Hippocampal Atrophy is Associated with

Subjective Memory Decline: The PATH

Through Life Study
Nicolas Cherbuin, Ph.D., Kerry Sargent-Cox, Ph.D., Simon Easteal, Ph.D.,
Perminder Sachdev, M.D., Ph.D., F.R.A.N.Z.C.P., Kaarin J. Anstey, Ph.D.

Objectives: To investigate whether subjective memory decline (SMD) in cognitively

healthy individuals is associated with hippocampal atrophy. Methods: Multiple
regression analyses assessing the relationship between hippocampal atrophy over 4
years and SMD at baseline and follow-up in 305 cognitively healthy individuals aged
60e64 years free from dementia, mild cognitive impairment, and other neurological
disorders. Results: SMD at baseline was not a signicant predictor of hippocampal
atrophy. However, SMD at follow-up was associated with greater hippocampal atrophy. Associations were reduced but remained signicant after controlling for anxiety
and depression symptomatology. Conclusions: Hippocampal atrophy was associated
with incident/persisting SMD and this association was not, or only partly, explained
by anxiety and depression symptomatology. These results are consistent with a biological origin to subjective memory decline. SMD should be included in screening and
neuropsychological batteries. (Am J Geriatr Psychiatry 2014; -:-e-)
Key Words: Cognitive decline, longitudinal, APOE 4, MRI

ubjective memory decline (SMD) in ageing is of

particular interest because it may be a prodromal
sign of pathological processes leading to dementia,
and because its relative ease of assessment makes it
well suited as a broad screen for individuals at risk.1,2
Moreover, concern about change in cognition
contributes to the diagnosis of mild cognitive
impairment (MCI), therefore ensuring that SMD is
reective of known pathological processes is highly
relevant to clinicians.

In epidemiological studies prevalence of SMD in

individuals in their seventies has been reported to
range between 22%e60% and to be somewhat higher
in women.3e5 SMD prevalence, however, is likely to
be inuenced by the formulation of questions
assessing its presence. For example, in the English
2007 Adult Psychiatry Morbidity Survey, which
included 7,461 participants aged 16 years and over,
31.7% reported forgetfulness in the last month but
only 6.4% reported having forgotten something

Received August 26, 2013; revised July 4, 2014; accepted July 21, 2014. From the Centre for Research on Ageing, Health and Wellbeing,
Australian National University (NC, KS-C, KJA), Canberra, Australia; the John Curtin School of Medical Research, Australian National
University (SE), Canberra, Australia; and the School of Psychiatry, University of New South Wales (PS), Sydney, Australia. Send correspondence and reprint requests to Nicolas Cherbuin, Ph.D., Centre for Research on Ageing, Health and Wellbeing, 62A Eggleston Rd.,
Australian National University, Canberra, ACT 0200, Australia. e-mail: nicolas.cherbuin@anu.edu.au
Supplemental digital content is available for this article in the HTML and PDF versions of this article on the journals Web site (www.
ajgponline.org).
2014 American Association for Geriatric Psychiatry
http://dx.doi.org/10.1016/j.jagp.2014.07.009

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Hippocampal Atrophy and Subjective Memory Decline

important in the last week.6 Although the prevalence
of forgetfulness did not vary between age groups, an
association between cognition was only found in
those above 60 years of age and only in those who
reported forgetting something important in the last
week. In those aged 16e60 years the only predictors
of forgetfulness were anxiety and depressive and
somatic symptoms. These ndings may indicate that
the etiology of SMD varies with age, with SMD being
more attributable to depression or anxiety symptomatology in younger age groups and to neurodegenerative processes in older individuals.
A link between presence of SMD in later life and
neurodegenerative processes is supported by studies
demonstrating associations between SMD and dementia, MCI, or related pathological processes. SMD has
been found to be associated with APOE 4 genotype,7
with an almost twofold increased risk of incident dementia,3,8,9 a fourfold increased risk of incident MCI,10
and with prospective cognitive decline.11,12 Associations between SMD and objective neuropsychological
measures have been found to be weak,13 however, and
SMD has low predictive value for dementia.14 In addition, SMD is linked with anxiety and depression
symptomatology, thus making it a less-specic clinical
marker and its signicance more difcult to interpret,15,16 although it should be noted that mood disorders are also risk factors for Alzheimer disease (AD).17 It
is therefore possible that the association of SMD with
cognitive decline is concurrent to or causally interrelated with its association with affective symptoms.
Of methodological importance, SMD and subjective memory complaints (SMCs) are terms that have
been used interchangeably. Although the two constructs are likely to overlap, SMD should not be
confused with SMC. Where SMD is assessed by asking
individuals, generally in community-based studies,
whether they have experienced a change in memory
performance, SMCs are based on individuals seeking
clinical advice and reporting concerns and therefore
may have different origins and clinical signicance.
For example, in a longitudinal investigation of
memory-clinic patients, whereas 41% of those reporting memory complaints presented with normal
cognitive function at baseline, 37% were classied as
having MCI and 22% as having dementia.18 Moreover,
after a 3-year follow-up 9% of those without objective
impairment converted to MCI, and 27% of those with
MCI progressed to dementia. Such associations

