Bender 2012

Accepted Manuscript
Title: Age-Related Differences in Memory and Executive

Functions in Healthy APOE ␧4 Carriers: The Contribution of
Individual Differences in Prefrontal Volumes and Systolic
Blood Pressure
Authors: Andrew R. Bender, Naftali Raz
PII: S0028-3932(12)00010-3
DOI: doi:10.1016/j.neuropsychologia.2011.12.025
Reference: NSY 4368
To appear in: Neuropsychologia
Received date: 12-8-2011

Revised date: 10-11-2011
Accepted date: 23-12-2011
Please cite this article as: Bender, A. R., \& Raz, N., Age-Related
Differences in Memory and Executive Functions in Healthy {\it{APOE}}
rmvarepsilon4 Carriers: The Contribution of Individual Differences in Prefrontal
Volumes and Systolic Blood Pressure, {\it{Neuropsychologia}} (2010),
doi:10.1016/j.neuropsychologia.2011.12.025
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Highlights:
 Studied: effects of genetic and physiological vascular risk on brain and cognition.
 Examined links of age, systolic BP, brain volumes, and cognition with path analysis.
 Found smaller prefrontal volumes in APOE 4 carriers with elevated systolic BP.
 Observed reduced cognitive performance in 4 carriers with high-normal BP.
 APOE 4 and physiological vascular risk act in synergy to reduce performance.
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BLOOD PRESSURE BRAIN VOLUMETRY COGNITION 2
Running head: BLOOD PRESSURE BRAIN VOLUMETRY COGNITION 2
1/5/2012
Age-Related Differences in Memory and Executive Functions in Healthy APOE 4 Carriers: The
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Contribution of Individual Differences in Prefrontal Volumes and Systolic Blood Pressure
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Andrew R. Bender
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Department of Psychology & Institute of Gerontology, Wayne State University
Naftali Raz
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Department of Psychology & Institute of Gerontology, Wayne State University
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Author Note
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Andrew R. Bender, Department of Psychology & Institute of Gerontology, Wayne State

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University; Naftali Raz, Department of Psychology & Institute of Gerontology, Wayne State
University.
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This study was supported in part by a grant from the National Institutes of Health (R37-
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AG-11230).
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Correspondence concerning this article should be addressed to Naftali Raz, 87 E. Ferry
Street, 226 Knapp Building, Detroit, MI 48202. Email: nraz@wayne.edu
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Abstract
Advanced age and vascular risk are associated with declines in the volumes of multiple brain
regions, especially, the prefrontal cortex, and the hippocampus. Older adults, even
unencumbered by declining health, perform less well than their younger counterparts in multiple
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cognitive domains, such as episodic memory, executive functions, and speed of perceptual
processing. Presence of a known genetic risk factor for cognitive decline and vascular disease,
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the ε4 allele of the apolipoprotein E (APOE) gene, accounts for some share of those declines;
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however, the extent of the joint contribution of genetic and physiological vascular risk factors on
the aging brain and cognition is unclear. In a sample of healthy adults (age 19-77), we examined
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the effects of a vascular risk indicator (systolic blood pressure, SBP) and volumes of
hippocampus (HC), lateral prefrontal cortex (lPFC), and prefrontal white matter (pFWM) on
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processing speed, working memory (WM), and recognition memory. Using path analyses, we
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modeled indirect effects of age, SBP, and brain volumes on processing speed, WM, and memory
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and compared the patterns of structural relations among those variables in APOE ε4 carriers and
ε3 homozygotes. Among ε4 carriers, age differences in WM were explained by increase in SBP,

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reduced FWM volume, and slower processing. In contrast, lPFC and FWM volumes, but not BP,
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explained a share of age differnces in WM among ε3 homozygotes. Thus, even in healthy older
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carriers of the APOE ε4 allele, clinically unremarkable increase in vascular risk may be
associated with reduced frontal volumes and impaired cognitive functions.
Keywords: Apolipoprotein E, aging, brain volume, cognition, blood pressure, vascular risk.
Word count: 250
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Age-Related Differences in Memory and Executive Functions in Healthy APOE 4 Carriers: The
Contribution of Individual Differences in Prefrontal Volumes and Systolic Blood Pressure
Advanced age is associated with reduced regional brain volume and impaired
performance in multiple cognitive domains (Raz & Rodrigue, 2006). These differences are
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exacerbated by multiple physiological and genetic variables. For example, hypertension, a
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common age-related vascular risk factor is associated with smaller brain volumes (Salerno et al.,
1992), disproportionately smaller prefrontal cortices (Raz, Rodrigue, & Acker, 2003), and
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accelerated shrinkage of the hippocampus (Raz et al., 2005). Hypertension is also linked to
reduced performance in multiple areas of age-sensitive areas of cognition: speed of perceptual-
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motor processing (Salthouse, 1996b), episodic memory (Brady, Spiro, & Gaziano, 2005;
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Harrington, Saxby, McKeith, Wesnes, & Ford, 2000; Singhmanoux & Marmot, 2005), and
executive functions (Kuo et al., 2004). It is important to keep in mind, however, that
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hypertension is a categorical diagnosis based on cut-off value of arterial blood pressure

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(Chobanian et al., 2003), which is a continuous variable. Therefore, it is plausible that individual
differences in blood pressure account for variance in brain volumes and cognitive performance,
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even in normotensive individuals.

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A significant proportion of individual differences in brain parameters, cognitive

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performance, and vascular risk are explained by genetic makeup (see Jagust, 2009 for
commentary and review; see Song, Stampfer, & Liu, 2004 for meta-analysis and review).
Among the multitude of genetic variants that contribute to variance in brain and cognition, the
best known is a polymorphism of a gene that controls a protein responsible for trafficking of
lipids in the blood vessels, apolipoprotein E (see Hauser, Narayanaswami, & Ryan, 2011 for
review). The protein, APOE, has three isoforms, E2, E3, and E4 that vary in their capability to
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transport lipids, and each isoform corresponds to a specific variant of APOE gene: ε2, ε3, ε4, and
thus is differentially expressed in the carriers of the respective alleles. The ancestral allele of
APOE, 4 is an established risk factor both for vascular disease (Haan & Mayeda, 2010; Song et
al., 2004) and Alzheimer’s dementia (AD; Roses et al., 1993; Lesser, Beeri, Schmeidler, Purohit,
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& Haroutunian, 2011), with ε4 homozygotes carrying a 10- to 12-fold risk for AD in comparison
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to ε3 homozygotes. Moreover, the deleterious effects of the 4 allele may be exacerbated by
advanced age (Haan & Mayeda, 2010; Haan, Shemanski, Jagust, Manolio, & Kuller, 1999;
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Nilsson et al., 2006). It stands to reason, therefore, that carriers of APOE ε4 may evidence
reductions in cerebral regions and cognitive skills that are particularly vulnerable to AD and
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cerebrovascular disease. The extant literature, though not entirely consistent, provides guarded
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support for that prediction (see Buckner, 2004 for a review).
Several studies associated 4 with smaller brain volumes, including prefrontal and medial
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temporal regions (Bartzokis et al., 2007; Espeseth et al., 2008; Honea, Vidoni, Harsha, & Burns,
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2009; Wishart et al., 2006), although others have not found such a link (Cherbuin et al., 2008),
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and in some small samples even the reversed effect was observed (Striepens et al., 2011). A
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recent meta-analysis showed that possession of the 4 allele by healthy adults is associated with
reduced performance on age-sensitive cognitive tasks, such as executive functions and episodic
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memory, and that the effects worsen in old age (Wisdom, Callahan, & Hawkins, 2011). Some
studies suggest that the negative effects of APOE 4 allele on brain volume and cognition are
mediated by phenotypic vascular risk factors, such as elevated systolic blood pressure (SBP;
Peila et al., 2001), or age-associated endothelial cell dysfunction (Yavuz et al., 2008). In addition
to phenotypic vascular risk, APOE 4 may also interact with genes involved in
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neurotransmission to yield impairments in white matter volume and perceptual-motor speed
(Espeseth et al., 2006).
Because cognitive abilities are correlated, it is unclear whether the effect of 4 on
episodic memory (Bondi et al., 1995; Wilson et al., 2002) is specific or reflects its association
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with other cognitive variables, such as processing speed, or working memory (WM) and
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executive processes (Blair, Vadaga, Shuchat, & Li, 2011; Parasuraman, Greenwood, &
Sunderland, 2002; Reinvang, Winjevoll, Rootwelt, & Espeseth, 2010; Wetter et al., 2005).
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Moreover, genetic risk conveyed by APOE ε4 and physiological vascular risk expressed by
various biomarkers may act in synergy in reducing cognitive performance. Vascular risk factors
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reported to interact with ε4 include elevated triglycerides (De Frias et al., 2007), homocysteine
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(Elias et al., 2008), and blood pressure (Haan & Mayeda, 2010; Haan et al., 1999; Kuller et al.,
1998).
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In this study, we examined whether the pattern and magnitude of contributions of

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individual differences in regional brain volumes and vascular risk to age-related differences in
age-sensitive areas of cognition differ between the carriers of a risky APOE ε4 allele in a lifespan
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sample of healthy adults. Specifically, we hypothesized that in APOE 4 carriers, higher

