Decreased Inter-Hemispheric Functional Connectivity in Cognitively Intact Elderly APOE ɛ 4 Carriers: A Preliminary Study

Abstract

The apolipoprotein E (APOE) ɛ4 allele is the best-known genetic risk factor for developing sporadic Alzheimer’s disease (AD). According to neuroimaging studies, the APOE ɛ4 allele is associated with localized altered brain function. However, in long-range circuitry, APOE ɛ4 allele-related alterations in functional communication between hemispheres have rarely been directly investigated. We examined the alteration of resting-state functional connectivity (RSFC) between inter-hemispheric homotopic regions in cognitively intact, elderly APOE ɛ4 carriers. The voxel-mirrored homotopic connectivity method was used to assess the inter-hemispheric RSFC. The current study included 13 cognitively intact, elderly APOE ɛ4 carriers (with at least one copy of APOE ɛ4 allele) and 22 well-matched ɛ3 homozygotes. Comparisons between the two groups were conducted, and subsequently, the correlation between the differential inter-hemispheric RSFC and cognitive ability was analyzed. Compared with ɛ3 homozygotes, APOE ɛ4 carriers showed decreased inter-hemispheric RSFC in the bilateral medial temporal lobe (MTL) and orbital frontal cortex (OFC). Moreover, in APOE ɛ4 carriers, the inter-hemispheric RSFC of the MTL correlated with the Wechsler Memory Scale-Logical Memory (WMS-LM) (immediate and delayed performance, r = 0.64, p < 0.05; r = 0.65, p < 0.05, respectively), and the inter-hemispheric RSFC of the OFC correlated with the WMS-LM delayed performance (r = 0.71, p < 0.05). In our study, the presence of the APOE ɛ4 allele was linked with decreased inter-hemispheric RSFC, which was attributed to memory performance in carriers.

Keywords

Alzheimer’s disease apolipoprotein E corpus callosum functional magnetic resonance imaging memory

INTRODUCTION

Alzheimer’s disease (AD) is the most common form of dementia and is clinically manifested by the decline of memory and other cognitive abilities. Multiple risk factors contribute to the presentation of AD. By far, the apolipoprotein E (ApoE, protein; APOE, gene) allele is the best-known genetic risk factor for developing sporadic AD, which accounts for 40% of AD cases [1 –4]. Moreover, APOE ɛ4 carriers (ɛ3/ɛ4) have a 4-fold increase in the relative risk compared with ɛ3 homozygotes [5, 6]. Primarily owing to the findings from previous animal studies, the APOE ɛ4 allele is thought to confer AD risk via insufficient myelin repair, decreased clearance, and accelerated aggregation of amyloid deposition [7 –11]. The well-established association between the APOE ɛ4 allele and AD suggests that assessing structural and functional brain changes in healthy APOE ɛ4 carriers may facilitate the understanding of AD pathogenesis and lead to earlier diagnoses and clinical treatments.

According to neuroimaging studies, the APOE ɛ4 allele is associated with widespread altered brain structure and function. Structurally, asymptomatic APOE ɛ4 carriers exhibited smaller volumes in the medial temporal lobe (MTL) [12], accelerated age-related volume loss in the corpus callosum (CC) [13, 14], and accelerated atrophy in the hippocampus (HP) relative to non-carriers [15]. Functionally, studies with positron emission tomography (PET) found that the APOE ɛ4 allele was associated with a pattern of reduced glucose metabolism in early AD-like brain regions, including regions of the prefrontal and temporal cortices [16]. In addition, during memory-encoding tasks, in most functional magnetic resonance imaging (fMRI) studies, the APOE ɛ4 allele was related to a reduction of task-induced deactivations in the default mode network (DMN [17]) [18 –20]. Recently, resting-state functional magnetic resonance imaging (rsfMRI) has been widely used to investigate brain functional differences in APOE ɛ4 carriers, and the majority of studies have reported significant resting-state functional connectivity (RSFC) differences in the DMN [21 –25]. However, most previous studies have been limited to regional alterations and are unable to assess the functional connectivity concerning long-range circuitry. Currently, AD is viewed as a disconnection syndrome that is characterized by the disruption of inter-regional functional connectivity [26]. Hence, to identify functional connectivity alterations in AD high-risk groups on a large scale, studies of APOE ɛ4 carriers are urgently needed.