appear to be substantially stronger than those found in

relation to SMD.14 For example, Luck and colleagues19
investigated incident MCI in 732 individuals living in
the community and free of impairment and found that
those reporting SMD (Do you have problems with
your memory?) were at only a twofold increased risk
of developing MCI over an 8-year follow-up. SargentCox and colleagues found that those reporting that
SMD interfered with their day-to-day life were at a
threefold increased risk of developing MCI over 4
years.10 Differences between reports and self-initiated
complaints may therefore reect important distinctions in the nature or the timing of underlying processes, although some overlap is likely. For example,
in cross-sectional analyses Anstey and colleagues20
found that individuals with stable MCI, who were
more likely to report having memory problems which
interfered with daily life, were also more likely to have
consulted a doctor about memory concerns.
Few studies have investigated the association between SMD and brain structure. In a cross-sectional
study Bartley et al.15 investigated associations between SMD (Do you feel like your memory or
thinking is becoming worse?) and white matter disease and found no association. In another study Lamar
et al.21 found that increased leukoaraiosis load was
associated with poorer learning in individuals with
SMD (Have you or anyone close to you noticed any
problems or change in your memory?). In a third
study of memory clinic patients (N 31; mean age: 67.6
years) responding yes to Do you feel like your memory is becoming worse? Scheef et al.22 found that SMD
were associated with smaller right but not left hippocampal volume and with hypometabolism in the right
precuneus and hypermetabolism in the right hippocampus, with no signicant differences in the corresponding left structures, thus suggestive of a possible
laterality effect. Moreover, they found that those
reporting difculties with their memory experienced
greater memory decline over an 8-month follow-up.
We are aware of only one study that investigated
prospectively whether SMD was associated with
longitudinal change in brain structure. In a sample of
1,336 individuals with a mean age of 72 years and free
of dementia at baseline, Stewart et al.23 found that
reporting SMD at follow-up 4 years later (Do you
have habitual forgetfulness during daily activities/
difculties remembering recent new information?)
was associated with prior hippocampal and gray

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Cherbuin et al.
matter atrophy and increase in white matter lesions.
Reporting SMD at baseline was only marginally
associated with change in brain structure suggesting
that SMD follows rather than precedes cerebral
changes. It is unclear, however, whether similar associations are also present in younger individuals in
whom cerebral changes are likely to be less prominent. Moreover, in a previous cross-sectional study of
the same sample associations between SMD and brain
volumes were already present at baseline.24 It is
therefore unclear whether larger regional volumes
earlier in life provide some brain reserve which may
have a protective effect against SMDs occurrence or
whether baseline associations indicate that changes in
cerebral structure associated with SMD occur before
the early 70s but are not detectable until the early 60s.
The aim of the present study is to investigate the association between SMD at baseline and follow-up and
hippocampal volume and atrophy over 4 years in a large
cohort of community-based individuals in their 60s and
free of dementia or MCI using manual tracings on high
resolution MRI scans. Other aims are to assess whether
depression and anxiety symptomatology might explain
any association detected between SMD and hippocampal structure and to conrm whether, as found by
Stewart et al., associations between SMD and brain
structure are more suggestive of brain changes preceding the occurrence of SMD rather than the reverse.