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indicators of physiological vascular risk (sub-clinically elevated SBP) would be associated with
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reduced brain volumes and impaired cognitive performance, whereas 3 homozygotes would not
demonstrate such vulnerability.
Method
Participants
Study data were collected as part of an ongoing study of the cognitive and neural
correlates of healthy aging taking place in the Detroit metropolitan area. All participants
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provided informed consent, consistent with the University Human Investigations Committee
guidelines. All participants completed a self-report health questionnaire to screen for health
issues including medical diagnosis of hypertension and use of prescribed anti-hypertensive
medication, as well as history of cardiovascular disease, neurological, or psychiatric disease.
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Participants denied history of cancer, head trauma accompanied by loss of consciousness for
more than five minutes, thyroid disorder, and diabetes. Persons who acknowledged prior or
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current treatment for drug or alcohol abuse, or taking more than three drinks per day were not
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recruited for this study. All participants denied taking anticonvulsive, antidepressant,
antihyperglycemic, antipsychotic, or anxiolytic medications. In addition, participants who
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reported taking anti-hypercholesterolemic medications were not included in the present study.
The participants were native English speakers, with at least high school diploma or
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equivalency; mean education corresponded to nearly a full four-year college: 15.8  2.4 years.
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Participants completed a questionnaire (CES-D; Radloff, 1977; cutoff = 15) to screen for
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depressed state, and an experimenter screened participants for cognitive impairment using the
Mini Mental Status Examination (MMSE; Folstein, Folstein, & McHugh, 1975; cutoff = 26).
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Participants were screened for near, far, and color vision problems (Optec 2000 Vision Tester,
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Stereo Optical Co., Inc., Chicago, IL) and speech-range hearing deficits (MA27 Screening
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Audiometer, Maico Diagnostics, Eden Prairie, MN). An experimenter measured participant
blood pressure with an analog mercury sphygmomanometer (Model 12-525; Country
Technology, Gays Mills, WI), using a left arm brachial cuff. Measurements were taken on three
separate days prior to cognitive testing with the participant comfortably seated in a quiet room;
measurements were averaged across occasions.
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The sample was composed of 72 adults, 19 to 77 years of age (see Table 1 for sample
descriptive statistics), including 50 women and 22 men. None of the participants reported
diagnosis of hypertension or use of anti-hypertensive medication. Men and women sub-samples
did not differ in mean age, years of education, MMSE scores, systolic and diastolic blood
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pressure, and proportion of participants reporting regular smoking or exercise. The sample
overlapped with prior studies from our lab as follows: 65% sample overlap with (Raz, Rodrigue,
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Kennedy, & Land, 2009), 60% sample overlap with (Raz et al., 2008), 64% sample overlap with
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(Raz, Dahle, Rodrigue, Kennedy, & Land, 2011), and 64% sample overlap with (Dahle, Jacobs,
& Raz, 2009).
Genomic analysis
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DNA was isolated from buccal cultures obtained in mouthwash samples with Gentra
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Autopure LS under the standard buccal cell protocol. DNA isolations and genotyping assays
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were conducted in the Wayne State University Applied Genomics Technology Center on an
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Applied Biosystems 7900. APOE (rs429358 and rs7412) polymorphisms were preamplified with
forward 5’-CAATGCTACCGAGTTTTCTTCC-3’ and reverse primers 5’-

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TTCAGATTCTTCACAGATGCGTA-3’ in a 25 µl reaction containing 2.5 mmol/l MgCl2, 0.5

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µmol/l of the primers, 1.25 U AmpliTaq Gold polymerase, and 200 µmol/l dATP, dCTP, dGTP,
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and dTTP. The mixture was denatured at 950C for 10 minutes and amplification achieved by 15
cycles of 940C for 30 seconds, 580C for 30 seconds, and 720C for 1 minute, followed by a final
extension at 720C for 10 minutes. One µl of this reaction was subsequently used for rs429358
and rs7412 5’-nuclease assays under standard conditions. The primers and probes for the rs7412
assay were 5’-TCCGCGATGCCGATGAC-3’, 5’-CCCCGGCCTGGTACAC-3’, VIC-
CAGGCGCTTCTGC-NFQ and FAM-CAGGCACTTCGC-NFQ. The primers and probes for the
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rs429358 assay were 5’-GCGGGCACGGCTGT-3’, 5’-GCTTGCGCAGGTGGGA-3’, VIC-
CATGGAGGACGTGTGC-NFQ and FAM-ATGGAGGACGTGCGC-NFQ.
DNA sequencing reactions was carried out using the 0.5X protocol for ABI PRISM BigDye
Terminator Cycle Sequencing Ready Reaction Kit (Applied Biosystems). The sequencing
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extension products were purified utilizing Sephadex, and analyzed on an ABI PRISM 3700 DNA
Analyzer with a 50 cm capillary array.
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Participants identified as APOE ε2 carriers were excluded from analysis because APOE
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alleles ε2 and ε4 may exercise opposite effects on memory and cognition (Helkala et al., 1995;
Small, Rosnick, Fratiglioni, & Bäckman, 2004), and there were too few APOE ε2 carriers for
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statistical comparison. The allelic distribution of all three polymorphisms fit the Hardy-Weinberg
equilibrium (all χ2 < 1). Mindful of reported differences among populations in prevalence of
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allelic distributions (Corbo & Scacchi, 1999), we evaluated APOE ε4 frequency among
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Caucasians and African-American participants. Within each group, the distribution conformed to
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Hardy-Weinberg equilibrium (χ2 = 1.12, p > .1, and χ2 = 0.93, p > .1, respectively) and there was
no significant difference in APOE ε4 frequency between African-American and Caucasian

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participants: n = 15 (40%) vs. n = 53 (25%), χ2 = 1.39, p > .1. There were too few participants
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from other ethnicities (n = 4) for additional analyses. Most of the participants were homozygous
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for ε3 allele (72%), whereas 25% were ε3/ ε4 heterozygotes and less then 3% were homozygous
for the ε4 allele; ε4 carriers made up 28% of the sample.
MRI Acquisition and Processing
MRI Acquisition. T1-weighted magnetization-prepared rapid acquisition with gradient
echo (MPRAGE) images were acquired using a 4T MRI system (Bruker Biospin, Ettlingen,
Germany) equipped with an 8-channel RF head coil. Sequence parameters were as follows: TR =
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1600 ms, TE = 4.38 ms, TI = 800 ms, FOV = 256  256 mm2, in plane resolution = 0.67  0.67
mm2, slice thickness = 1.34 mm, matrix size = 384  384, number of slices = 176.
MRI Processing. Image volumes were created from DICOM images and filtered to
correct for field-inhomogeneity using Analyze software (Biomedical Imaging Resource, Mayo
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Clinic, Rochester, MN). Filtered volumes were adjusted to correct for variability in head pitch,
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rotation, and tilt using the oblique sections and orthogonal alignment tools in Analyze. Using a
parasagittal view, separate images were generated aligned along the anterior and posterior
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commissure line (see Raz, 2004 for details), and perpendicular to the longitudinal axis of the
hippocampus for measurement of frontal and hippocampal volumes, respectively.
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Volumetry. Images were displayed on a 21” LCD digitizing tablet (Wacom Cintiq 21UX,
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WACOM, Vancouver, Washington; see Raz, 2004 for details). All regions of interest (ROIs)
were manually measured in the coronal plane using the ROI tool in the Analyze software, except
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for intracranial volume (ICV), which was measured in the axial plane. Regional volumes were
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calculated by multiplying the summed bilateral area by slice thickness. Each ROI was regressed
on ICV and the slopes were compared for men and women prior to adjustment to ensure
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equivalence of regression slopes between sexes. The following equation was applied to each
volume to correct for individual differences in head and body size: Volumeadj = Volumeraw –
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b(ICV – Mean ICV). Here, Volumeadj is adjusted volume, Volumeraw is raw volume, b is the
unstandardized regression coefficient from regressing the ROI on ICV, and Mean ICV is taken
from the entire sample.
ROI Demarcation Procedures.
Inter- and intra-rater reliability for measurement of regional volumes was determined by
an intraclass correlation formula that assumes random assignment and independence of raters,
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(ICC[2]/ICC[3]; P. E. Shrout & Fleiss, 1979). All regions were traced by six-seven reliable raters
and ICC(2) values ranged from .94 to .99.
Lateral Prefrontal Cortex (lPFC). The lPFC was traced on 10 to 14 coronal slices found
within 40% of the distance between the frontal pole and first slice on which the genu was visible.
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Starting with the first slice, every other slice (1.34 mm) was traced for a total of 9 to 12 lPFC
slices. The lPFC ROI included superior, middle, and inferior frontal gyri, and corresponds to
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Brodmann areas 9 and 46 with partial overlap with areas 8, 10, and 45. Figure 1a shows an
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example of the lPFC ROI, which is bounded superiorly by the frontal cortex’s most dorsomedial
point and inferiorly by the lateral orbital sulcus.
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Prefrontal White Matter (pFWM). The pFWM was traced on the same slices as lPFC; all
white matter was traced on each slice, whether or not it was contiguous with other visible white
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matter (Figure 1b). Care was taken to exclude the frontal horns of the lateral ventricles and other
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non-white matter from the measurements.

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Hippocampus (HC). The HC was traced in a para-coronal view, orthogonal to the
longitudinal axis of the right HC. The slice on which the mammillary bodies were most visible
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marked beginning of the range of measurement, and the slices in which fornices emerge from the
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fimbria mark the posterior limit. HC measurements excluded amygdala from rostral tracings,
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and care was taken not to include the fimbria in the ROI. As shown in Figure 1c, HC tracings
included the entire hippocampal formation, and the inferomedial boundary was the most medial
aspect of the parahippocampal gyrus, just below the hippocampal sulcus. Temporal lobe white
matter and the temporal horn of the lateral ventricles were the inferior and lateral boundaries,
respectively.
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ICV. Using the auto-trace function in Analyze, the ICV was traced in the axial plane
starting at the cerebral vertices on the first slice where cortical gray matter was visible. A total of
10 slices were measured with a gap of 14 slices (9.4 mm) in between. This range corresponds to
the majority of the cranial vault, excluding the extra-cortical cranial vertex and base of the brain
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below the level of the orbits. A seed point for the auto-trace was chosen on the edge of the
cranium and the auto-limit adjusted to include the entire cranium in the ROI, and the auto-traced
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ROI was manually edited as needed to ensure consistency with apparent anatomy.
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Cognitive Tests
Participants completed a series of cognitive tests of age-sensitive abilities including WM,
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speed of perceptual processing, and episodic memory. Five separate measures of WM included
spatial, verbal, and non-verbal stimuli, using a combination of task designs (e.g., span tasks, n-
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back tasks); this heterogeneity improves construct validity. Similarly, speed of processing was
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assessed with well-validated verbal and nonverbal tasks (Salthouse, 1996b). In light of
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disproportionate age-related impairments in associative recognition, we administered the task
used by Naveh-Benjamin (2000) in his test of an associative deficit hypothesis.

