This study used functional connectivity MRI to analyze differences in brain activity patterns between cognitively normal older adults who carry the APOE4 gene, which increases risk for Alzheimer's disease, and those who do not carry the gene. The study found that APOE4 carriers showed reduced connectivity in parts of the default mode network, including the frontal, parahippocampal and temporal cortex, compared to non-carriers. APOE4 carriers also showed increased connectivity in other parts of the default mode network, including the frontal, temporal and parietal cortex. These differences suggest that functional connectivity is altered in cognitively normal older adults at genetic risk for Alzheimer's disease.

1. Introduc)on
Functional connectivity magnetic resonance
imaging (fcMRI) is a brain imaging technique
that permits researchers to investigate the
covarying pattern of activity (i.e., functional
connections) in the brain. The default network
(DMN), which consists of those functionally
connected brain regions that are most active
during the resting state, is preferentially
vulnerable to the deposition of amyloid
plaques, a cardinal neuropathological feature of
Alzheimer’s disease (AD). In this study, we
analyzed fcMRI data acquired in an ongoing
longitudinal study of cognitively normal older
adults with two copies, one copy and no copies
of the apolipoprotein E4 (APOE4) allele, the
major AD susceptibility gene, to test the
hypothesis that functional connections in the
DMN are altered in persons at genetic risk for
AD, thus extending preliminary findings
generated in other laboratories. Our aim in this
examination is to assess the possible utility of
this measure for use in clinical prevention
studies.
Materials and methods
Automated brain mapping algorithms
(DPARSF and SPM5) were used to characterize
and compare Baseline Blood Oxygen Level
Dependent Functional (BOLD) MRIs (i.e.,
fcMRIs), in 19 APOE4 carriers and 23 non-
carriers. Brain imaging data from each
individual were spatially deformed into the
coordinates of a standard brain atlas,
superimposed, and used to characterize and
compare the extent to which different voxels
throughout the cerebral cortex were connected
to those in a posterior cingulate cortex seed
region, after controlling for differences in age.
(continued)
The carriers were 69±4 years old, included 7
homozygotes and 12 heterozygotes, and
included 17 females and 2 males. The non-
carriers included were 65±7 years old and
included 15 females and 8 males (Table 1).
Table 1. Comparison of demographic and
cognitive test data for APOE4 carriers and
noncarriers.
Results
The cognitively normal APOE4 carriers were
distinguished from the non-carriers by
significantly reduced functional connectivity
with the posterior cingulate cortex in frontal,
parahippocampal, and temporal cortex
locations within the DMN (Figure 1) and by
increased functional connectivity in other
frontal, temporal and parietal locations within
the DMN (Figure 2) (p < 0.005, uncorrected for
multiple comparisons).
Figure 1. Regions with lower functional
connectivity to the posterior cingulate in
APOE4 carriers than in noncarriers. Activation
of these areas of the Default Mode Network
(DMN), which is active in the resting state, is
not as strongly correlated with activation of the
rest of the DMN in carriers as it is in
noncarriers.
Figure 2. Regions with higher functional
connectivity to the posterior cingulate in
APOE4 carriers than in noncarriers. Activation
of these areas of the Default Mode Network
(DMN), which is active in the resting state, is
more strongly correlated with activation of the
rest of the DMN in carriers than in noncarriers.
Conclusions
Cognitively normal older adult carriers of the
APOE4 allele have an altered pattern of
functional connectivity in the DMN. Additional
studies are needed to extend our findings to
larger samples, relate them to three levels of
genetic risk for AD (i.e., to 2, 1 or 0 copies of
the APOE4 allele), determine the extent to
which the pattern of functional connectivity
changes over time, the extent to which these
measurements could predict the subsequent
onset of cognitive decline, and the extent to
which they could be used to help evaluate
treatments for the prevention of AD. (continued)
Should this measure prove useful for clinical
use, it could replace much more expensive
amyloid PET imaging techniques in many
instances.
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Acknowledgements
Many thanks to the Miller Internship Award and
the Banner Research Summer Internship
Program. Additional thanks to the National
Institute of Health and private donors for
general research funding at Banner Alzheimer’s
Institute.
For further informa)on
Please contact rhoades@lclark.edu. More
information on the Alzheimer’s Prevention
Initiative can be obtained at
www.endalznow.org. More information on the
Banner Alzheimer’s Institute can be found at
www.banneralz.org.
J. Rhoades1,2, A. Roon)va1, W. Lee1, A. Li1, E. Peshkin1, K. Chen1, E. Reiman1, A. Fleisher1
1Banner Alzheimer’s Ins1tute, 901 E. Wille:a Street, Phoenix, AZ 85006
2Lewis & Clark College, 615 SW Pala1ne Hill Road, Portland, OR 97219
Altered Default Mode Network Func)onal Connec)vity in cogni)vely
normal older adults at gene)c risk for Alzheimer’s disease
.005
p – value
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p – value
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