Hao Shu

Opposite Neural Trajectories of Apolipoprotein E ϵ4 and ϵ2 Alleles with Aging Associated with Different Risks of Alzheimer's Disease

The apolipoprotein E (APOE) ϵ4 allele is a confirmed genetic risk factor and the APOE ϵ2 allele is a protective factor related to late-onset Alzheimers disease (AD). Intriguingly, recent studies demonstrated similar brain function alterations between APOE ϵ2 and ϵ4 alleles, despite their opposite susceptibilities to AD. To address this apparent discrepancy, we recruited 129 cognitively normal elderly subjects, including 36 ϵ2 carriers, 44 ϵ3 homozygotes, and 49 ϵ4 carriers. All subjects underwent resting-state functional MRI scans. We hypothesized that aging could influence the APOE ϵ2 and ϵ4 allele effects that contribute to their appropriate AD risks differently. Using the stepwise regression analysis, we demonstrated that although both ϵ2 and ϵ4 carriers showed decreased functional connectivity (FC) compared with ϵ3 homozygotes, they have opposite aging trajectories in the default mode network-primarily in the bilateral anterior cingulate cortex. As age increased, ϵ2 carriers showed elevated FC, whereas ϵ4 carriers exhibited decreased FC. Behaviorally, the altered DMN FC positively correlated with information processing speed in both ϵ2 and ϵ4 carriers. It is suggested that the opposite aging trajectories between APOE ϵ2 and ϵ4 alleles in the DMN may reflect the antagonistic pleiotropic properties and associate with their different AD risks.

Imbalanced hippocampal functional networks associated with remitted geriatric depression and apolipoprotein E ε4 allele in nondemented elderly: A preliminary study

BACKGROUND Apolipoprotein E (APOE) ε4 allele and a history of geriatric depression are confirmed risk factors of Alzheimer׳s disease (AD). Coexistence of both factors could notably enhance the risk of cognitive impairment in nondemented elderly. However, neural basis of the association remains unclear. METHODS Thirty-one remitted geriatric depression (RGD) patients and 29 cognitively normal subjects were recruited and underwent resting-state functional MRI scans. They were further divided into four groups according to their APOE genotypes. Hippocampal seed-based network analysis and two-way factorial analysis of covariance were employed to detect the main effects and interactive effects of RGD and APOE ε4 allele on the hippocampal functional connectivity (HFC) networks. Partial correlation analysis was applied to examine the cognitive significance of these altered HFC networks. RESULTS The HFC networks of RGD patients were decreased in the dorsal frontal and increased in the right temporal-occipital regions. For APOE ε4 carriers, the HFC networks were reduced primarily in medial prefrontal regions and enhanced in the bilateral insula. Additionally, when both factors coexisted, the left HFC network was significantly disrupted in the dorsal anterior cingulate cortex and increased in somatomotor and occipital regions. Importantly, the extent of network alterations was linked to inferior cognitive performances in RGD patients and APOE ε4 carriers. LIMITATIONS The small sample size may limit the generalizability of our findings. CONCLUSIONS RGD and APOE ε4 allele, and their interaction, are associated with the imbalanced HFC network, which may contribute to cognitive deterioration for subjects with a high risk of AD.

The Interaction of APOE Genotype by Age in Amnestic Mild Cognitive Impairment: A Voxel-Based Morphometric Study