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Working Memory: Size Judgment Span. Designed by Cherry & Park (1993) this measure
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requires participants to hold items in WM, make comparisons based on semantic features, and
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order them by ascending physical size for subsequent verbal report. In each trial an experimenter
reads lists of items, and there are three trials per set. The test initially presents two items per trial
and the number of items increases by one upon successful completion of each three-trial set. The
task’s estimated reliability coefficient is .79 (Cherry & Park, 1993), which corresponds to the
disattenuated test-retest correlation (Spearman, 1904) observed in our longitudinal study (Raz,
unpublished data) further confirming the measure’s reliability in our larger sample.
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Working Memory: Spatial Recall. A modified, computerized test adapted from the task
described by Salthouse (1974, 1975; Salthouse, Kausler, & Saults, 1988), was used to assess
spatial WM. A computer program displayed 30 5  5 matrices, each with seven darkened cells
for 3 s. The experimenter provided participants with response forms that included three pages
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of two columns of five blank matrices. The experimenter informed participants that following the
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presentation of each matrix, they were to recall the locations of the darkened squares by drawing
an X in seven cells on corresponding blank matrix on the response form; participants were told to
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guess if necessary. The task provided five practice trials, followed by 25 test trials. Test
performance was calculated by averaging the total number correct across the 25 test trials.
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Cronbach’s alpha (α) was .89, as computed across the 25 test trials.
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Working Memory: Listening Span. The Listening Span (LSPAN; Salthouse, Mitchell,
Skovronek, & Babcock, 1989) task requires participants to listen to simple sentences, answer a
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multiple choice question about the sentence, and freely recall its final word (see Raz, Gunning-
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Dixon, Head, Dupuis, & Acker, 1998 for a full description). The LSPAN is organized into of
seven blocks of three trials each. Starting with the first block, participants complete one item per
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trial, and the number of items increases by one for each successive block. Following presentation
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of all items in a trial, participants are told to recall as many of the final words as possible, in the
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original order of presentation. Participants are required to correctly answer questions in order to
receive credit for reporting final words from the presented sentences. Participants receive one
point for each correctly recalled and ordered final words. The absolute span (AS) is the sum of
trials in errorless blocks, and has been used previously (Raz et al., 1998) as a measure of WM
capacity.
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Working Memory: N-Back Tests. An experimenter administered computerized n-back
tests to assess WM storage and maintenance; separate tasks assessed verbal and nonverbal
performance (modeled after Dobbs & Rule, 1989; Hultsch, Hertzog, & Dixon, 1990). The verbal
n-back test displayed single-digit numbers on a CRT monitor, and the nonverbal n-back test
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presented abstract shapes. Participants were tested separately on 1-, 2-, and 3-back tests; sub-test
order was counterbalanced across participants in a Latin square design. After all items in a trial
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were presented, the participants selected the item presented in the specified position for a given
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task. Number of correct responses (out of 20) was the performance index for both tasks in the
present study. The tasks’ estimated reliability coefficients are .91 for the verbal and .88 for the
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nonverbal tests (Salthouse, 1996c). The present study only used data from the 3-back verbal and
nonverbal tasks.
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Processing Speed. Participants completed Letter Comparison and Pattern Comparison
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tests (Salthouse, 1996b) to assess speed of perceptual processing. Both tests required participants
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make same/different judgments on two pages of side-by-side letter strings or line patterns. An
experimenter instructed participants to respond quickly and accurately; participants were given
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30 seconds to complete as many items as possible on each page. The total number correct for
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both pages, divided by time allotted (number correct / 60 s) is the index of performance. The
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estimated reliabilities for letter and pattern comparison are .77 and .87, respectively (Salthouse &
Meinz, 1995).
Episodic Memory
Participants were administered a recognition test for word pairs (see Bender, Naveh-
Benjamin, & Raz, 2010 for details; Naveh-Benjamin, 2000). Task conditions were intentional: an
experimenter told participants to study and remember both the individual words and the pairs,
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and that they would be tested on both. Custom testing software written by laboratory staff in
Visual Basic serially presented each participant with 26 pairs of unrelated words, at rate of 5.5 s
per pair with a 200 ms inter-stimulus interval. After the study phase, participants were given a
randomly generated 900 number and were told to count backwards by threes for 60 s to minimize
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rehearsal. Following study and distractor phases, participants completed separate recognition
tests for items (individual words) and associations (word pairs), the order of which was
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counterbalanced across the sample. Both tests used a single item, yes/no design. The item test
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presented 16 individual words (8 targets/8 foils), and the associative recognition test presented
16 pairs (8 intact pairs/8 recombined pairs); participants indicated via keyboard button press
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whether or not a word was studied and whether pairs were intact or recombined. Upon
completion of both tests the process was repeated with a second list of 26 new word pairs. Lists
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were randomly selected from a pool of six possible lists, and the order was randomized across
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the sample.
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Data Conditioning
Participant age, mean SBP, and the ICV-adjusted lPFC, pFWM, and HC volumes were
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centered at their respective sample means and standardized to z-scores.

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Working Memory Composite. The five performance indices from the corresponding tests
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of WM were screened for deviations from normality. A log transformation was applied to the
AS performance index from LSPAN to correct for skewness in the distribution; no other
transformations were required for the other WM measures. Results of an unrotated principal
components analysis (PCA) showed that all five WM indices loaded onto a single common
component. Component loadings are as follows: size judgment span = .78, spatial recall = .61,
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LSPAN = .79, 3-back verbal = .61, 3-back nonverbal = .76. A WM composite was therefore
created, consisting of the averaged, standardized scores from the five measures.
Processing Speed. A PCA performed on the two scores from the processing speed
measures showed both loaded onto a common component (both loadings > .90). Therefore, the
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scores were standardized and averaged to yield a single composite.
Recognition Tests. Prior to analysis of performance on the recognition tests, trials with
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response times shorter than 200 ms or longer than 10 s were excluded as such responses were
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likely due to error or may reflect other memory processes. The performance index for tests of
recognition was A’, a non-parametric index of discriminability (Pollack & Norman, 1964); A’
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was calculated using hit rate and false alarm rate, or proportions of correct target and incorrect
lure responses, respectively (Stanislaw & Todorov, 1999). An arcsine transformation was
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applied to the A’ scores to correct for significant skewness in the distribution. Item and
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associative recognition A’ scores were averaged across the two lists and standardized to create
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composite measures of item and associative recognition performance.
Statistical Analyses
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The present study used a structural equations modeling (SEM) approach to conduct path
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analysis of statistical mediation. However, path and mediational analyses can provide valid
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estimates of neither direct causation nor change. Recent critical analyses confirmed both that
correlational methods cannot inform causation and that cross-sectional regression and path
coefficients cannot establish age-related change (Lindenberger & Pötter, 1998; Hofer et al.,
2006; Maxwell & Cole, 2007; Lindenberger et al., 2011; Raz & Lindenberger, 2011). Thus,
although we use familiar SEM terminology, “mediation” should only be considered as
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demonstrating consistent hierarchical partitioning of variance/covariance whereby individual
differences in one variable are associated with individual differences in another.
To investigate the role of SBP as a contributor to the associations of age, hypothesized
regional brain volumes, and different cognitive abilities, we used grouped path analysis in Mplus
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6.0 (Muthén & Muthén, 2010). This approach involves specification of an initial model
containing multiple hypothesized paths reflecting heterogeneous partitioning of variance based
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on group membership. Paths that are not hypothesized for a given group are constrained to zero
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to allow groups to feature different patterns of associations among the variables nested under a
common model.
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Because of statistical power limitations, the role of SBP as a mediator of the effects of
age was modeled separately for WM via speed of processing, and for recognition of items and
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associations. In all models we used maximum likelihood (ML) estimation. Path analyses
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employed bias-corrected (BC) bootstrap resampling with 1000 draws to generate estimates and
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95% confidence intervals (CIs) of indirect effects (Cheung & Lau, 2007; MacKinnon &
Fairchild, 2009; Williams & MacKinnon, 2008); indirect effects are calculated as the product of
p
two or more direct paths. BC bootstrapped indirect effects are widely considered superior
ce
estimates of mediation (MacKinnon & Fairchild, 2009; MacKinnon, Lockwood, Hoffman, West,
Ac
& Sheets, 2002; Patrick E. Shrout & Bolger, 2002; Williams & MacKinnon, 2008) over other
commonly used approaches such as those described by Baron and Kenny (1986) or Sobel (1982).
Because this approach produces 95% CIs, any significant, non-zero indirect effect indicates
mediation. Indirect effects were specified to test hypothesized mediation of age-volumetry and
age-cognition associations. Model fit was assessed using several indices: the comparative fit
index (CFI) and Tucker-Lewis Index (TLI) compare model fit to that of a null model, and values
Page 17 of 43
of .95 were cutoffs for both the CFI and TLI. For chi-square (χ 2) tests of model fit, a
nonsignificant (p > .05), smaller χ 2 value indicates acceptable fit in comparison to a null model.
A related, more informative fit statistic, χ 2 divided by degrees of freedom (Jöreskog & Sörbom,
1993) used a fairly conservative cut-off value of ≤ 2.0 (Mueller, 1996). In addition, model fit
t
ip
was evaluated by inspection of root mean square error of approximation (RMSEA) and square
root mean square residual (SRMR), measures of model misspecification and explained variance;
cr
acceptable fit was indicated by values of .05 and below for both the RMSEA and SRMR.
us
The first set of models assessed whether SBP mediates relationships between age and
lPFC and pFWM volumes, processing speed, and WM. The initial model specified the following
an
paths: age to the other five variables, SBP to both brain volumes, WM and processing speed,
paths from both regional volumes to both processing speed and WM, and a path from processing
M
speed to WM. The model was constrained differently for each group, consistent both with the
d
hypothesis that SBP mediates the effects of age for carriers of the 4 allele, but not for non-
te
carriers, and with zero-order correlations (Table 2). Thus, for 4 carriers, the direct effects of
age on all measures except for SBP were constrained to zero; similarly, the direct effects of SBP
p
ce
on the two brain volumes and two cognitive composites were constrained to zero for non-
carriers. Additional zero-constraints were also imposed to remove unreliable paths from the
Ac
initial or nested models, yielding reduced grouped (mediational) path models (Figure 3a).
Indirect effects were specified to test potential statistically causal paths, by which multiple
variables are linked in mediating various associations therein. Indirect effects from Age to WM,
speed, and pFWM and lPFC volumes freely estimated all possible indirect effects in the model.
The second set of models examined potential mediation of the associations between age
and recognition of items and associations by SBP, lPFC and hippocampal volumes. The path
Page 18 of 43
analysis included the two arcsine-transformed recognition memory scores, A’ (for item and
association), age, SBP, lPFC and HC volumes. The initial model specified paths from age to
SBP, lPFC and HC volumes, and the two recognition indices; direct paths were also specified
from SBP to both brain volumes and both recognition indices, as well as from HC and lPFC
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volumes to the two recognition indices. In the nested model for carriers of the 4 allele, paths
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from age to brain volumes and from age to associative memory were constrained to zero,
whereas in the nested model for 3 homozygotes paths from SBP to item recognition, prefrontal
us
volume, and hippocampal volume were all constrained to zero. Thus, because paths were
differentially constrained to zero by genotype, different indirect effects were possible in the
an
nested models. As with the prior model of WM and speed, unreliable paths were constrained to
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zero; the resultant reduced grouped mediational path model (Figure 3b) included additional
degrees of freedom due to estimation of fewer parameters. Indirect effects from Age to item and
d
associative recognition, HC and lPFC volumes were estimated from the paths specified in the
te
model.
Age-related differences in blood pressure or brain volumes may reflect individual