METHODS
Study Sample
The sample for this study comprised the participants from the MRI sub-study of the rst two waves
of the larger PATH Through Life project, which has
been described elsewhere.25 Briey, participants
(60e64 years) who were residents of the cities of
Canberra and Queanbeyan, Australia, were recruited
randomly through the electoral roll to participate in a
longitudinal study of ageing. Enrollment to vote is
compulsory for Australian citizens. A total of 2,551
participants were included at baseline (2001), representing a 58.3% response rate. Of those, 2,076 agreed
to be contacted regarding magnetic resonance imaging (MRI) assessment; 622 randomly selected participants were offered a scan, and 479 completed a
structural MRI scan. Of those, 431 underwent an MRI

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FIGURE 1. Sample selection process.

scan at wave 2 (2005) and after excluding participants

with MRI images of poor quality (N 42), neurological disorders (N 66; MCI 20, abnormal
MRI 22, stroke 21, epilepsy 3), and incomplete
data (N 18), 305 participants were available for
consideration in the present investigation (see Fig. 1).
All participants were screened for cognitive impairment and dementia, those scoring below specied
thresholds received a neuropsychological assessment
and consensus clinical diagnoses were given based
on established criteria (see Anstey et al.20,26 for a
detailed description of the methodology used). No
case of dementia was present at either wave 1 or
wave 2 in the MRI sub-sample.
Standard Protocol Approvals, Registrations, and
Patient Consents
The study was approved by the Australian National University Ethics Committee and all participants provided written informed consent.

Hippocampal Atrophy and Subjective Memory Decline

Sociodemographic and Health Measures
Total years of education, stroke, and depression and
anxiety symptomatology (Goldberg depression and
anxiety scale27), diabetes, and physical health (SF-12)
were assessed by self-report. Body mass index was
computed with the formula weight (kg)/height  height
(m2) based on self-report of weight and height. Systolic
and diastolic blood pressures were computed over
two measurements using an Omron M4 monitor
(Hoofddorp, the Netherlands) after a rest of at least 5
minutes. Participants were classied as hypertensive if
their mean diastolic or systolic blood pressure measures
were higher than 90 and 140 mm Hg, respectively, or if
they took antihypertensive medication.
APOE genotypes were determined using Taqman
assays on genomic DNA obtained from buccal
swabs, as previously described.28 Because the number of individuals in the sample with APOE 4/4
homozygous genotypes was small (N 3), they were
combined with those with the two possible 4 heterozygous genotypes (4/2 and 4/3) to form the 4
carrier genotype class, thereby, in effect, assuming a
dominant effect of the 4 allele.
Subjective Memory Decline
SMD was assessed by self-report at wave 1 and wave
2. Participants were asked the question Do you feel you
can remember things as well as you used to? and were
categorized as experiencing SMD if they responded no.
MRI Scan Acquisition
All participants were imaged with a 1.5-Tesla Philips
Gyroscan ACS-NT scanner (Philips Medical Systems,
Best, The Netherlands) for T1-weighted 3-D structural
MRI in coronal orientation using a fast-eld echo
sequence: Wave 1 repetition time (TR) 28.05 msec;
echo time (TE) 2.64 msec; ip angle 30 ; matrix size
256  256; eld of view (FOV) 260  260 mm; slice
thickness 2.0 mm and mid-slice to mid-slice distance
1.0 mm, yielding over-contiguous coronal slices;
Wave 2 TR 8.93 msec, TE 3.57 msec, ip angle 8 ,
matrix size 256  256, FOV 256  256 mm. Slices
were contiguous with slice thickness of 1.5 mm.
Image Analysis
Hippocampal volumes were determined by manually tracing the periphery of the region of interest

(ROI) on each slice of a T1-weighted scan in coronal

orientation using Analyze 5.0 (Brain Imaging
Resource, Mayo Clinic, Rochester, MN). The outlining
of the hippocampus always proceeded from anterior
to posterior and was traced according to the protocol
outlined by Watson and colleagues29 with a modication suggested by Brierly et al.30 Volume estimations were repeated on 10 randomly selected scans
and intraclass correlations between raters exceeded
0.95 for all structures.31,32 Intracranial volume (ICV)
was computed with Freesurfer 4.3 (http://surfer.nmr.
mgh.harvard.edu) for wave 1 and wave 2 images.
Statistical Analysis
Descriptive analyses were conducted using c2 tests
for categorical data and t tests to compare groups on
continuous variables. Hippocampal volumes were
normalized for ICV using the formula:
adjusted volume raw volume  b  ICV  mean ICV

where b is the slope of regression of an ROI volume

on ICV. Associations between SMD and hippocampal volumes and atrophy were investigated using
hierarchical multiple regression analyses while controlling for sex, age, APOE genotype in model I and
for sex, age, APOE genotype, depression and anxiety
symptomatology, diabetes, and hypertension for
model II. Diabetes and hypertension were added as
covariate due to their associations with neurodegenerative processes, particularly in the hippocampus.33,34 Hippocampal atrophy was assessed by
using wave 2 volume as dependent variable and
controlling for wave 1 volume as covariate in the
analyses, while also controlling for elapsed time between assessments. In addition, because the image
acquisitions were different between waves, the difference in ICV between wave 1 and wave 2 was also
controlled for by entering it as a covariate in the analyses, an approach already applied elsewhere.35 Interactions between SMD and sex and APOE genotype
were also tested. Alpha was set at 0.05.