The apolipoprotein E (APOE) gene has been confirmed as the major genetic risk factor for the conversion of amnestic mild cognitive impairment (aMCI) to Alzheimers disease (AD). The present study was to assess whether there was a specific interaction of APOE by the aging process on brain morphology in aMCI. The analysis of gray matter (GM) voxel-based morphometry was performed in 85 aMCI and 100 healthy controls (HC). A significant interaction of APOE genotype by age on GM volume was found in the left calcarine, the left insula, and the left medial frontal gyrus in aMCI. GM volume in aMCI decreased significantly with ε 2-carriers < ε3/ε3 < ε4-carriers in above brain regions (except the left insula) while there was only a reduced tendency in HC. The multivariate regression analysis showed the well-known negative relationship for ε4-carriers and the positive relationship for ε2-carriers (except the left insula), while no correlations were found for ε3/ε3 between age and GM volumes on above brain regions. Moreover, the reduced GM volumes in the left calcarine and insula correlated with the impairment of visuo-spatial cognition and episodic memory in ε4- and ε2-carriers but not ε3/ε3, respectively. These results suggest that the APOE ε4 and ε2 alleles have the opposing effects on brain morphology across the spectrum of cognitive aging. Moreover, the interaction of APOE by age on brain morphology may accelerate the pathological progression of late-life cognitive decline in aMCI with ε4-carriers and delay the possible conversion from aMCI with ε2-carriers to AD.

Association study of candidate gene polymorphisms with amnestic mild cognitive impairment in a Chinese population.

To investigate the relationship between amnestic mild cognitive impairment (aMCI) and candidate gene polymorphisms in a Chinese population, 116 aMCI patients and 93 normal controls were recruited. Multi-dimensional neuropsychological tests were used to extensively assess the cognitive functions of the subjects. MassARRAY and iPLEX systems were used to measure candidate single nucleotide polymorohisms (SNPs) and analyse allelic, genotypic or haplotypic distributions. The scores of the neuropsychological tests were significantly lower for the aMCI patients than for the normal controls. The distributions of SNPs relating to the amyloid cascade hypothesis (TOMM40 rs157581 G and TOMM40 rs2075650 G), to the cholesterol metabolism hypothesis (ApoE rs429358 C, LDLR rs11668477 G and CH25H rs7091822 T and PLAU rs2227564 CT) and to the tau hypothesis (MAPT/STH rs242562 GG) in aMCI were significantly different than those in normal controls. Interactions were also found in aMCI amongst SNPs in LDLR rs11668477, PLAU rs2227564, and TOMM40 rs157581, between SNPs in TOMM40 rs157580 and BACE2 rs9975138. The study suggests that aMCI is characterised by memory impairment and associated with SNPs in three systems relating to the pathogenesis of AD-those of the amyloid cascade, tau and cholesterol metabolism pathways. Interactions were also observed between genes in the amyloid pathway and between the amyloid and cholesterol pathways.

Altered functional connectivity networks of hippocampal subregions in remitted late-onset depression: a longitudinal resting-state study

The regional specificity of hippocampal abnormalities in late-life depression (LLD) has been demonstrated in previous studies. In this study, we sought to examine the functional connectivity (FC) patterns of hippocampal subregions in remitted late-onset depression (rLOD), a special subtype of LLD. Fourteen rLOD patients and 18 healthy controls underwent clinical and cognitive evaluations as well as resting-state functional magnetic resonance imaging scans at baseline and at ∼21 months of follow-up. Each hippocampus was divided into three parts, the cornu ammonis (CA), the dentate gyrus, and the subicular complex, and then six seed-based hippocampal subregional networks were established. Longitudinal changes of the six networks over time were directly compared between the rLOD and control groups. From baseline to follow-up, the rLOD group showed a greater decline in connectivity of the left CA to the bilateral posterior cingulate cortex/precuneus (PCC/PCUN), but showed increased connectivity of the right hippocampal subregional networks with the frontal cortex (bilateral medial prefrontal cortex/anterior cingulate cortex and supplementary motor area). Further correlative analyses revealed that the longitudinal changes in FC between the left CA and PCC/PCUN were positively correlated with longitudinal changes in the Symbol Digit Modalities Test (r = 0.624, P = 0.017) and the Digit Span Test (r = 0.545, P = 0.044) scores in the rLOD group. These results may provide insights into the neurobiological mechanism underlying the cognitive dysfunction in rLOD patients.