p
ce
differences in memory or cognition because those variables serve as proxies for another variable
not included in the models. Mindful of this possibility, for both models we also tested two
Ac
alternate path analyses: a reversed-mediation model and an exclusively correlational model to
test the possibility that the relationships without specific directionality may fit the data as well.
Both models were specified based on the final path model with no re-specification except for
reversing the paths between blood pressure, brain volumes, and cognitive variables in the
reversed-mediation model and substitution of correlations for direct paths in the correlational
model. In the former, paths from age were specified as bidirectional correlational relationships.
Page 19 of 43
Thus, three separate models were evaluated for both speed/WM and recognition memory: a
reduced group mediational model, a reversed-mediation model, and a correlational model.
Results
To examine genetic differences in the associations of age and SBP with regional brain
t
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volumes and cognitive measures, we compared zero-order correlations transformed via Fisher r-
to-z formula (Table 2) in APOE 4 carriers and 3 homozygotes. We found that the relationship
cr
between age and hippocampal volume was stronger among 4 carriers (r = .62, p < .001) than 3
us
homozygotes (r = .29, p < .05; z = 1.5, p < .05). In addition, whereas among 4 carriers higher
an
SBP was significantly associated with smaller hippocampal volumes (r = -.61, p < .01), slower
processing speed (r = .74, p < .001), and reduced WM capacity (r = -.75, p < .001), no such
M
associations were evident for 3 homozygotes (p > .1 for all). The scatter plots and regressions
illustrating age differences in regional volumes in APOE ε4 carriers and ε3 homozygotes are
d
presented in Figure 2.
te
Path Analysis - Processing Speed and Working Memory

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We proceeded to compare the patterns of associations among the variables in two APOE
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ε-variant groups via path analyses. Evaluation of the three path models (reduced grouped
mediational, reversed-mediational, correlational) showed that the reduced grouped mediational

Ac
model (Figure 3a) fit the data well, according to all goodness-of-fit indices (Table 3). In
contrast, neither the reversed-mediational model nor the exclusively correlational model fit the
data well. Therefore, we will focus only on the reduced grouped mediational path model in
which there were several significant indirect effects. Among APOE 3 homozygotes, WM was
independently associated with lPFC volume and speed of processing (Table 4). Greater age was
associated with higher SBP, smaller pFWM and lPFC volumes, and slower processing; however,
Page 20 of 43
SBP was unrelated to volumes or cognitive variables. Carriers of the APOE 4 allele displayed a
different pattern of associations: SBP through pFWM volume, and via speed of processing
mediated the effects of age on WM. That is, older 4 carriers with higher SBP had smaller
pFWM volumes, and persons with smaller pFWM had slower perceptual-motor speed, which
t
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was in turn associated with poor performance on WM tasks. It is important to note this larger
cr
indirect effect subsumes multiple other significant indirect effects in the model (Table 4), each
indicating a different mediation effect. Furthermore, age differences in WM were associated with
us
individual differences in speed, which were associated with individual differences in SBP. As
shown in Figure 3a, the model showed both a significant direct effect of SBP on processing
an
speed and a significant indirect effect in which individual differences in SBP were associated
M
with individual differences in pFWM, which in turn explained variance in processing speed.
Significant indirect effects also demonstrated that only among 4 carriers, age differences in
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pFWM and lPFC volume were explained in part by individual differences in SBP.
te
Path Analysis - Item and Associative Recognition Memory

p
Inspection of the fit indices in Table 3 shows that the reduced grouped mediational path
ce
model (Figure 3b) fit the data well. As with the speed-WM models, neither the reversed-
mediational nor the correlational models fit the data well (Table 3). There were several
Ac
significant indirect effects in the reduced grouped mediational model.
Among APOE 3 homozygotes, greater age was associated with higher SBP, which was
in turn associated with poor associative memory; however, the indirect effect linking the three
was not significant (p > .15). Age was directly, negatively associated with recognition of both
items and associations, which were significantly correlated. Similarly, greater age was also
directly associated with smaller HC and lPFC volumes. However, there were no indirect effects
Page 21 of 43
for 3 homozygotes. In contrast, older carriers of the APOE 4 allele with higher blood pressure
had smaller lPFC volumes and poorer associative recognition (Table 4). In addition, SBP
mediated the effects of age on recognition of items and associations, independent lPFC volume.
Notably, SBP mediated the effects of age on lPFC volume but not hippocampal volume.
t
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Discussion
cr
In a sample of healthy adults, genotypic and phenotypic vascular risk factors were
associated with smaller prefrontal volumes, reduced speed of perceptual processing, poorer WM
us
performance, and weaker verbal recognition memory. It appears that for the carriers of APOE 4
allele the effects of elevated vascular risk may have more dire consequences: older ε4 carriers
an
with high-normal SBP had smaller prefrontal volumes than those who had lower SBP, as
M
indicated by the negative paths in Figure 3a. Moreover, the overall model fit (Table 3) supported
the absence of such a mediational pattern among ε3 homozygotes. The combination of a

d
relatively mild elevation in physiological indicators of vascular risk with a genetic risk factor is
te
associated with poorer state of brain and cognition than would be expected. The observed
synergy between genetic and physiological risks in explaining cognitive deficits is in accord with
p
ce
previous reports regarding APOE ε4 (De Frias et al., 2007; Elias et al., 2008; Fuzikawa, Peixoto,
Taufer, Moriguchi, & Lima-Costa, 2008; Peila et al., 2001) and the met allele of BDNF val66met
Ac
polymorphism (Raz et al., 2008). Thus, this finding is in accord with the growing evidence that
“normal” should be viewed in the context of individual’s genetic predisposition (Raz, 2011).
Previous reports indicated greater ventriculomegaly and reduced performance on tests of
episodic memory and executive functions in ε4 carriers with elevated SBP, in comparison to
participants with only one of the risk factors (Zade et al., 2010). In community samples of typical
older adults, the APOE ε4 allele is associated with increased burden of white matter
Page 22 of 43
abnormalities when blood pressure is elevated (de Leeuw et al., 2004) and with reduced brain
volume and ventriculomegaly when overt cardiovascular disease is present (DeCarli et al., 1999).
However, this is the first report of synergistic contribution of vascular risk and ε4 to age-related
differences in volume of a selected brain region in a sample of healthy, normotensive individuals
t
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within a broad age range. In the present sample, SBP mediated the effects of age on prefrontal
cortical and white matter volumes only among 4 carriers.
cr
The results reported here add to the existing literature on the associations among age,
us
brain, and cognition. Individual differences in lPFC volume explained some of the age
differences in WM performance in one previous study (Head, Rodrigue, Kennedy, & Raz, 2008),
an
whereas in another sample, we observed no association of age differences in WM with individual
M
differences in lPFC volume (Raz et al., 1998). There may be many reasons for such inter-study
discrepancies, including the demographics of the sample, and health screening. One important
d
distinction may be the selection of measurement for WM. Various tests, conceived to measure
te
WM are actually not highly associated and may not form a well-defined construct (Kane,
Conway, Miura, & Colflesh, 2007; Roberts & Corkin, 1997). However, all WM tasks used to
p
form the WM composite in the present study, including both n-back and span task indices,
ce
loaded onto a single component. Thus, a strength of the present study is enhanced WM construct
Ac
validity.
The present findings demonstrate markedly different patterns of associations between 4
carriers and 3 homozygotes. Despite previous reports of reduced processing speed and impaired
cognitive resource allocation by 4 carriers relative to ε3 homozygotes (see Parasuraman et al.,
2002 for a review), we did not observe such differences in mean performance by APOE genotype
(speed: t = .56, p > .1; working memory: t = .44, p > .1). In contrast to the findings reported by
Page 23 of 43
Liu and colleagues (2010), we found that old age and 4 did not independently influence
cognition. Rather, the present results showed that individual differences in SBP explained age-
related variance in speed of perceptual processing and verbal recognition memory, only among
4 carriers. However, Liu et al. did not model interactions between age, APOE genotype, and
t
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vascular risk on cognitive performance. Moreover, our results were derived from a lifespan
cr
sample of healthy adults, and whereas Liu and colleagues used a population-based sample of
typical older individuals. Similar to its effects on regional brain volume, elevated SBP in midlife
us
is associated with poorer cognitive outcomes (Qiu, Winblad, & Fratiglioni, 2005), but
particularly for 4 carriers (Peila et al., 2001). Thus, the 4 allele appears to predispose
an
individuals to the deleterious effects of small elevations in physiological vascular risk which
M
become manifest in older age.
The results reported here are in accord with previous findings that older APOE 4 carriers
d
show increased white matter degradation and slower cognitive processing speed, (Espeseth et al.,
te
2006) particularly in frontal lobes, as compared to non-carriers (Bartzokis et al., 2007). Age-
p
associated differences in processing speed mediate individual differences WM performance,

ce
which can in turn explain variance in episodic memory (Salthouse, 1991, 1996a). However, the
roles of and interactions between genetic and phenotypic vascular risk factors in modifying these
Ac
relations have not been previously examined.
The 4 allele of APOE is associated with impairments in episodic memory (Bondi et al.,
1995; Honea et al., 2009). In comparison to non-carriers, older 4 carriers show greater deficits
in recall than recognition (Nilsson et al., 2006), poorer verbal recall (Helkala et al., 1996) and
greater longitudinal decline in memory for faces and words (Small, Basun, & Backman, 1998).
In addition, 4 is associated with increased longitudinal decline in episodic memory relative to
Page 24 of 43
performance on measures of executive function (Wilson et al., 2002). However, of two meta-
analyses evaluating the impact of APOE genotype on cognition, only Wisdom and colleagues
(2011) demonstrated negative effects of 4 on processing speed, executive functioning, and
episodic memory. In an earlier meta-analysis of the effects of 4 on cognition, Small and
t
ip
colleagues (2004) found an association between 4 and reduced performance on executive
cr
function and episodic memory, although the effect sizes were very small. Thus, it is possible that
individual differences in vascular risk factors may have explained such effects. However, such
us
data are infrequently collected as the normal course of such investigations and are rarely
an
accounted for statistically.
Limitations and Future Directions

