings in the extant literature because, depending
on sample size and diagnostic stage included, collapsing
across sexes may lead to masked or exaggerated findings.
The present result showing that sex moderates the
effect of A+ and diagnosis on learning and memory also
has implications for clinical diagnosis of AD in women.
Specifically, as has been suggested in the past [
memory reserve in women could delay prodromal AD
diagnosis even in the face of positive biomarkers such as
A+. However, the present results suggest that
longitudinal assessment of the potentially steeper decline in
memory for women between NC and prodromal AD,
which is absent in SNAP, or combining measures of
memory with other biomarkers, possibly with an
approach that places heavier weight on biomarkers such as
A+ early on, could increase diagnostic accuracy. This
finding could also be relevant for development of
therapeutics for AD, both with respect to inclusion criteria
for trials (e.g., guidelines including a memory or learning
score deficit requirement could exclude women with
preclinical AD unintentionally) as well as outcome
measures (e.g., the differing trajectories of memory decline
in men and women could either exaggerate or mask
important findings, depending on group composition, if
sex is not considered).
With respect to HV, our present findings suggest
moderating effects of sex for right HV. Similar to the pattern
of results for the cognitive data, there was no
relationship of A+ with right HV in women with NC. For
women with eMCI, those with prodromal AD, but not
SNAP, showed smaller right HV. The pattern in men
was weaker and not significant, but it was similar. No
moderating effects of sex were found for left HV.
Taken together, these findings may suggest that
women have a neural reserve at the level of the
hippocampus, such that hippocampal integrity is robust to
effects of A+ in preclinical stages in women. Importantly,
the present results do not imply that women have larger
hippocampi and thus more volume to lose. Instead, they
would suggest that neural reserve could be defined as a
robustness to neurodegeneration, beginning at similar
neural volume as men, when adjusting for TIV.
Replication in even larger samples, as well as in samples of
clinic-typical patients, will be important for
understanding whether this is a true example of sex-specific neural
reserve or whether findings would be significant in men
with larger cohorts. If the latter were true, it might
alternatively suggest that A+ is sensitive to concurrent HV
loss in early clinical disease stages but not in NC. Larger
cohort replication might also be helpful in determining
whether the present lateralized findings might be
consistent or whether bilateral effects would emerge.
Certainly, left hemisphere effects might be expected, given
the literature showing that women with NC and women
with eMCI have stronger verbal memory [
our lateralized results deserve further investigation.
Of note, in the present HV analysis, we intentionally
employed a residual correction methodology for TIV
], based on our specific sample composition as well
as on guidelines recently published [
]. Previous work
has suggested that a major source of variability in
literature describing assessment of HV sex differences may be
lack of [
], or differing methods for [
], correcting HV
for total brain or intracranial volume. Use of a deliberate
statistical approach taking sex into account at all levels
may help to reduce or explain contradictory results in
the literature relating A+ and sex to HV across NC and
eMCI. Further research is needed to determine what
pattern of sex moderation may exist at AD dementia
stages at which women have been shown to have more
rapid trajectories of decline [
Strengths of the present study include use of a large,
well-characterized study sample employing the
prodromal AD diagnosis and rigorous control of potential
confounding variables. Limitations include lack of
longitudinal analysis, which could help to clarify causality,
and use of a smaller cohort of individuals with HV data.
It was also beyond the scope of the present analysis to
explore ways in which HV may itself be a moderator of
cognitive decline or to further probe HV at the level of
Future research is warranted on the longitudinal
implications of these findings, as is replication in a larger
cohort. In particular, because the present analysis employs
clinically defined diagnostic stage groups in which men
and women would be expected to express similar clinical
symptoms, fine-grained examination of when exactly—or
how much—pathology such as amyloid burden leads to
cognitive, atrophic, and clinical symptom expression is
needed. In addition, further validation and exploration of
the currently used modification of the MoCA
eliminating the memory component will also be important.
Finally, examining the moderating effect of sex on
other outcome measures, including hippocampal
subfields, nonverbal memory, and resting state functional
MRI, may be interesting.
The present study shows that sex moderates the
relationship of A+ and diagnosis with verbal learning
performance and marginally moderates the effect of A+ and
diagnosis on verbal delayed recall and right hemisphere
HV. Whereas women with NC show learning and
memory scores that are robust to A+ effects, women with
prodromal AD lose this advantage; in contrast, A+
impacts men’s learning and memory scores in a less
significant way or not at all and comparably across NC and
eMCI. For right HV, the marginal sex moderation effect
showed that women with NC had no effect of A+ on
HV. Women with prodromal AD, but not those with
SNAP, lost that advantage in right HV neural integrity;
effects among men remain unclear. Further study of sex
effects in prodromal AD and AD dementia has the
potential to lead to clinical developments that increase
diagnostic accuracy at early stages, as well as to increase
the accuracy of treatment group formation and outcome
assessment when developing novel therapeutics.