Robust inter-hemispheric homotopic RSFC is one of the modes of the brain’s intrinsic functional architecture [27, 28]. Inter-hemispheric RSFC is highly related to brain information communication and integration processes. Additionally, bi-hemispheric interactions play an important role in many high-order cognitive domains, such as decision-making and memory functions [29 –32]. Relative to normal controls, perfusion and coactivation abnormalities in APOE ɛ4 carriers occur mainly in the lateral regions [21 , 23–25], and structural impairments of the CC are frequently reported [8 , 34]. Thus, we speculated that inter-hemispheric connectivity abnormalities could be one of the gene-expression profiles that exist in APOE ɛ4 carriers.

In the current study, we utilized a validated image analysis method called voxel-mirrored homotopic connectivity (VMHC) [35], which quantifies the RSFC between geometrically matched regions in two hemispheres to investigate differences in inter-hemispheric connectivity between cognitively intact, elderly APOE ɛ4 carriers and non-carriers. Based on previous data, we hypothesized that the APOE ɛ4 carriers had an abnormal inter-hemispheric RSFC, particularly in the DMN areas. In addition, to validate the relationship between inter-hemispherical RSFC changes and clinical cognitive performances, correlation analyses were performed.

MATERIALS AND METHODS

Alzheimer’s disease neuroimaging initiative

Data used in this study were obtained from the Alzheimer’s disease Neuroimaging Initiative (ADNI) database (http://adni.loni.usc.edu). The ADNI was launched in 2003 by the National Institute on Aging (NIA), the National Institute of Biomedical Imaging and Bioengineering (NIBIB), the Food and Drug Administration (FDA), private pharmaceutical companies and non-profit organizations, as a $60 million, 5-year public-private partnership. The primary goal of ADNI has been to test whether serial MRI, PET, other biological markers, and clinical and neuropsychological assessment can be combined to measure the progression of MCI and early AD. Determination of sensitive and specific markers of very early AD progression is intended to aid researchers and clinicians in developing new treatments and monitor their effectiveness, as well as lessen the time and cost of clinical trials. For up-to-date information, see http://www.adni-info.org.

Study participants

This study was approved by the Institutional Review Boards of all of the participating institutions, and informed written consent was obtained from all participants at each site. At the time of analysis, individuals carrying at least one APOE ɛ4 allele (genotype ɛ4/ɛ4 and ɛ4/ɛ3) were classified as APOE ɛ4 carriers, while individuals with genotype ɛ3/ɛ3 were classified as non-carriers. Individuals with the ɛ2 allele (such as genotype ɛ2/ɛ4) were excluded due to its possible protective effects [36]. Using the ADNI GO and ADNI 2 databases, 40 right-handed cognitively intact healthy participants, comprised of 14 APOE ɛ4 carriers and 26 non-carriers, who had undergone structural scans, REST scans, and neuropsychological assessments, were identified. These study data were downloaded from the ADNI publically available database prior to November 15, 2014. For the ADNI, to be classified as control normal (CN), the subject had an MMSE between 24 –30 (inclusive), a clinical dementia rating (CDR) score of 0; besides, the subjects were required to meet distinctive cutoffs for Wechsler Memory Scale-Logical Memory (WMS-LM) delay score (in detail: ≥9 for subjects with 16 or more years of education; ≥5 for subjects with 8–15 years of education; and ≥3 for 0–7 years of education). Additionally, they were non-depressed (geriatric depression scale score <5), and non-demented. All subjects were screened and excluded for a history of obvious head trauma, other neurological or major psychiatric disorder and alcohol or drug abuse. Besides, we excluded those individuals who are subjective memory complaints (without objective cognitive ability impairment) defined by ADNI database. After careful screening of the data, one participant was excluded because of depression; one participant was excluded due to big calcification in the occipital cortex; one participant was excluded for excessive head motion (details later); two subjects were excluded because of damaged structural image. Table 1 presents the demographic data for the remaining 35 subjects.