M
Analytic approaches such as path analysis are based on variance/covariance partitioning.
Therefore, such methods can only elucidate of the role of individual differences and cannot be
d
interpreted as estimates of age-related change or causal relations among the variables

te
(Lindenberger, von Oertzen, Ghisletta, & Hertzog, 2011). Rather, the present findings
p
underscore the contributions of other statistical correlates of age-related differences in indices of

ce
regional brain volume and cognitive performance. Furthermore, the present findings suggest that
regardless of age, normotensive carriers of the APOE 4 allele with elevated SBP are more likely
Ac
to also possess smaller prefrontal volumes, and have slower processing speed, lower WM
capacity, and reduced verbal recognition than 4 carriers with lower SBP. Although advanced
age is negatively associated with the outcome variables, we cannot be clear if such deficits are
the result of the aging process; only longitudinal analysis can shed light on individual differences
in age-related decline. In addition, although bias-corrected bootstrap resampling in generation of
confidence intervals around indirect effects is acknowledged as the most rigorous method for
Page 25 of 43
establishing statistical mediation in SEM-based models (MacKinnon et al., 2002; Preacher &
Hayes, 2008), the stability of multi-mediator associations has not been clearly established.
Even beyond the matter of extrapolating from cross-sectional differences to age-related
change, many extant studies exhibit an additional flaw, for which they have been recently
t
ip
subjected to a systematic critique criticized, i.e., many fail to consider alternative hypotheses
about the age – brain – cognition relations (Salthouse, 2011). Here we ruled out alternate
cr
explanations, such as “reversed causation” or simple correlational association and showed that
us
individual differences in prefrontal volume and SBP explain age-related differences in cognition,
and not the other way around.
an
In the present study, we did not evaluate many markers of vascular risk previously shown
to interact with APOE genotype in vascular risk and correlate with cognitive performance
M
decrements, such as homocysteine (Elias et al., 2008), triglycerides (De Frias et al., 2007), or
d
LDL cholesterol (Fuzikawa et al., 2008). In addition, according to some studies, APOE 4 may
te
be associated with increased hippocampal atrophy in older women, but not men (Cohen, Small,
Lalonde, Friz, & Sunderland, 2001). According to others, APOE 4 may be associated with
p
ce
poorer WM and cognitive control among older men than women (Reinvang et al., 2010).
However, sample size limitations precluded analysis of sex differences in the present study.
Ac
Thus, additional work is needed to evaluate the effects of and interactions between APOE
genotype, sex, and individual differences in sex hormones, age, regional brain volumes, and
cognitive performance. The small number of 4 carriers in this study precluded modeling of
additional variables of interest and of more complex interactions.
Peila et al. (2001) reported that carriers of the APOE 4 allele are more susceptible to the
negative effects of hypertension on cognition than non-carriers, and suggest that antihypertensive
Page 26 of 43
medication can assuage such decline. Because genetic factors may alter what may be considered
an appropriate threshold for diagnosis and treatment of hypertension, such an approach may be
warranted for future studies. It is possible reduced brain volumes associated with high-normal
blood pressure in 4 carriers reflects target-organ damage commonly associated with
t
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hypertension. Although according to longitudinal investigations, treatment of hypertension may
cr
not eliminate brain shrinkage (Raz et al., 2005; Jennings et al., 2011), to date, no studies have
evaluated the effects of interventions aimed to reduce blood pressure and cholesterol levels on
us
brain and cognitive decline in otherwise healthy or younger samples of 4 carriers. Such
intervention should not be limited to pharmacotherapy. Recent evidence indicates that increased
an
physical activity may ameliorate the effects of 4 on brain activity associated with semantic
M
memory processing (Smith et al., 2011). Thus, for at-risk individuals (ε4 carriers) exercise
regimen may bring benefits if started early enough. The present findings support calls for better
d
understanding of the contributions of vascular risk to age-related brain atrophy (Wright & Sacco,
te
2010), and emphasize the need for future studies to evaluate interactions between age and both
p
genotypic and manifest vascular risk factors on neural and cognitive correlates.
ce
In conclusion, possession of the APOE4 allele appears to predispose older adults to the
negative effects of minor elevations in SBP on prefrontal brain volumes, processing speed, WM,
Ac
and verbal recognition memory. In comparison to APOE 3 homozygotes, individual differences
in SBP among normotensive carriers of the APOE 4 mediate age-related variance in prefrontal
white matter volume and lateral prefrontal cortical volumes. Furthermore, the present findings
show that for APOE 4 carriers the variance-covariance structure and statistical linkage between
age, vascular risk, regional brain volumes, and associated cognitive performance differs from
Page 27 of 43
those of the APOE ε3 homozygotes. Multiple risk factors for cognitive decline act in concert and
the impact of a physiological measure may depend on individual genetic contexts.
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an
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p te
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Page 28 of 43
References
Baron, R. M., & Kenny, D. A. (1986). The moderator-mediator variable distinction in social
psychological research: Conceptual, strategic, and statistical considerations. Journal of
Personality and Social Psychology, 51(6), 1173-1182.
Bartzokis, G., Lu, P., Geschwind, D., Tingus, K., Huang, D., Mendez, M., . . . Mintz, J. (2007).
Apolipoprotein E affects both myelin breakdown and cognition: Implications for age-
related trajectories of decline into dementia. Biological Psychiatry, 62(12), 1380-1387.
t
doi: 10.1016/j.biopsych.2007.03.024
ip
Bender, A. R., Naveh-Benjamin, M., & Raz, N. (2010). Associative deficit in recognition
memory in a lifespan sample of healthy adults. Psychology and Aging, 25(4), 940-948.
doi: 10.1037/a0020595
cr
Blair, M., Vadaga, K. K., Shuchat, J., & Li, K. Z. H. (2011). The role of age and inhibitory
efficiency in working memory processing and storage components. The Quarterly
us
Journal of Experimental Psychology, 64(6), 1157-1172. doi:
10.1080/17470218.2010.540670
Bondi, M. W., Salmon, D. P., Monsch, A. U., Galasko, D., Butters, N., Klauber, M. R., . . .
Saitoh, T. (1995). Episodic memory changes are associated with the APOE-epsilon 4
an
allele in nondemented older adults. Neurology, 45(12), 2203-2206.
Brady, C. B., Spiro, A., III, & Gaziano, J. M. (2005). Effects of age and hypertension status on
cognition: The Veterans Affairs normative aging study. Neuropsychology, 19(6), 770-
777. doi: 10.1037/0894-4105.19.6.770
M
Buckner, R. L. (2004). Memory and executive function in aging and AD: Multiple factors that
cause decline and reserve factors that compensate. Neuron, 44(1), 195-208. doi:
10.1016/j.neuron.2004.09.006
d
Cherbuin, N., Anstey, K. J., Sachdev, P. S., Maller, J. J., Meslin, C., Mack, H. A., . . . Easteal, S.
(2008). Total and regional gray matter volume is not related to APOE*E4 status in a
te
community sample of middle-aged individuals. The Journals of Gerontology: Series A,

Medical Sciences, 63(5), 501-504.
Cherry, K. E., & Park, D. C. (1993). Individual difference and contextual variables influence
p
spatial memory in younger and older adults. Psychology and Aging, 8(4), 517-526.
Cheung, G. W., & Lau, R. S. (2007). Testing mediation and suppression effects of latent
ce
variables: Bootstrapping with structural equation models. Organizational Research

Methods, 11(2), 296-325. doi: 10.1177/1094428107300343
Chobanian, A. V., Bakris, G. L., Black, H. R., Cushman, W. C., Green, L. A., Izzo Jr, J. L., . . .
Ac
Wright Jr, J. T. (2003). Seventh report of the joint national committee on prevention,
detection, evaluation, and treatment of high blood pressure. Hypertension, 42(6), 1206-
1252.
Cohen, R. M., Small, C., Lalonde, F., Friz, J., & Sunderland, T. (2001). Effect of apolipoprotein
E genotype on hippocampal volume loss in aging healthy women. Neurology, 57(12),
2223-2228.
Corbo, R., & Scacchi, R. (1999). Apolipoprotein E (APOE) allele distribution in the world. Is
APOE *4 a thrifty allele? Annals of human genetics, 63(4), 301-310.
Dahle, C. L., Jacobs, B. S., & Raz, N. (2009). Aging, vascular risk, and cognition: blood glucose,
pulse pressure, and cognitive performance in healthy adults. Psychology and Aging,
24(1), 154-162. doi: 10.1037/a0014283
Page 29 of 43
De Frias, C. M., Bunce, D., Wahlin, A., Adolfsson, R., Sleegers, K., Cruts, M., . . . Nilsson, L.-
G. (2007). Cholesterol and triglycerides moderate the effect of Apolipoprotein E on
memory functioning in older adults. The Journals of Gerontology: Series B, Social and
Psychological Sciences, 62B(2), 112-118.
de Leeuw, F. E., Richard, F., de Groot, J. C., van Duijn, C. M., Hofman, A., van Gijn, J., &
Breteler, M. (2004). Interaction between hypertension, apoE, and cerebral white matter
lesions. Stroke, 35(5), 1057-1060. doi: 10.1161/01.STR.0000125859.71051.83
t
DeCarli, C., Reed, T., Miller, B. L., Wolf, P. A., Swan, G. E., & Carmelli, D. (1999). Impact of
ip
Apolipoprotein E e4 and vascular disease on brain morphology in men from the NHLBI
Twin Study. Stroke, 30(8), 1548-1553.
Dobbs, A. R., & Rule, B. G. (1989). Adult age differences in working memory. Psychology and
cr
Aging, 4(4), 500-503.
Elias, M. F., Robbins, M. A., Budge, M. M., Elias, P. K., Dore, G. A., Brennan, S. L., . . . Nagy,
us
Z. (2008). Homocysteine and cognitive performance: Modification by the ApoE
genotype. Neuroscience Letters, 430(1), 64-69. doi: 10.1016/j.neulet.2007.10.021
Espeseth, T., Greenwood, P. M., Reinvang, I., Fjell, A. M., Walhovd, K. B., Westlye, L. T., . . .
Parasuraman, R. (2006). Interactive effects of APOE and CHRNA4 on attention and
an
white matter volume in healthy middle-aged and older adults. Cognitive, Affective, &
Behavioral Neuroscience, 6(1), 31-43.
Espeseth, T., Westlye, L. T., Fjell, A. M., Walhovd, K. B., Rootwelt, H., & Reinvang, I. (2008).
Accelerated age-related cortical thinning in healthy carriers of apolipoprotein E epsilon 4.
M
Neurobiology of Aging, 29(3), 329-340. doi: 10.1016/j.neurobiolaging.2006.10.030
Folstein, M. F., Folstein, S. E., & McHugh, P. R. (1975). "Mini-mental state". A practical
method for grading the cognitive state of patients for the clinician. Journal of Psychiatric
d
Research, 12(3), 189-198.