RESULTS
Participants were on average 62.6 years (range:
60e65; SD: 1.39) at wave 1 with a mean follow-up of
4 years (range: 3.3e4.6; SD: 0.21). Of the 305 participants included, 70 reported SMD at wave 1 (23%)

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TABLE 1. Participants Demographic and Health Characteristics

Demographic Variables

No SMD (N [ 218)

Female, N (%)
Agea, years (SD)
Educationa, years (SD)
APOE 4, N (%)
Depression, score (SD)
Anxiety, score (SD)
Diabetes, N (%)
Hypertension, N (%)
Physical Health SF-12 (SD)
BMI, kg/m2 (SD)
Systemic BP, mm Hg (SD)
Diastolic BP, mm Hg (SD)
Left HC, mm3 (SD)
Right HC, mm3 (SD)

110
62.68
14.08
67
1.72
2.39
20
135
49.64
26.70
139.64
82.84
2,815.21
2,880.06

(50.50)
(1.32)
(2.65)
(30.70)
(1.84)
(2.40)
(9.20)
(61.90)
(8.90)
(4.85)
(18.29)
(10.48)
(436.53)
(466.45)

W1 SMD (N [ 70)
18
62.13
14.78
16
0.76
1.26
4
48
52.14
26.30
141.71
85.96
2,905.65
2,930.99

(25.71)**
(1.42)**
(2.53)
(22.86)
(1.01)**
(1.56)**
(5.70)
(68.60)
(7.04)
(3.71)
(18.08)
(11.41)*
(406.13)
(423.15)

W2 SMD (N [ 56)
18
62.41
14.36
11
0.86
1.25
4
33
50.88
26.27
140.58
86.05
2,861.72
2,934.08

(32.14)
(1.51)
(2.95)
(19.64)
(1.38)yy
(1.89)yy
(7.10)
(58.90)
(8.03)
(3.70)
(17.84)
(12.44)
(347.23)
(365.57)

W1DW2 SMD (N [ 39)

9
62.26
14.50
8
0.56
1.10
2
23
51.70
25.95
140.09
86.47
2,882.29
2,930.68

(23.10)AA
(1.43)
(2.89)
(20.51)
(0.82)AA
(1.35)AA
(5.10)
(59.00)
(7.77)
(3.88)
(19.20)
(13.22)
(361.67)
(388.23)

Notes: SMD: subjective memory decline; SF-12: short form of the Health Survey; BMI: body mass index; BP: blood pressure; W1: wave 1;
W2: wave 2.
Differences were tested with t tests (df: W1 286, W2 272, W1W2 255) for continuous variables and c2 tests (df 1) for categorical
variables; difference between W1 SMD and no SMD signicant at *p <0.05 and **p <0.01; difference between W2 SMD and no SMD
signicant at yp <0.05 and yyp <0.01; difference between W1W2 SMD and no SMD signicant at AAp <0.01.
a
At wave 1.

and 56 at wave 2 (18%), with 39 participants reporting SMD both at wave 1 and 2 (13%) and 31 participants reporting SMD at wave 1 but not at wave 2
(44%). Demographic measures for all participants are
presented in Table 1 for each SMD group. Those who
reported SMD at wave 1 were more likely to be male,
were slightly younger, had lower depression and
anxiety symptomatology, and had a higher diastolic
blood pressure than those who did not. Those who
reported SMD at wave 2 or at both waves were more
likely to be male and had lower depression and
anxiety symptomatology but did not differ in age or
diastolic blood pressure (see Table 1).
Because ICVs at wave 1 and wave 2 differed, with the
wave 2 volume being slightly (2.7%) but signicantly
smaller (t(332) 8.185, p <0.001), the possible impact of
ICV differences was further investigated with correlational analyses (not shown) which demonstrated that
the difference in ICV between wave 1 and 2 explained
less than 1.5% of the variance in ROI volume change.
Association between hippocampal volume or atrophy and SMD present at either wave 1, wave 2, or at both
waves 1 and 2 are presented in Tables 2, 3, and 4. In a rst
model, analyses were controlled for sex, age, and APOE
genotype and in the second model depression and
anxiety symptomatology, diabetes, and hypertension
were controlled for in addition to confounders included
in the rst model. Atrophy was assessed by controlling
for wave 1 volume and time between wave 1 and 2