Association of the interleukin 1 beta gene and brain spontaneous activity in amnestic mild cognitive impairment

PurposeThe inflammatory response has been associated with the pathogenesis of Alzheimer’s disease (AD). The purpose of this study is to determine whether the rs1143627 polymorphism of the interleukin-1 beta (IL-1β) gene moderates functional magnetic resonance imaging (fMRI)-measured brain regional activity in amnestic mild cognitive impairment (aMCI).MethodsEighty older participants (47 with aMCI and 33 healthy controls) were recruited for this study. All of the participants were genotyped for variant rs1143627 in the IL1B gene and were scanned using resting-state fMRI. Brain activity was assessed by amplitude of low-frequency fluctuation (ALFF).ResultsaMCI patients had abnormal ALFF in many brain regions, including decreases in the inferior frontal gyrus, the superior temporal lobe and the middle temporal lobe, and increases in the occipital cortex (calcarine), parietal cortex (Pcu) and cerebellar cortex. The regions associated with an interaction of group X genotypes of rs1143627 C/T were the parietal cortex (left Pcu), frontal cortex (left superior, middle, and medial gyrus, right anterior cingulum), occipital cortex (left middle lobe, left cuneus) and the bilateral posterior lobes of the cerebellum. Regarding the behavioral significance, there were significant correlations between ALFF in different regions of the brain and with the cognitive scores of each genotype group.ConclusionsThe present study provided evidence that aMCI patients had abnormal ALFF in many brain regions. Specifically, the rs1143627 C/T polymorphism of the IL1B gene may modulate regional spontaneous brain activity in aMCI patients.

The apolipoprotein E gene affects the three-year trajectories of compensatory neural processes in the left-lateralized hippocampal network.

Previous cross-sectional studies that investigated the effects of apolipoprotein E (ApoE) ε4 status on hippocampal networks have shown inconsistent results. Aging is a well-known risk factor for Alzheimer’s disease (AD) and could strongly interact with ApoE-related vulnerabilities to affect AD risk. However, no longitudinal data have been published regarding the interaction of the ApoE genotype and aging on hippocampal networks. Fifty-one patients with amnestic-type mild cognitive impairment (aMCI) and 64 matched cognitively normal elderly subjects underwent resting-state fMRI scans and neuropsychological tests at baseline and at a 35-month follow-up. Hippocampal resting-state functional connectivity (FC) data were analyzed utilizing a mixed analysis of covariance with ApoE genotype, time points and disease as fixed factors, controlling for age, sex and years of education. The notable finding was that the FC between the left hippocampus and right frontal regions for ε4 carriers longitudinally increased in the normal subjects, but decreased in aMCI patients, whereas the FC for non-carriers was maintained in normal subjects but increased in aMCI patients. Specifically, the longitudinal increases in hippocampal FC with the right inferior frontal gyrus were positively correlated with the changes in episodic memory test scores in non-carriers with aMCI. The interaction between the ApoE genotype, aging and disease suggested that aging should be considered a key regulator of the impact of the ApoE genotype on the phenotypic variants of AD. These findings also demonstrated that compensatory neural processes were accelerated in genetically high risk individuals, but could be subsequently exhausted with the onset of cognitive impairment.

Convergent and divergent intranetwork and internetwork connectivity patterns in patients with remitted late-life depression and amnestic mild cognitive impairment