Fuzikawa, A. K., Peixoto, S. V., Taufer, M., Moriguchi, E. H., & Lima-Costa, M. F. (2008).
te
Association of ApoE polymorphisms with prevalent hypertension in 1406 older adults:

the Bambui Health Aging Study (BHAS). Brazilian Journal of Medical and Biological
Research, 41(2), 89-94.
p
Haan, M. N., & Mayeda, E. R. (2010). Apolipoprotein E genotype and cardiovascular diseases in
the elderly. Current Cardiovascular Risk Reports, 4(5), 361-368. doi: 10.1007/s12170-
ce
010-0118-4
Haan, M. N., Shemanski, L., Jagust, W. J., Manolio, T. A., & Kuller, L. (1999). The role of
APOE ε4 in modulating effects of other risk factors for cognitive decline in elderly
Ac
persons. JAMA: The Journal of the American Medical Association, 282(1), 40-46. doi:
10.1001/jama.282.1.40
Harrington, F., Saxby, B. K., McKeith, I. G., Wesnes, K., & Ford, G. A. (2000). Cognitive
performance in hypertensive and normotensive older subjects. Hypertension, 36(6), 1079-
1082.
Hauser, P. S., Narayanaswami, V., & Ryan, R. O. (2011). Apolipoprotein E: From lipid transport
to neurobiology. Progress in Lipid Research, 50(1), 62-74. doi:
10.1016/j.plipres.2010.09.001
Head, D., Rodrigue, K. M., Kennedy, K. M., & Raz, N. (2008). Neuroanatomical and cognitive
mediators of age-related differences in episodic memory. Neuropsychology, 22(4), 491-
507. doi: 10.1037/0894-4105.22.4.491
Page 30 of 43
Helkala, E. L., Koivisto, K., Hänninen, T., Vanhanen, M., Kervinen, K., Kuusisto, J., . . .
Riekkinen, P. (1995). The association of apolipoprotein E polymorphism with memory:
A population based study. Neuroscience Letters, 191(3), 141-144. doi: 10.1016/0304-
3940(95)11575-h
Helkala, E. L., Koivisto, K., Hänninen, T., Vanhanen, M., Kervinen, K., Kuusisto, J., . . .
Riekkinen, P., Sr. (1996). Memory functions in human subjects with different
apolipoprotein E phenotypes during a 3-year population-based follow-up study.
t
Neuroscience Letters, 204(3), 177-180. doi: 030439409612348X [pii]
ip
Honea, R. A., Vidoni, E., Harsha, A., & Burns, J. M. (2009). Impact of APOE on the healthy
aging brain: A voxel-based MRI and DTI study. Journal of Alzheimer's Disease, 18(3),
553-564. doi: 10.3233/JAD-2009-1163
cr
Hultsch, D. F., Hertzog, C., & Dixon, R. A. (1990). Ability correlates of memory performance in
adulthood and aging. Psychology and Aging, 5(3), 356-368.
us
Jagust, W. J. (2009). Genes and cognitive aging. Frontiers in Neuroscience, 3(2), 161-162. doi:
10.3389/neuro.01.020.2009
Jöreskog, K. G., & Sörbom, D. (1993). LISREL 8: Structural equation modeling with the
SIMPLIS command language. Lincolnwood, IL: Scientific Software.
an
Kane, M. J., Conway, A. R. A., Miura, T. K., & Colflesh, G. J. H. (2007). Working memory,
attention control, and the n-back task: A question of construct validity. Journal of
Experimental Psychology: Learning, Memory, and Cognition, 33(3), 615-622. doi:
10.1037/0278-7393.33.3.615
M
Kuller, L. H., Shemanski, L., Manolio, T., Haan, M., Fried, L., Bryan, N., . . . Bhadelia, R.
(1998). Relationship between ApoE, MRI findings, and cognitive function in the
Cardiovascular Health Study. Stroke, 29(2), 388-398.
d
Kuo, H. K., Sorond, F., Iloputaife, I., Gagnon, M., Milberg, W., & Lipsitz, L. A. (2004). Effect
of blood pressure on cognitive functions in elderly persons. The Journals of Gerontology:
te
Series A, Medical Sciences, 59(11), 1191-1194.

Lesser, G. T., Beeri, M. S., Schmeidler, J., Purohit, D. P., & Haroutunian, V. (2011). Cholesterol
and LDL relate to neuritic plaques and to APOE4 presence but not to neurofibrillary
p
tangles. Current Alzheimer Research, 8, 303-312.

Lindenberger, U., von Oertzen, T., Ghisletta, P., & Hertzog, C. (2011). Cross-sectional age
ce
variance extraction: what's change got to do with it? Psychology and Aging, 26(1), 34-47.
doi: 10.1037/a0020525
Liu, F., Pardo, L. M., Schuur, M., Sanchez-Juan, P., Isaacs, A., Sleegers, K., . . . Witteman, J. C.
Ac
M. (2010). The apolipoprotein E gene and its age-specific effects on cognitive function.
Neurobiology of Aging, 31(10), 1831-1833. doi: 10.1016/j.neurobiolaging.2008.09.015
MacKinnon, D. P., & Fairchild, A. J. (2009). Current directions in mediation analysis. Current
Directions in Psychological Science, 18(1), 16-20. doi: 10.1111/j.1467-
8721.2009.01598.x
MacKinnon, D. P., Lockwood, C. M., Hoffman, J. M., West, S. G., & Sheets, V. (2002). A
comparison of methods to test mediation and other intervening variable effects.
Psychological Methods, 7(1), 83-104. doi: 10.1037//1082-989X.7.1.83
Mueller, R. O. (1996). Basic principles of structural equation modeling: An introduction to
LISREL and EQS. New York: Springer Verlag.
Muthén, L., & Muthén, B. (2010). Mplus User’s Guide (6th ed.). Los Angeles: Muthén &
Muthén.
Page 31 of 43
Naveh-Benjamin, M. (2000). Adult age differences in memory performance: Tests of an

associative deficit hypothesis. Journal of Experimental Psychology: Learning, Memory,
and Cognition, 26(5), 1170-1187. doi: 10.1037//0278-7393.26.5.1170
Nilsson, L.-G., Adolfsson, R., Bäckman, L., Cruts, M., Nyberg, L., Small, B. J., & Van
Broeckoven, C. (2006). The influence of APOE status on episodic and semantic memory:
Data from a population-based study. Neuropsychology, 20(6), 645-657. doi:
10.1037/0894-4105.20.6.645
t
Parasuraman, R., Greenwood, P. M., & Sunderland, T. (2002). The apolipoprotein E gene,
ip
attention, and brain function. Neuropsychology, 16(2), 254-274.
Peila, R., White, L. R., Petrovich, H., Masaki, K., Ross, G. W., Havlik, R. J., . . . Poirier, J.
(2001). Joint effect of the APOE gene and midlife systolic blood pressure on late-life
cr
cognitive impairment: The Honolulu-Asia aging study editorial comment: The Honolulu-
Asia aging study. Stroke, 32(12), 2882-2889. doi: 10.1161/hs1201.100392
us
Pollack, I., & Norman, D. A. (1964). A non-parametric analysis of recognition experiments.
Psychonomic Science, 1, 125-126.
Preacher, K. J., & Hayes, A. F. (2008). Asymptotic and resampling strategies for assessing and
comparing indirect effects in multiple mediator models. Behavior Research Methods,
an
40(3), 879-891. doi: 10.3758/BRM.40.3.879
Qiu, C., Winblad, B., & Fratiglioni, L. (2005). The age-dependent relation of blood pressure to
cognitive function and dementia. The Lancet Neurology, 4(8), 487-499. doi:
10.1016/s1474-4422(05)70141-1
M
Radloff, L. S. (1977). The CES-D scale: A self-report depression scale for research in the general
population. Applied Psychological Measurement, 1(3), 385-401. doi:
10.1177/014662167700100306
d
Raz, N., Gunning-Dixon F, Head D, Rodrigue KM, Williamson A, &Acker JD. (2004). Aging,
sexual dimorphism, and hemispheric asymmetry of the cerebral cortex: replicability of
te
regional differences in volume. Neurobiology of Aging, 25(3), 377-396. doi:

10.1016/s0197-4580(03)00118-0
Raz, N. (2011). Diabetes: Brain, mind, insulin-what is normal and do we need to know? Nature
p
Reviews Endocrinology, 7(11):636-637. doi: 10.1038/nrendo.2011.149.