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assessments while predicting wave 2 volume. These

analyses showed that SMD at wave 1 (Table 2) was not
associated with hippocampal volumes at wave 1 or with
hippocampal atrophy over 4 years in either models. In
contrast, SMD at wave 2 (Table 3) was negatively associated with left (trend) and right hippocampal volumes
at wave 2 as well as with left and right hippocampal
atrophy. These associations were attenuated but
remained signicant, except for left hippocampal atrophy (trend), after controlling for depression and anxiety
symptomatology in model II. Moreover, presence of
SMD at both wave 1 and 2 (Table 4) was associated with
greater right but not left hippocampal atrophy and with
lower right but not left wave 2 hippocampal volumes.
No signicant association was detected in relation to
wave 1 hippocampal volume (data not shown). These
associations remained signicant for atrophy (trend for
volume) after controlling for depression and anxiety
symptomatology in model II. None of the sex or APOE
interactions reached signicance.
Additional analyses were conducted to investigate
associations between SMD and hippocampal volume/atrophy in those who only reported SMD at
wave 1 and in those who only reported SMD at wave
2 (excluding those with SMD at both waves). Sociodemographic characteristics for these groups are reported in Supplementary Table A1 (available online),
and associations with hippocampal volume/atrophy
are presented in Tables A2 and A3 (available online).

p
b (SE)
Models

b (SE)

Right
Left

Notes: Signicant results at p <0.05 are highlighted in the table with bold font. b: unstandardized coefcient; SE: standard error; W1: wave 1; W2: wave 2.
a
After normalization for intracranial volume.
Multiple regression analyses (df 304) controlling for bsex, age, APOE genotype (model I); and csex, age, W1eW2 intracranial volume difference, APOE genotype, elapsed time
between assessment, and baseline volume (model II). Atrophy in model II is assessed by controlling for baseline hippocampal volume, therefore a positive association reects less
atrophy.

p
b (SE)
b (SE)
b (SE)

Left

Right

b (SE)

Right
Left

Wave 1 Hippocampal Volume

Hippocampal Atrophy

Wave 1 Hippocampal Volume

Sex
L279 (48) 0.001 L327 (50) 0.001 L99 (37) 0.008 L177 (38) 0.001 L278 (48) 0.001 L325 (50) 0.001 L99 (37) 0.008 43 (185) 0.817
Age
13 (17) 0.451
17 (18) 0.350
3 (13) 0.812
7 (13) 0.565
13 (17) 0.457
17 (18) 0.335
2 (12) 0.876
6 (13)
0.622
APOE 4
3 (52) 0.966
12 (55) 0.823 L98 (38) 0.01
L89 (38) 0.022
3 (52) 0.957
11 (54) 0.840 L95 (38) 0.012 L86 (38) 0.025
Hypertension
27 (49) 0.587
46 (40) 0.249 21 (36) 0.564
31 (36) 0.391
25 (49) 0.608
20 (51) 0.700 18 (36) 0.614 28 (36)
0.442
Diabetes
60 (84) 0.471
25 (88) 0.781
170 (61) 0.006
158 (61) 0.010
64 (84) 0.453
18 (88) 0.835
159 (61) 0.011 144 (62) 0.020
Depression
5 (18) 0.778
28 (19) 0.138
16 (14) 0.214
19 (13)
0.157
Anxiety
10 (14) 0.465
19 (14) 0.174
4 (10) 0.656
1 (10)
0.927
SMD at W1
18 (57) 0.760
46 (60) 0.450
17 (42) 0.692
33 (42) 0.439
12 (59) 0.838
40 (61) 0.514
36 (43) 0.402 15 (43)
0.730
0.000
0.002
0.000
0.001
0.000
0.001
0.002
0.000
Part. Eta2

b (SE)
b (SE)

Right
Left

Hippocampal Atrophya,c
II
a,b
a,c

I
a,b

TABLE 2. Associations Between SMD at Wave 1 and Hippocampal Volume at Wave 1 and Atrophy Between Wave 1 and Wave 2 (N [ 305)