INTRODUCTION Both remitted late-life depression (rLLD) and amnesiac mild cognitive impairment (aMCI) alter brain functions in specific regions of the brain. They are also disconnection syndromes that are associated with a high risk of developing Alzheimers disease (AD). OBJECTIVES Resting-state functional connectivity magnetic resonance imaging (rs-fcMRI) was performed to define the shared and distinct aberrant patterns in intranetwork and internetwork connectivity between rLLD and aMCI and to determine how knowledge of these differences might contribute to our essential understanding of the altered sequences involved in functional systems both inside and outside of resting-state networks. METHODS We used rs-fcMRI to investigate in five functionally well-defined brain networks in two large cohorts of subjects at high risk for AD (55 rLLD and 87 aMCI) and 114 healthy controls (HC). RESULTS A reduced degree of functional connectivity was observed in the bilateral inferior temporal cortex and supplemental motor area, and reduced correlations were observed within the sensory-motor network (SMN) and in the default mode network (DMN)-control network (CON) pair in the rLLD group than the HC group. The aMCI group showed only focal functional changes in regions of interest pairs, a trend toward increased correlations within the salience network and SMN, and a trend toward a reduced correlation in the DMN-CON pair. Furthermore, the rLLD group exhibited more severely altered functional connectivity than the aMCI group. Interestingly, these altered connectivities were associated with specific multi-domain cognitive and behavioral functions in both rLLD and aMCI. The degree of functional connectivity in the right primary auditory areas was negatively correlated with Hamilton Depression Scale scores in rLLD. Notably, altered connectivity between the right middle temporal cortex and the posterior cerebellum was negatively correlated with Mattis Dementia Rating Scale scores in both rLLD and aMCI. CONCLUSIONS These results demonstrate that rLLD and aMCI may share convergent and divergent aberrant intranetwork and internetwork connectivity patterns as a potential continuous spectrum of the same disease. They further suggest that dysfunctions in the right specific temporal-cerebellum neural circuit may contribute to the similarities observed in rLLD and aMCI conversion to AD.

Brain insulin resistance deteriorates cognition by altering the topological features of brain networks

Insulin resistance represents one of the mechanisms underlying the link between type 2 diabetes (T2D) and Alzheimers disease (AD), and we explored its in vivo neurobiology related to cognition based on a pathway-based genetic association analyses. Eighty-seven mild cognitive impairment (MCIs) subjects and 135 matched controls (HCs) were employed at baseline, and they underwent functional MRI scans, clinical evaluations and exon sequencings of 20 genes related to brain insulin resistance. A longitudinal study for an average of 35 months was performed to assess their cognitive decline over time. By using cognition as the phenotype, we detected genes that modified cognitive impairments, including AKT2, PIK3CB, IGF1R, PIK3CD, MTOR, IDE, AKT1S1 and AKT1. Based on these loci, the mass univariate modeling was utilized to construct the functional network. The MCIs showed disconnections mainly in the cerebellum-frontal-temporal regions, while compensations may occur in frontal-parietal regions to maintain the overall network efficiency. Moreover, the behavioral significance of the network was highlighted, as topological characteristics of the medial temporal lobe and the prefrontal cortex partially determine longitudinal cognitive decline. Our results suggested that the restoration of insulin activity represents a promising therapeutic target for alleviating cognitive decline associated with T2D and AD.

Cortical Thickness and Microstructural White Matter Changes Detect Amnestic Mild Cognitive Impairment

Both the apolipoprotein E (APOE) ɛ4 allele and amnestic mild cognitive impairment (aMCI) are considered to be risk factors for Alzheimers disease (AD). The primary aim of this study was to determine whether the aMCI-related abnormality in gray matter (GM) cortical thickness and white matter (WM) tracts integrity would be modified by the APOE genotype. A total of 146 older adults, including 64 aMCI patients (28 ɛ4 carriers and 36 non-carriers) and 82 healthy controls (39 ɛ4 carriers and 43 non-carriers), underwent a standardized clinical interview, neuropsychological battery assessment, and multi-modal brain magnetic resonance imaging scans. Compared with control subjects, the patients with aMCI showed significantly reduced cortical thickness bilaterally in the parahippocampal gyrus and disrupted WM integrity in the limbic tracts (e.g., increased mean diffusivity in the right parahippocampal cingulum and bilateral uncinate fasciculus). However, no significant main effects of the APOE genotype and diagnosis-by-genotype interaction on GM thickness and WM integrity were observed. Further, diffusivity measures of the limbic WM tracts were significantly correlated with the parahippocampal atrophy in aMCI. Importantly, the parahippocampal thickness and diffusivity measures of the limbic WM tracts were significantly correlated with the cognitive performance (i.e., episodic memory Z score) in patients with aMCI. These results demonstrate that WM microstructural disruptions in the limbic tracts are present at the early stage of AD in an APOE-independent manner; and this degeneration may occur progressively, in parallel with parahippocampal atrophy, and may specifically contribute to early initial impairment in episodic memory.