A−: Florbetapir positron emission tomography amyloid negativity; A
+: Florbetapir positron emission tomography amyloid positivity; Aβ:
βAmyloid; AD: Alzheimer’s disease; ADNI: Alzheimer’s Disease Neuroimaging
Initiative; ADNI2: Alzheimer’s Disease Neuroimaging Initiative Second Cohort;
ADNI-GO: Alzheimer’s Disease Neuroimaging Initiative Grand Opportunity
Cohort; aHV: Adjusted hippocampal volume; APOE: Apolipoprotein E;
CDR: Clinical Dementia Rating; eMCI: Early mild cognitive impairment;
18FFDG: Fluorodeoxyglucose; HV: Hippocampal volume; ICV: Intracranial volume;
MMSE: Mini Mental State Examination; MoCA: Montreal Cognitive
Assessment; MRI: Magnetic resonance imaging; NC: Normal cognition;
PET: Positron emission tomography; RAVLT: Rey Auditory Verbal Learning
Test; SNAP: Suspected non-Alzheimer’s disease pathophysiology;
SUVr: Regional standardized uptake value; TIV: Total intracranial volume;
UCSF: University of California, San Francisco
We thank Dr. Susan Landau of the University of California, Berkley, for
answering our early questions about ADNI volumetric data. We also thank
the ADNI investigators. Data used in preparation of this article were obtained
from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database
(adni.loni.usc.edu). As such, the investigators within the ADNI contributed to
the design and implementation of ADNI and/or provided data but did not
participate in the analysis or writing of this report. A complete listing of
ADNI investigators can be found at http://adni.loni.usc.edu/wp-content/
This work was supported by the Alzheimer’s Disease Neuroimaging Initiative
(ADNI) (National Institutes of Health grant U01 AG024904) and the U.S.
Department of Defense ADNI (Department of Defense award number
W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the
National Institute of Biomedical Imaging and Bioengineering, as well as
through generous contributions from the following: AbbVie; the Alzheimer’s
Association; the Alzheimer’s Drug Discovery Foundation; Araclon Biotech;
BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Eisai Inc.;
Elan Pharmaceuticals, Inc.; Eli Lilly and Company; Euroimmun; F. Hoffmann-La
Roche Ltd. and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare;
IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC;
Johnson & Johnson Pharmaceutical Research & Development LLC; Lumosity;
Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC; NeuroRx Research;
Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.;
Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition
Therapeutics. The Canadian Institutes of Health Research is providing funds to
support ADNI clinical sites in Canada. Private sector contributions are facilitated
by the Foundation for the National Institutes of Health (www.fnih.org). The
grantee organization is the Northern California Institute for Research and
Education, and the study is coordinated by the Alzheimer’s Disease Cooperative
Study at the University of California, San Diego. ADNI data are disseminated by
the Laboratory for Neuro Imaging at the University of Southern California.
Research reported in this publication was supported by an institutional
development award (IDeA) from the National Institute of General Medical
Sciences of the National Institutes of Health under grant number
5P20GM109025. In addition, research reported in this publication was supported
in part by a grant from A Woman’s Nation/Maria Shriver (to JZKC, SJB).
Availability of data and materials
The data that support the findings of this study are available from the
Alzheimer’s Disease Neuroimaging Initiative (ADNI), but some restrictions
apply to the availability of these data, including a data use agreement and
publication agreement. The data published herein were used under these
agreements and so are not publicly available. Data are, however, available
from the authors upon reasonable request and with permission of the ADNI.
JZKC acquired data, designed the study, analyzed and interpreted data, and
prepared the manuscript. JLB acquired data and prepared the manuscript.
JLC provided critical revision of the manuscript for intellectual content. SJB
designed the study, interpreted data, and provided critical revision of the
manuscript for intellectual content. All authors read and approved the final
Ethics approval and consent to participate
All data included in this article were collected for research use as part of the
Alzheimer’s Disease Neuroimaging Initiative (ADNI) project. ADNI is a
longitudinal, multisite AD biomarker study (www.adni-info.org) that offers
de-identified data meeting criteria for limited datasets to qualified
researchers with scientific or educational institution affiliations, upon review.
Ethics approval for data collection in ADNI was obtained by each ADNI
participating institution’s institutional review board. All participants gave
written informed consent at participating institutions. The authors of this
paper were granted approved access to the ADNI data, and the ADNI Data
Sharing and Publications Committee (DPC) approved this paper for submission
to Alzheimer’s Research and Therapy (date of approval, February 24, 2017).
Consent for publication
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