Hippocampal Atrophy and Subjective Memory Decline

DISCUSSION
The main nding of this study was that SMD at
follow-up, but not at baseline, was associated with
longitudinal hippocampal atrophy over 4 years. This
is an important result because it is more consistent in
our view with previous ndings that SMD tends to
follow rather than precede cerebral changes. Moreover, this effect was found in younger individuals
(62e66 years) than those surveyed in a previous
study23 (72e76 years). Interestingly, although Stewart et al. found that baseline SMD at age 72 was
associated with brain structure in cross-sectional analyses, associations between baseline SMD and brain
changes over the following 4 years were low. In the
present investigation baseline SMD was not associated with baseline hippocampal volume. This may
indicate that a link between SMD and cerebral
changes becomes detectable in the early 60s without
prior association earlier in life. This explanation is
consistent with previous ndings from the English
2007 Adult Psychiatry Morbidity Survey which
showed that forgetfulness is equally prevalent across
the adult lifespan but that an association between
forgetfulness and cognition only becomes apparent in
those aged greater than 60 years.6 It is also consistent
with revised models of biomarker progression proposed by Jack et al., which suggest that those at
increased risk of developing AD present with relatively stable hippocampal volumes although somewhat below the norm until the early 60s, after which
a progressive decline is observed.36
Combined with other ndings in the literature the
present results appear to indicate that detectable
volumetric differences associated with neurodegenerative processes predictive of SMD become salient in
the early 60s and seem to mostly precede the emergence of functional difculties. In the mid to late 60s
volumetric changes and SMD seem to co-occur, as
shown in our and Scheef et al.s22 cross-sectional analyses at a similar age. In the late 60s and 70s SMD
becomes more strongly associated with the development of MCI and dementia,14,19 conditions whose
neurodegenerative impact are well documented. It
should also be noted, however, that in the present
investigation a sub-sample of those with SMD at
wave 1 who also reported SMD at wave 2 did present
with prospective hippocampal atrophy, although this

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L117 (50) 0.020

0.015
0.055

Notes: Signicant results at p <0.05 are highlighted in the table with bold font. b: unstandardized coefcient; SE: standard error; W1: wave 1; W2: wave 2.
a
After normalization for intracranial volume.
Multiple regression analyses (df 304) controlling for bsex, age, APOE genotype (model I); and csex, age, W1eW2 intracranial volume difference, APOE genotype, elapsed time
between assessment, and baseline volume (model II). Atrophy in model II is assessed by controlling for baseline hippocampal volume, therefore a positive association reects less
atrophy.

0.001
0.584
0.018
0.262
0.015
0.797
0.320
0.019
0.002 L187 (37)
0.978
7 (12)
0.008 L91 (38)
0.465
41 (36)
0.010
150 (61)
0.110
3 (12)
0.443
10 (11)
0.080 L107 (46)
0.012
0.001 L113 (37)
0.940
1 (12)
0.032 L103 (38)
0.330
26 (36)
0.023
159 (61)
0.049
1 (12)
0.494
8 (10)
0.044
79 (45)
0.007
0.001 L296 (39)
0.715
1 (14)
0.017 L92 (43)
0.316
49 (50)
0.006
158 (70)
0.282
29 (15)
0.821
8 (11)
0.090 L103 (51)
0.011
0.001 L229 (39)
0.547
5 (15)
0.012 L104 (43)
0.283
41 (40)
0.010
184 (70)
16 (15)
3 (11)
L88 (44) 0.046 L116 (44) 0.009
87 (51)
0.009
0.014
0.008
0.003 L183 (37)
0.940
7 (12)
0.005 L96 (38)
0.486
39 (36)
0.006
158 (61)
0.001 L110 (36)
0.843
1 (12)
0.027 L106 (38)
0.249
25 (36)
0.020
167 (81)

p
b (SE)
p
b (SE)
Models

0.001 L296 (39)

0.772
3 (14)
0.015 L95 (43)
0.268
46 (40)
0.005
174 (69)

p
b (SE)
b (SE)

b (SE)

b (SE)

Right
Left
Right
Left
Right
Left

Sex
L228 (39)
Age
4 (14)
APOE 4
L106 (43)
Hypertension
45 (40)
Diabetes
194 (69)
Depression
Anxiety
SMD at W2
97 (50)
0.011
Part. Eta2

b (SE)
b (SE)

Right
Left

II
Wave 2 Hippocampal Volumea,b
Hippocampal Atrophya,c
I
Wave 2 Hippocampal Volumea,b