Raz N, & Lindenberger U. (2011). Only time will tell: cross-sectional studies offer no solution to
ce
the age-brain-cognition triangle: comment on Salthouse (2011). Psychological Bulletin,

137(5):790-795.
Raz, N., Dahle, C. L., Rodrigue, K. M., Kennedy, K. M., & Land, S. (2011). Effects of age,
Ac
genes, and pulse pressure on executive functions in healthy adults. Neurobiology of

Aging, 32(6), 1124-1137. doi: 10.1016/j.neurobiolaging.2009.05.015
Raz, N., Dahle, C. L., Rodrigue, K. M., Kennedy, K. M., Land, S. J., & Jacobs, B. S. (2008).
Brain-derived neurotrophic factor Val66Met and blood glucose: a synergistic effect on
memory. Frontiers in Human Neuroscience, 2, 1-12. doi: 10.3389/neuro.09.012.2008
Raz, N., Gunning-Dixon, F. M., Head, D., Dupuis, J. H., & Acker, J. D. (1998).
Neuroanatomical correlates of cognitive aging: Evidence from structural magnetic
resonance imaging. Neuropsychology, 12(1), 95-114.
Raz, N., Lindenberger, U., Rodrigue, K. M., Kennedy, K. M., Head, D., Williamson, A., . . .
Acker, J. D. (2005). Regional brain changes in aging healthy adults: General trends,
individual differences and modifiers. Cerebral Cortex, 15(11), 1676-1689. doi:
10.1093/cercor/bhi044
Page 32 of 43
Raz, N., & Rodrigue, K. (2006). Differential aging of the brain: Patterns, cognitive correlates and
modifiers. Neuroscience & Biobehavioral Reviews, 30(6), 730-748. doi:
10.1016/j.neubiorev.2006.07.001
Raz, N., Rodrigue, K. M., & Acker, J. D. (2003). Hypertension and the brain: Vulnerability of
the prefrontal regions and executive functions. Behavioral Neuroscience, 117(6), 1169-
1180. doi: 10.1037/0735-7044.117.6.1169
Raz, N., Rodrigue, K. M., Kennedy, K. M., & Land, S. (2009). Genetic and vascular modifiers of
t
age-sensitive cognitive skills: Effects of COMT, BDNF, ApoE, and hypertension.
ip
Neuropsychology, 23(1), 105-116. doi: 10.1037/a0013487
Reinvang, I., Winjevoll, I. L., Rootwelt, H., & Espeseth, T. (2010). Working memory deficits in
healthy APOE epsilon 4 carriers. Neuropsychologia, 48(2), 566-573. doi:
cr
10.1016/j.neuropsychologia.2009.10.018
Roberts, R. M., & Corkin, S. (1997). Poor correlations among verbal working memory tests
us
Fourth Annual Meeting of the Cognitive Neuroscience Society: Boston, MA.
Salerno, J. A., Murphy, D., Horwitz, B., DeCarli, C., Haxby, J. V., Rapoport, S. I., & Schapiro,
M. B. (1992). Brain atrophy in hypertension. A volumetric magnetic resonance imaging
study. Hypertension, 20(3), 340-348.
an
Salthouse, T. A. (1974). Using selective interference to investigate spatial memory
representations. Memory & Cognition, 2(4), 749-757.
Salthouse, T. A. (1975). Simultaneous processing of verbal and spatial information. Memory &
Cognition, 3(2), 221-225. doi: 10.3758/BF03212901
M
Salthouse, T. A. (1991). Mediation of adult age differences in cognition by reductions in working
memory and speed of processing. Psychological Science, 2(3), 179-183.
Salthouse, T. A. (1996a). General and specific speed mediation of adult age differences in
d
memory. The Journals of Gerontology Series B: Psychological Sciences and Social

Sciences, 51(1), P30-42.
te
Salthouse, T. A. (1996b). The processing-speed theory of adult age differences in cognition.

Psychological Review, 103(3), 403-428.
Salthouse, T. A. (1996c). Where in an ordered sequence of variables do independent age-related
p
effects occur? The Journals of Gerontology: Series B, Social and Psychological Sciences,
51(3), P166-178.
ce
Salthouse, T. A. (2011). Neuroanatomical substrates of age-related cognitive decline.

Psychological Bulletin, 137(5), 753-784. doi: 10.1037/a0023262
Salthouse, T. A., Kausler, D. H., & Saults, J. S. (1988). Investigation of student status,
Ac
background variables, and feasibility of standard tasks in cognitive aging research.

Psychology and Aging, 3(1), 29-37.
Salthouse, T. A., & Meinz, E. J. (1995). Aging, inhibition, working memory, and speed. The
Journals of Gerontology: Series B, Social and Psychological Sciences, 50B(6), 297-306.
Salthouse, T. A., Mitchell, D. R. D., Skovronek, & Babcock, R. L. (1989). Effects of adult age
and working memory on reasoning and spatial abilities. Journal of Experimental
Psychology. Learning, Memory, and Cognition, 15(3), 507-516.
Shrout, P. E., & Bolger, N. (2002). Mediation in experimental and nonexperimental studies: New
procedures and recommendations. Psychological Methods, 7(4), 422-445. doi:
10.1037//1082-989x.7.4.422
Shrout, P. E., & Fleiss, J. L. (1979). Intraclass correlations: Uses in assessing rater reliability.
Psychological Bulletin, 86(2), 420-428.
Page 33 of 43
Singhmanoux, A., & Marmot, M. (2005). High blood pressure was associated with cognitive
function in middle-age in the Whitehall II study. Journal of Clinical Epidemiology,
58(12), 1308-1315. doi: 10.1016/j.jclinepi.2005.03.016
Small, B. J., Basun, H., & Backman, L. (1998). Three-year changes in cognitive performance as
a function of apolipoprotein E genotype: Evidence from very old adults without
dementia. Psychology and Aging, 13(1), 80-87.
Small, B. J., Rosnick, C. B., Fratiglioni, L., & Bäckman, L. (2004). Apolipoprotein E and
t
cognitive performance: A meta-analysis. Psychology and Aging, 19(4), 592-600.
ip
Smith, J. C., Nielson, K. A., Woodard, J. L., Seidenberg, M., Durgerian, S., Antuono, P., . . .
Rao, S. M. (2011). Interactive effects of physical activity and APOE-ε4 on BOLD
semantic memory activation in healthy elders. NeuroImage, 54(1), 635-644. doi:
cr
10.1016/j.neuroimage.2010.07.070
Sobel, M. E. (1982). Asymptotic confidence intervals for indirect effects in structural equation
us
models. In S. Leinhardt (Ed.), Sociological Methodology (Vol. 13, pp. 290-312).
Washington, D.C.: American Sociological Association.
Song, Y., Stampfer, M. J., & Liu, S. (2004). Meta-analysis: apolipoprotein E genotypes and risk
for coronary heart disease. Annals of Internal Medicine, 141(2), 137-147.
an
Spearman, C. (1904). The proof and measurement of association between two things. The
American Journal of Psychology, 15(1), 72-101.
Stanislaw, H., & Todorov, N. (1999). Calculation of signal detection theory measures. Behavior
Research Methods, Instruments, & Computers, 31(1), 137-149.
M
Striepens, N., Scheef, L., Wind, A., Meiberth, D., Popp, J., Spottke, A., . . . Jessen, F. (2011).
Interaction effects of subjective memory impairment and ApoE4 genotype on episodic
memory and hippocampal volume. Psychol Med, 41(9), 1997-2006. doi:
d
10.1017/S0033291711000067
Wetter, S. R., Delis, D. C., Houston, W. S., Jacobson, M. W., Lansing, A., Cobell, K., . . . Bondi,
te
M. W. (2005). Deficits in inhibition and flexibility are associated with the APOE-E4
allele in nondemented older adults. Journal of Clinical and Experimental
Neuropsychology, 27(8), 943-952. doi: 10.1080/13803390490919001
p
Williams, J., & MacKinnon, D. P. (2008). Resampling and distribution of the product methods
for testing indirect effects in complex models. Structural Equation Modeling, 15(1), 23-
ce
51. doi: 10.1080/10705510701758166

Wilson, R. S., Schneider, J. A., Barnes, L. L., Beckett, L. A., Aggarwal, N. T., Cochran, E. J., . .
. Bennett, D. A. (2002). The apolipoprotein E epsilon 4 allele and decline in different
Ac
cognitive systems during a 6-year period. Archives of Neurology, 59(7), 1154-1160.

Wisdom, N. M., Callahan, J. L., & Hawkins, K. A. (2011). The effects of apolipoprotein E on
non-impaired cognitive functioning: A meta-analysis. Neurobiology of Aging, 32(1), 63-
74. doi: 10.1016/j.neurobiolaging.2009.02.003
Wishart, H. A., Saykin, A. J., McAllister, T. W., Rabin, L. A., McDonald, B. C., Flashman, L.
A., . . . Rhodes, C. H. (2006). Regional brain atrophy in cognitively intact adults with a
single APOE ε4 allele. Neurology, 67(7), 1221-1224. doi:
10.1212/01.wnl.0000238079.00472.3a
Wright, C. B., & Sacco, R. L. (2010). Cardiac index as a correlate of brain volume: Separating
the wheat of normal aging from the chaff of vascular cognitive disorders. Circulation,
122(7), 676-678. doi: 10.1161/circulationaha.110.970301
Page 34 of 43
Yavuz, B. B., Yavuz, B., Sener, D. D., Cankurtaran, M., Halil, M., Ulger, Z., . . . Ariogul, S.
(2008). Advanced age is associated with endothelial dysfunction in healthy elderly
subjects. Gerontology, 54(3), 153-156. doi: 10.1159/000129064
Zade, D., Beiser, A., McGlinchey, R., Au, R., Seshadri, S., Palumbo, C., . . . Milberg, W. (2010).
Interactive effects of apolipoprotein E type 4 genotype and cerebrovascular risk on
neuropsychological performance and structural brain changes. Journal of Stroke and
Cerebrovascular Diseases, 19(4), 261-268. doi:
t
10.1016/j.jstrokecerebrovasdis.2009.05.001
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Acknowledgement
We thank Cheryl Dahle, Yiquin Yang, and Peng Yuan for the help in collection of the cognitive
and neuroimaging data and Susan Land for APOE genotyping. This work was supported in part
by a grant from the National Institute on Aging R37-AG011230 to NR.
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Table 1 Sample Demographic Characteristics
Men Women
Variable Mean ± SD Mean ± SD t or χ2a p
Age 49.0 ± 17.3 50.40 ± 12.9 0.36 0.72
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Education 15.7 ± 2.7 15.8 ± 2.3 0.18 0.86
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MMSE 28.8 ± 1.2 28.9 ± 1.1 0.45 0.65
SBP (mm Hg) 122.3 ± 10.2 119.6 ± 12.8 1.19 0.24
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Diastolic BP (mm Hg) 75.6 ± 8.6 73.1 ± 6.5 1.36 0.18
Smokers 1 (4.5%) 8 (16.0%) 1.83 0.18
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Exercise 18 (82.0%) 41 (81.8%) 0.00 0.99
Exercise Frequency 3.6 ± 2.2 3.6 ± 2.3 0.07 0.94
APOE ε4 Carriers 5 (22.8%) 15 (30.0%) 0.40 0.53
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Non-whites 9 (40.9%) 10 (20.0%) 3.43 0.06
ε3 Homozygotes ε4 Carriers
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Variable Mean ± SD Mean ± SD t or χ2a p
Age 48.3 ± 14.4 54.2 ± 13.2 1.56 0.12

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Education 15.9 ± 2.6 15.6 ± 2.0 0.55 0.58

MMSE 28.7 ± 1.2 29.2 ± 0.7 1.90 0.06
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SBP (mm Hg) 121.3 ± 11.9 119.5 ± 12.9 0.56 0.58