Neuropsychological assessment and APOE genotyping

The neuropsychological assessment used in the current study was downloaded from the ADNI database. In this study, we focused on the results of general cognitive ability tests and tests targeting memory, decision-making, language, processing speed, and visuospatial functioning. Table 1 presents the details of the neuropsychological performances of the subjects.

Genotyping of all subjects for APOE allele status was performed using DNA extracted from peripheral blood cells. The cells were collected in 1 EDTA plastic tubes (10ml) and sent by express mail to the University of Pennsylvania AD Biofluid Bank Laboratory by overnight delivery at room temperature. Please see the ADNI-1 Procedures manual for more detailed information.

Data acquisition

Both the structural scans and REST scans were downloaded from the ADNI database. All participants were scanned using a 3.0-Tesla Philips MRI scanner The structural images were acquired using a 3D MPRAGE T1-weighted sequence with the following parameters: Repetition time (TR) = 2300 ms; echo time (TE) = 2.98 ms; inversion time (TI) = 900 ms; 170 sagittal slices; within plane FOV = 256 × 240mm²;voxel size = 1.1 × 1.1 × 1.2 mm³; flip angle = 9°; bandwidth = 240 Hz/pix. Resting-state functional MRI images were obtained using an echo-planar imaging sequence with the following parameters: 140 time points; TR = 3000 ms; TE = 30 ms; flip angle = 80°; number of slices = 48; slice thickness = 3.3 mm; spatial resolution = 3.31 × 3.31 × 3.31 mm³; matrix = 64 × 64.

Imaging preprocessing

Data preprocessing was performed using the Data Processing Assistant for Resting-state fMRI (DPARSF, Yan and Zang; http://rfmri.org/DPASFA), which is based on the Statistical Parametric Mapping software (SPM8) package (http://www.fil.ion.ucl.ac.uk/spm/; Wellcome Trust Center for Neuroimaging, University College London, United Kingdom) and Resting-State fMRI Data Analysis Toolkit (REST; Song et al., http://restfmri.net). The first 10 image volumes of REST scans were discarded for the signal equilibrium and subject’s adaptation to the scanning noise. The remaining 130 images were corrected for timing differences between each slice and head motion (six-parameter rigid body). Datasets with more than 2.0mm maximum displacement in any of the x, y, or z directions or 2.0° of any angular motion were discarded. Subsequently, based on through rigid-body transformation, the T1-weighted image was co-registered to the mean rsfMRI image, and spatially normalized to the Montreal Neurological Institute (MNI) stereotactic space, then re-sampled them into of 3 mm × 3 mm × 3 mm cubic voxels. The functional images spatially smoothed with a Gaussian kernel of 6 × 6 × 6 mm³ full width at half maximum to decrease spatial noise. Finally, linear trends and temporally filter (0.01Hz < f < 0.08 Hz) were performed. To remove any residual effects of motion and other non-neuronal factors, six head motion parameters, white matter signal, cerebrospinal fluid signal were used as nuisance variables in the functional connectivity analysis. Given the disputation of removing the global signal in the pre-processing of rsfMRI data, we omit regress the global signal out. Finally, given that two groups may different for occurrence of micromotions’ artifact, the framewise displacement (FD) value was computed for each subject.

For VMHC computation, first, a mean T1 image was generated from the average of 35 spatially normalized T1 images. Next, the symmetric brain template was obtained by flipping the left or right hemispheres along the midline of the x-axis and averaged with the original image to create the final template. Then, the T1 image from each individual subject was co-registered nonlinearly to this group-specific symmetric template. The same transformation was then applied to the rsfMRI images. More details regarding VMHC data processing are available in the literature [35 , 38]. Homotopic RSFC between any pair of symmetrical inter-hemispheric voxels was calculated with Pearson’s correlation and then transformed by the Fisher’s z test. The resultant values were defined as the VMHC and were used for subsequent group-level analyses.