TABLE 3. Associations Between SMD at Wave 2 and Hippocampal Volume at Wave 2 and Atrophy Between Wave 1 and 2 (N [ 305)

Hippocampal Atrophya,c

Cherbuin et al.
effect was smaller than that detected in all those with
SMD at wave 2. This appears to suggest that either
SMD preceded brain changes in these individuals or
that the neurodegenerative processes were initiated
earlier in this group. Unfortunately, this study cannot
provide conclusive answers to these questions and
future investigations including multiple assessments
will be able to test these hypotheses with time-lag
analyses.
Interestingly, a number of our analyses, particularly in those reporting SMD at both assessments,
demonstrated associations with the right but not the
left hippocampus. These ndings are consistent with
cross-sectional results reported by Scheef et al.22
showing smaller right but not left hippocampal volumes in those reporting SMD. Such effects should be
further investigated in future studies because the left
and right hemispheres have been reported to differ in
their vulnerability to AD neurodegenerative processes, which tend to start earlier and progress faster
in the left hemisphere.37,38
The prevalence of SMD in the present sample was
similar to rates reported in the literature for epidemiological samples with 23% reporting SMD at baseline and
18% at follow-up.3,23 Because individuals with dementia, MCI, or neurological disorder were excluded, SMD
was not associated with pre-existing clinical disorders.
This suggests that it might be a useful marker, rather
than a co-morbid feature, of prior hippocampal atrophy, which is itself a predictor of future cognitive
decline and dementia.
These ndings elicit important questions. Because
SMD has been shown to be associated prospectively
with dementia and cognitive decline, it would be
particularly useful to know whether SMD in early old
age is the consequence of developing AD or vascular
pathology, or of other causes. Signicant associations
between SMD and increase in white matter lesions
support a vascular origin. Increased prevalence of
SMD in APOE 4 carriers,7 however, would suggest a
role of amyloidosis. One postmortem study has
investigated associations between SMD (How often
do you have trouble remembering things, How is
your memory compared to 10 years ago) and neuritic
plaques and neurobrillary tangles and found that
those reporting memory decline antemortem had
higher AD pathology.39 Importantly, this association
was found both in those diagnosed with AD and
those without, and although the main analyses were

Notes: Signicant results at p <0.05 are highlighted in the table with bold font. b: unstandardized coefcient; SE: standard error; W1: wave 1; W2: wave 2.
a
After normalization for intracranial volume.
Multiple regression analyses (df 304) controlling for bsex, age, APOE genotype (model I); and csex, age, W1eW2 intracranial volume difference, APOE genotype, elapsed time
between assessment, and baseline volume (model II). Atrophy in model II is assessed by controlling for baseline hippocampal volume, therefore a positive association reects less
atrophy.

p
b (SE)
p
b (SE)
Models

0.001
0.271
0.007
0.104
0.003
0.868
0.750
0.046

p
b (SE)
p
b (SE)
p
b (SE)
p
b (SE)
p
b (SE)
b (SE)

Right
Left
Right
Left

0.001 L91 (38) 0.017 L178 (40) 0.001 L200 (41) 0.001 L290 (42) 0.001 L93 (38) 0.016 L180 (40)
0.617
18 (13) 0.175
15 (14) 0.269
8 (15) 0.582
4 (15) 0.792
18 (13) 0.176
15 (14)
0.028 L119 (39) 0.002 L113 (40) 0.006 L98 (45) 0.031
82 (45) 0.073 L121 (39) 0.002 L111 (41)
0.164
58 (36) 0.118
61 (38) 0.110
41 (40) 0.316
49 (50) 0.330
58 (37) 0.116
62 (38)
0.003
220 (63) 0.001
204 (65) 0.002
184 (70) 0.006
158 (70) 0.023
214 (64) 0.001
200 (66)
23 (15) 0.137
41 (16) 0.009
7 (13) 0.604
2 (13)
2 (12) 0.846
11 (12) 0.366
1 (11) 0.920
4 (11)
0.026
52 (50) 0.299 L114 (52) 0.029
44 (60) 0.463 103 (60) 0.088
46 (52) 0.375 L107 (54)
0.003
0.012
0.002
0.009
0.002
0.010