Diastolic BP (mm Hg) 74.1 ± 7.7 73.3 ± 6.3 0.39 0.70
p
Smokers 7 (13.4%) 2 (10.0%) 0.15 0.69

Exercise 44 (84.6%) 15 (75.0%) 0.80 0.43
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Exercise Frequency 3.4 ± 2.0 3.9 ± 2.6 0.90 0.34

Non-whites 12 (23.1%) 7 (35.0%) 1.39 0.24
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single-degree of freedom chi-square test
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Percentages are by group, not total
Page 37 of 43
Table 2. Zero-order Correlations among Study Variables
Total Sample
Variable 1 2 3 4 5 6 7 8
1. Age −
2. SBP .36** −
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3. HC Volume -.46*** -.16 −
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4. lPFC Volume -.61*** -.34** .47*** −
5. pFWM Volume -.49*** -.32** .44*** .81*** −
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6. Processing Speed -.51*** -.31** .36** .50*** .47*** −
7. Working Memory -.53*** -.36** .41*** .51*** .49*** .67*** −
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8. Item Recognition -.24* -.21 .12 .22 .21 .42*** .35** −
9. Assoc. Recognition -.42*** -.40*** .13 .36** .27* .48*** .61*** .62***
ε4 carriers
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Variable 1 2 3 4 5 6 7 8
1. Age −
2. SBP .62** −
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3. HC Volume -.74*** -.61** −
4. lPFC Volume -.47* -.53* .37 −
5. pFWM Volume -.49* -.49* .57** .76*** −
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6. Processing Speed -.65** -.74*** .63** .80*** .78*** −

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7. Working Memory -.58** -.75*** .69*** .63** .65** .87*** −

8. Item Recognition -.21 -.52* .12 .10 .08 .32 .35 −
9. Assoc. Recognition -.48* -.62** .24 .56* .45* .69*** .58** .74***
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ε3 homozygotes
Variable 1 2 3 4 5 6 7 8
1. Age −
2. SBP .29* −
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3. HC Volume -.34* .05 −

4. lPFC Volume -.65*** -.29* .51*** −
5. pFWM Volume -.47*** -.28* .37** .83*** −
6. Processing Speed -.47*** -.12 .23 .40** .36** −
7. Working Memory -.51*** -.20 .27* .47*** .42** .58*** −
8. Item Recognition -.26 -.08 .13 .26 .26 .46*** .35* −
9. Assoc. Recognition -.41** -.32* .09 .31* .22 .41** .62*** .58***
Notes: * p < .05, ** p < .01, *** p < .001
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Table 3. Goodness-of-Fit Indices
χ2 /
Model χ2 df p CFI TLI RMSEA SRMR
df
SBP Mediating Age-Speed-WM
PFC/FWM Mediation 14.8 15 1.0 .464 1.00 1.00 .000 .055
t
PFC/FWM Reversed Mediation 40.6 8 5.1 .000 0.85 0.42 .337 .205
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PFC/FWM Correlation 53.6 8 6.7 .000 0.79 0.19 .398 .267
SBP Mediating Age-Recognition
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PFC/HC Mediation 13.1 14 0.9 .519 1.00 1.01 .000 .051
PFC/HC Reversed Mediation 39.2 14 2.8 .000 0.75 0.50 .223 .150
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PFC/HC Correlation 21.9 14 1.6 .082 0.94 0.88 .125 .134
Notes: CFI = Comparative Fit Index; TLI = Tucker-Lewis Index; RMSEA = Root mean square
error of approximation; SRMR = standardized root mean residual.
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Table 4. Significant Indirect Effects From Model 3
Std.
Indirect Effect p 95% CI
Estimate
Model of SBP Mediating Age Differences in Speed of Processing and WM
t
ε3 homozygotes
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Age → lPFC → WM -.18 .025 -.35 to -.02
Age → Speed → WM -.18 .045 -.35 to .00
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ε4 carriers
Age → SBP → pFWM → Speed → WM -.15 .006 -.25 to -.04
Age → SBP → Speed → WM -.25 .004 -.42 to -.08
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Age → SBP → Speed -.28 .010 -.48 to -.10
SBP → pFWM → Speed → WM -.24 .001 -.38 to -.09
SBP → Speed → WM -.40 .000 -.57 to -.24
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pFWM → Speed → WM .48 .000 .31 to .67
Age → SBP → pFWM -.30 .008 -.53 to -.08
Age → SBP → pFWM → Speed -.17 .003 -.28 to -.02
SBP → pFWM → Speed -.27 .000 -.42 to -.12
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Age → SBP → lPFC -.33 .020 -.06 to -.05
Model of SBP Mediating Age Differences in Recognition Memory

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ε4 carriers
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Age → SBP → Assoc. Recognition -.21 .021 -.40 to -.03

Age → SBP → lPFC → Assoc. Recog. -.15 .040 -.03 to -.01
p
SBP → lPFC → Assoc. Recognition -.25 .016 -.44 to -.05

Age → SBP → Item Recognition -.32 .004 -.53 to -.11
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Age → SBP → lPFC -.34 .007 -.59 to -.09
Notes: SBP=Systolic Blood pressure; lPFC = lateral prefronal volume; pFWM = prefrontal white
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matter volume; WM = WM composite; Speed = processing speed
Page 40 of 43
AGING ASSOCIATIVE MEMORY
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Figure 1. Representative examples of manual measurement of regions of interest. Images are in
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radiological orientation. A. Example of lateral prefrontal cortex ROI; B. Example of prefrontal
white matter ROI (from same slice as A.); C. Depiction of hippocampal ROI.
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Figure 2. Age differences in regional volumes for APOE ε4 carriers (empty circles, dashed line) and ε3 homozygotes (filled circles,
sold line).
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Figure 3. Nested path models for ApoE 4 carriers and ApoE 3 homozygotes from reduced
grouped mediational models. Only significant direct paths are shown. A. Models for mediation
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of associations with processing speed and working memory; B. Models for mediation of
associations with recognition memory for items and associations. * p < .05, ** p < .01, *** p <
.001
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Page 43 of 43

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Accepted Manuscript

Title: Age-Related Differences in Memory and Executive

Authors: Andrew R. Bender, Naftali Raz

To appear in: Neuropsychologia

Received date: 12-8-2011

Running head: BLOOD PRESSURE BRAIN VOLUMETRY COGNITION 2

Andrew R. Bender, Department of Psychology & Institute of Gerontology, Wayne State

Correspondence concerning this article should be addressed to Naftali Raz, 87 E. Ferry

Street, 226 Knapp Building, Detroit, MI 48202. Email: nraz@wayne.edu

ε3 homozygotes. Among ε4 carriers, age differences in WM were explained by increase in SBP,

associated with reduced frontal volumes and impaired cognitive functions.

Word count: 250

Contribution of Individual Differences in Prefrontal Volumes and Systolic Blood Pressure

reduced performance in multiple areas of age-sensitive areas of cognition: speed of perceptual-

hypertension is a categorical diagnosis based on cut-off value of arterial blood pressure

even in normotensive individuals.

A significant proportion of individual differences in brain parameters, cognitive

neurotransmission to yield impairments in white matter volume and perceptual-motor speed

(Espeseth et al., 2006).

Because cognitive abilities are correlated, it is unclear whether the effect of 4 on

In this study, we examined whether the pattern and magnitude of contributions of

sample of healthy adults. Specifically, we hypothesized that in APOE 4 carriers, higher

demonstrate such vulnerability.

issues including medical diagnosis of hypertension and use of prescribed anti-hypertensive

medication, as well as history of cardiovascular disease, neurological, or psychiatric disease.

antihyperglycemic, antipsychotic, or anxiolytic medications. In addition, participants who

Audiometer, Maico Diagnostics, Eden Prairie, MN). An experimenter measured participant

blood pressure with an analog mercury sphygmomanometer (Model 12-525; Country

measurements were averaged across occasions.

diagnosis of hypertension or use of anti-hypertensive medication. Men and women sub-samples

& Raz, 2009).

forward 5’-CAATGCTACCGAGTTTTCTTCC-3’ and reverse primers 5’-

TTCAGATTCTTCACAGATGCGTA-3’ in a 25 µl reaction containing 2.5 mmol/l MgCl2, 0.5

assay were 5’-TCCGCGATGCCGATGAC-3’, 5’-CCCCGGCCTGGTACAC-3’, VIC-

CAGGCGCTTCTGC-NFQ and FAM-CAGGCACTTCGC-NFQ. The primers and probes for the

rs429358 assay were 5’-GCGGGCACGGCTGT-3’, 5’-GCTTGCGCAGGTGGGA-3’, VIC-

CATGGAGGACGTGTGC-NFQ and FAM-ATGGAGGACGTGCGC-NFQ.

Analyzer with a 50 cm capillary array.

no significant difference in APOE ε4 frequency between African-American and Caucasian

for the ε4 allele; ε4 carriers made up 28% of the sample.

MRI Acquisition and Processing

MRI Acquisition. T1-weighted magnetization-prepared rapid acquisition with gradient

hippocampus for measurement of frontal and hippocampal volumes, respectively.

from the entire sample.

ROI Demarcation Procedures.

and ICC(2) values ranged from .94 to .99.

point and inferiorly by the lateral orbital sulcus.

non-white matter from the measurements.

Hippocampus (HC). The HC was traced in a para-coronal view, orthogonal to the

Participants completed a series of cognitive tests of age-sensitive abilities including WM,

disproportionate age-related impairments in associative recognition, we administered the task

used by Naveh-Benjamin (2000) in his test of an associative deficit hypothesis.

Working Memory: N-Back Tests. An experimenter administered computerized n-back

centered at their respective sample means and standardized to z-scores.

composite measures of item and associative recognition performance.

although we use familiar SEM terminology, “mediation” should only be considered as

demonstrating consistent hierarchical partitioning of variance/covariance whereby individual

differences in one variable are associated with individual differences in another.

To investigate the role of SBP as a contributor to the associations of age, hypothesized

containing multiple hypothesized paths reflecting heterogeneous partitioning of variance based

Age-related differences in blood pressure or brain volumes may reflect individual

alternate path analyses: a reversed-mediation model and an exclusively correlational model to

reduced group mediational model, a reversed-mediation model, and a correlational model.

Path Analysis - Processing Speed and Working Memory

6. Processing Speed -.65 -.74* .63 .80* .78*** −

7. Working Memory -.58 -.75* .69* .63 .65 .87* −

Notes: * p < .05, p < .01, * p < .001