Statistical analyses

Statistical analyses were performed using SPSS version 19.0 software. Group differences were assessed using Student’s t-test and chi-square tests. In detail, two sample t-tests were used for sociodemographic continuous variables, including age, education, neuropsychological assessments and mean FD value. The chi-square test was used for categorical variables, including gender and family history. The group comparisons of the VMHC were conducted using a two-sample t-test (p < 0.05, corrected with a single voxel height of p < 0.01 and a cluster size >87 using the AFNI AlphaSim program (http://afni.nimh.nih.gov/pub/dist/doc/manual/AlphaSim.pdf)) within the unilateral gray matter mask mentioned above (excluding the cerebellum due to scanning range).

RESULTS

Demographics, behavioral, and micromotions data

There were no significant differences regarding age, gender, or education between the groups (p > 0.05). Moreover, the gender ratio and family history of dementia among first-degree relatives were equally distributed between the carriers and non-carriers (χ² = 3.98; p = 0.07). Other than the APOE ɛ4 carriers having higher semantic verbal fluency (SVF) scores than the non-carriers (p < 0.05), no significant differences in other neuropsychological assessments were observed between the groups. In addition, no significant differences in mean FD value were observed between the groups (p > 0.05). The detailed results are shown in Table 1.

The inter-hemispheric RSFC differences between APOE ɛ4 carriers and non-carriers

APOE ɛ4 allele carriers showed reduced inter-hemispheric RSFC relative to non-carriers in two separate clusters located in the MTL (including the hippocampal, parahippocampal, and olfaction regions) and the OFC (medial and inferior frontal cortex) (p < 0.05, AlphaSim corrected). The detailed results are shown in Table 2 and Figs. 1 and 2.

Correlation between inter-hemispheric RSFC and behavioral data

Regions showing significantly changed VMHC were defined as region of interests (ROIs), and the inter-hemispheric RSFC was extracted and averaged within the ROI. A partial correlation analysis between the inter-hemispheric RSFC of the ROIs and behavioral data were performed after controlling for education and family history. The covariance was controlled in the correlation analysis because: 1) first-degree family history of AD may represent a complicated risk factor, mirror the influence of known and unknown susceptibility genes and other non-genetic risks, and interact with the APOE ɛ4 allele [18]; and 2) there was a trend that the education of non-carriers was higher than APOE ɛ4 carriers (p = 0.098), which might influence the results.

Inter-hemispheric RSFC of the MTL was significantly correlated with the WMS-LM immediate and delay performance only with APOE ɛ4 carriers (r = 0.64, p < 0.05; r = 0.65, p < 0.05, respectively; after corrected by education and first-degree family history); meanwhile, the inter-hemispheric RSFC of the OFC was strongly correlated with WMS-LM delayed performance (r = 0.71, p < 0.05; after corrected by education and first-degree family history). The scatter diagram and related group interaction map was displayed in Fig. 3.

DISCUSSION

The specific findings of this study are as follows: 1) a significantly decreased inter-hemispheric RSFC in APOE ɛ4 carriers was observed in the MTL and OFC compared with well-matched ɛ3 homozygotes; and 2) only APOE ɛ4 carriers demonstrated a positive correlation between memory and the inter-hemispheric RSFC in those regions. Considered together, carrying the APOE ɛ4 allele decreases bi-hemispheric RSFC, which might reflect a dysfunction of cooperation and integration between hemispheres; in addition, this disrupted cooperative function is related to the memory decline in cognitively intact elderly APOE ɛ4carriers.