Right
Left

Wave 2 Hippocampal Volume

Hippocampal Atrophy
Wave 2 Hippocampal Volume

Sex
L201 (40) 0.001 L293 (42)
Age
13 (15) 0.387
8 (15)
APOE 4
L117 (44) 0.009 L100 (45)
Hypert
64 (41) 0.120
59 (42)
Diabetes
253 (71) 0.001
223 (73)
Depression
Anxiety
SMD at W1W2
60 (57) 0.294 L131 (58)
0.004
0.016
Part. Eta2

Right
Left

Hippocampal Atrophya,c
II
a,b
a,c

I
a,b

TABLE 4. Associations Between SMD Present at Both Waves 1 and 2 in the Same Individuals and Hippocampal Volume at Wave 2 and Atrophy Between Wave 1 and 2
(n [ 257) After Controlling for Age, Gender, and APOE Genotype (Model I) and After Controlling for Age, Gender, APOE Genotype, Diabetes, Hypertension,
Depressive and Anxiety Symptomatology (Model II).

Hippocampal Atrophy and Subjective Memory Decline

conducted using a global measure of AD pathology
(neuritic plaques and neurobrillary tangles combined), further analyses showed that both pathological features equally predicted the presence of SMD.
Moreover, adjusting for depressive symptomatology
and chronic health conditions did not substantially
moderate these associations. In aggregate, these
ndings suggest both a vascular and an AD component to SMD, but it is not clear whether this is also
likely to be the case in early old age and this question
should be further scrutinized in future research.
Depression and anxiety are important confounders
that are known to be associated with SMD and
memory complaints across the lifespan. Furthermore,
diabetes and hypertension are associated with
neurodegenerative processes and hippocampal atrophy. In the present investigation we specically
considered their effect. We found that although the
associations between SMD and hippocampal volume/atrophy were somewhat weaker after controlling for anxiety and depression symptomatology on
their own (results not shown) or in conjunction to
diabetes and hypertension, they remained signicant
in most instances. Importantly, those with SMD had
lower anxiety and depression symptomatology, suggesting that SMD without anxiety and/or depression
should be considered particularly seriously.
It is also interesting to note that those with SMD
had on average a higher level of education, did not
differ in their APOE genotype frequency, and had a
similar physical health prole compared with those
without SMD, which further highlights the fact that
SMD, in the context of normal physical and mental
health, may be of particular signicance in early old
age. APOE genotype is associated with hippocampal
volume and atrophy in most analyses, consistent with
some but not all previous ndings in both AD patients and healthy subjects.28,40e42 We found, however, that hippocampal volume was signicantly
associated with SMD when controlling for the effect
of APOE genotype, suggesting an independent effect.
This study has a number of strengths, including
manual tracing of the hippocampus, a large sample
size, a longitudinal design, and the use of a communitybased narrow-age sample which reduces the risk of
cohort bias. There were also a number of limitations,
however. Scanning parameters differed at baseline and
follow-up and although this difference cannot explain
the pattern of result observed (as all participants were

Am J Geriatr Psychiatry

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2014

Cherbuin et al.
scanned with the same methodology at each wave), it
could have inuenced the magnitude of our ndings.
In addition, SMD was assessed in a relatively crude
way and although this is the norm in this area of
research, and some have presented the simplicity and
relative non-threatening nature of such surveys as an
advantage,2 more ne-grained assessment of SMD
may provide important additional information. In
addition, although the sample size was large for a
study of this type it may not have provided sufcient
statistical power in sub-analyses to detect sex and
APOE genotype interactions. For example, if indeed
hippocampal atrophy precedes SMD, it would have
been expected that a signicant association would be
detected between SMD present at follow-up only and
hippocampal atrophy. No such association was
demonstrated. This was possibly because the small
number of participants presenting with SMD at
follow-up only (N 17) did not provide sufcient

statistical power to more convincingly inform this

question. Alternatively, it is also possible that SMD
and hippocampal atrophy follow a more concurrent
development. This question will need further attention in future longitudinal investigations.
The authors are grateful to Peter Butterworth, Anthony Jorm, Helen Christensen, Chantal Reglade-Meslin,
Jerome Maller, Patricia Jacomb, Karen Maxwell, and the
PATH project interviewers. The study was supported by
National Health and Medical Research Council grants
973302, 179805, 157125, 1063907, and ARC grant
1063907. Nicolas Cherbuin is funded by ARC Research
Fellowship 120100227 and Kaarin Anstey by NHMRC
Research Fellowship 1002560. This research was partly
undertaken on the National Computational Infrastructure
(NCI) facility in Canberra, Australia, which is supported
by the Australian Commonwealth Government.
The authors have reported no conicts of interest.

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