The MTL, including the entorhinal cortex, HP, and parahippocampal cortex, is a component of the DMN and plays a key role in declarative memory processing [39 –41]. In the current study, we observed a widespread decrease in the inter-hemispheric RSFC in APOE ɛ4 carriers, and the largest effect was seen in the MTL region. Although this region is sensitive to artifacts, the current result was partially supported by white matter microstructural data reporting that the APOE ɛ4 allele was associated with decreased FA in the splenium of the CC, which is the principal underlying structural white matter pathway of the bilateral MTL region [14, 34]. Moreover, Gold et al. [42] reported that APOE ɛ4 carriers had reduced integrity of tracts with direct and secondary connections to the MTL, and these findings also support our results. More recently, one study constructed the functional network on the basis of resting-state functional MRI and the structural network on the basis of DTI in cognitively intact elderly; and it suggested that right parahippocampal gyrus was only region with simultaneous functional and structural damage in APOE ɛ4 carriers [24]. The supportive evidence still came from previous resting-state related researches. Using a seed-based analysis, one study revealed decreased in-phase connectivity in regions of the posterior default mode network that included the middle temporal gyrus in the APOE ɛ4 carriers [22]. In cognitively normal elderly without preclinical fibrillar amyloid deposition, Sheline et al. suggested that APOE ɛ4 carriers had decreased RSFC between precuneus seed region and MTL region, including the left HP, left parahippocampus and middle temporal cortex [23]. Despite differences in methodology, these relevant structural and functional studies partially supported our observation.

Only in the APOE ɛ4 carriers was the RSFC within the bilateral MTL significantly and positively correlated with both the WMS-LM immediate and delayed performances (Fig. 3), which mainly reflect episodic memory performance. This result may reflect the information integration processes within the bilateral MTL that contributes to memory. This observation is largely congruent with one study that focused on inter-hemispheric RSFC in HP, which showed that the RSFC in the HP could predict the performance of episodic memory [43]. Similarly, Westlye et al. found a significant negative correlation between memory performance and the RSFC of the right HP [21]. Apart from these studies, the supportive evidence for our assumption also came from studies of split-brain patients. These subjects have severely impaired cooperation processes between hemispheres that are accompanied by serious memory deficits [44 –47]. Collectively, memory is the earliest cognitive domain affected by AD, and greater impairments occur in APOE ɛ4 carriers relative to non-carriers [48, 49]. A decreased inter-hemispheric RSFC of the MTL in APOE ɛ4 carriers may reflect the earliest imaging-derived endophenotypes underlying memory decline.

Widespread amyloid deposition has been observed in the OFC at early AD stages and indicates that the OFC is a highly sensitive region to AD-related pathology [50]. Previous studies on APOE ɛ4 carriers have shown that the presence of the APOE ɛ4 allele was associated with gray matter atrophy in the OFC and accelerated age-related deficits of white matter integrity in the medial OFC [12, 51]. Here, significantly decreased inter-hemispheric RSFC within the bilateral OFC was found in APOE ɛ4 carriers. The work of Filippini et al. [52] supports our results by showing that the APOE ɛ4 allele was associated with volume loss in the prefrontal CC, which constitutes a primary fiber pathway with the bilateral OFC. In addition, our results extend the work of Wang et al. [53], who reported a trend of gradually decreased inter-hemispheric RSFC (AD <MCI <control) in the bilateral OFC. Our results further indicated a deterioration of the inter-hemispheric connection in this region in APOE ɛ4 carriers relative to non-carriers. In a subsequent analysis, decreased inter-hemispheric RSFC of the OFC was positively correlated with WMS-LM delay performance, which mainly represents long-term memory performance (Fig. 3). While the OFC is not typically a primary target site for memory-related research, the OFC anatomically possesses robust structural connections with the limbic areas of the MTL, and it receives projections from the subiculum/CA1 region of the HP [54]. One study suggested that successful memory depends on prefrontal-temporal network activity, which includes both the MTL and OFC regions [55]. Moreover, in fMRI studies involving memory encoding, OFC activation has frequently been reported [56, 57]. Overall, the main function of inter-hemispheric cooperation between the OFC and memory may be regulating the motivational and emotional aspects of novel stimuli [57], which is very important for long-term memory. Further research is needed to explore the relationship between the cooperative processes of the bilateral OFC and memory performance.

It was difficult to ascribe the exact mechanism underlying the APOE ɛ4 allele directly to the differences in inter-hemispheric RSFC, and it may be attributed to two interpretations. However, without histological data, such interpretations should be made with caution. First, these deficits might be a consequence of the early events of APOE ɛ4 allele-mediated reductions in the clearance process of amyloid plaques. In the MTL and OFC, which are susceptible to amyloid plaques [50], accumulated amyloid plaques disrupt local gray matter structure, further impair the neuropil and decrease RSFC with contralateral regions. Moreover, the mechanism of the APOE ɛ4 allele impacts inter-hemispheric RSFC and can also be considered from the perspective of myelin metabolism. The ApoE is the most abundant cholesterol transporter in the brain, and cholesterol is an essential component of myelin sheaths [13, 58]. The number of ApoE molecules in APOE ɛ4 carriers available for myelination is 12% lower than non-carriers [7, 11], and the APOE ɛ4 allele is specifically associated with axonal degeneration [59]. Thus, the decrements or failure of the myelination process of APOE ɛ4 carriers may contribute to white matter pathway abnormalities and disrupt the bi-hemispheric RSFC due to the infidelity of neurotransmission.

Consistent with most APOE-related studies, we found no differences in behavioral data between APOE ɛ4 carriers and non-carriers, except for the SVF score [60]. This finding may indicate that neuropsychological batteries may be too insensitive to reliably capture the most APOE ɛ4-specific gene-expression profiles (compared to assessing inter-hemispheric RSFC). Meanwhile, these results may reflect the performance of older adults who recruit additional regions to compensate for changes that occur with aging. One notable observation in our study was that APOE ɛ4 carriers had significantly higher SVF scores than non-carriers. This observation is largely consistent with the work of Alexander [60]. In the current data, the relatively higher education level and younger age of APOE ɛ4 carriers may account for this finding. Furthermore, the antagonistic pleiotropy of the APOE ɛ4 allele, and specifically that the carriers may experience positive effects during their youth, despite being associated with a terminal illness in the elderly population, may also support this observation [60, 61]. However, this correlation analysis revealed no significant relationships between inter-hemispheric RSFC and the SVF results. Further studies are needed to verify this observation.

Limitations

Based on the current study was a preliminary study, several obvious limitations should be considered. First, this cross-sectional study is lacking of clinical follow-up to make any possible inference between current findings and AD; thus, longitudinal studies are needed to determine whether decreased inter-hemispheric RSFC within MTL and OFC region are associated with a higher risk of developing later AD-related pathological changes. Second, the sample we used was small with a relatively narrow age range and weak statistical power. Future studies with larger sample sizes and broader age ranges are required. Finally, the brain is not a symmetrical shape; however, we used a standard symmetrical template and smoothed functional imaging data to measure the functional correlations between mirrored regions.

CONCLUSION

To summarize, we initially documented the presence of the APOE ɛ4 allele in cognitively intact, elderly subjects who had decreased inter-hemispheric functional connectivity in the MTL and OFC regions, which might reflect impaired cooperation and integration function between hemispheres. Further correlation analysis suggested that in APOE ɛ4 carriers, the subtly damaged cooperation processes between the bilateral MTL and OFC might contribute to memory performance. Moreover, the current study might support the practicality of inter-hemispheric functional connectivity as an endophenotype in imaging geneticsstudies.

ACKNOWLEDGMENTS

This work is supported by the 12th Five-year Plan for National Science and Technology Supporting Program of China (Grant No. 2012BAI10B04) and the National Natural Science Foundation of China (Grant Nos. 81371519 and 81301190).

Authors’ disclosures available online (http://www.j-alz.com/manuscript-disclosures/15-0989).

Data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Abb Vie, Alzheimer’s

Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliatedcompany Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso ScaleDiagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis PharmaceuticalsCorporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; andTransition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (http://www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.

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