Directed Network Motifs in Alzheimer’s Disease and Mild Cognitive Impairment

Directed network motifs are the building blocks of complex networks, such as human brain networks, and capture deep connectivity information that is not contained in standard network measures. In this paper we present the first application of directed network motifs in vivo to human brain networks, utilizing recently developed directed progression networks which are built upon rates of cortical thickness changes between brain regions. This is in contrast to previous studies which have relied on simulations and in vitro analysis of non-human brains. We show that frequencies of specific directed network motifs can be used to distinguish between patients with Alzheimer’s disease (AD) and normal control (NC) subjects. Especially interesting from a clinical standpoint, these motif frequencies can also distinguish between subjects with mild cognitive impairment who remained stable over three years (MCI) and those who converted to AD (CONV). Furthermore, we find that the entropy of the distribution of directed network motifs increased from MCI to CONV to AD, implying that the distribution of pathology is more structured in MCI but becomes less so as it progresses to CONV and further to AD. Thus, directed network motifs frequencies and distributional properties provide new insights into the progression of Alzheimer’s disease as well as new imaging markers for distinguishing between normal controls, stable mild cognitive impairment, MCI converters and Alzheimer’s disease.     

Metalloproteinase’s Activity and Oxidative Stress in Mild Cognitive Impairment and Alzheimer’s Disease

Matrix metalloproteinases (MMPs) and oxidative stress have been implicated in neurological diseases such as Alzheimer’s disease (AD). Plasma MMP-2 and MMP-9 activities were assessed in Mild Cognitive Impairment (MCI) and AD subjects compared with aged-matched controls, and subsequently analysed in relation to oxidative stress markers. Both MMP-2 and MMP-9 showed no significant changes versus control subjects. Plasma glutathione peroxidase Se-dependent (GPx-Se) activity and malondialdehyde (MDA) levels were higher in AD than in controls (P < 0.05), suggesting a role for GPx-Se in controlling oxidative stress in AD. Negative correlations were observed between MMPs and MDA in AD and MCI patients (P < 0.05). In conclusion, oxidative stress events did not include activation of MMPs and this similar pattern in AD and MCI suggests that both are biochemically equivalent.     

A fuzzy-based system reveals Alzheimer’s Disease onset in subjects with Mild Cognitive Impairment

Alzheimer’s Disease (AD) is the most frequent neurodegenerative form of dementia. Although dementia cannot be cured, it is very important to detect preclinical AD as early as possible. Several studies demonstrated the effectiveness of the joint use of structural Magnetic Resonance Imaging (MRI) and cognitive measures to detect and track the progression of the disease. Since hippocampal atrophy is a well known biomarker for AD progression state, we propose here a novel methodology, exploiting it as a searchlight to detect the best discriminating features for the classification of subjects with Mild Cognitive Impairment (MCI) converting (MCI-c) or not converting (MCI-nc) to AD. In particular, we define a significant subdivision of the hippocampal volume in fuzzy classes, and we train for each class Support Vector Machine SVM classifiers on cognitive and morphometric measurements of normal controls (NC) and AD patients. From the ADNI database, we used MRI scans and cognitive measurements at baseline of 372 subjects, including 98 subjects with AD, and 117 NC as a training set, 86 with MCI-c and 71 with MCI-nc as an independent test set. The accuracy of early diagnosis was evaluated by means of a longitudinal analysis. The proposed methodology was able to accurately predict the disease onset also after one year (median AUC = 88.2%, interquartile range 87.2%–89.0%). Besides its robustness, the proposed fuzzy methodology naturally incorporates the uncertainty degree intrinsically affecting neuroimaging features. Thus, it might be applicable in several other pathological conditions affecting morphometric changes of the brain.     

Demyelination in Mild Cognitive Impairment Suggests Progression Path to Alzheimer’s Disease

The preclinical Alzheimer''s disease (AD) - amnestic mild cognitive impairment (MCI) - is manifested by phenotypes classified into exclusively memory (single-domain) MCI (sMCI) and multiple-domain MCI (mMCI). We suggest that typical MCI-to-AD progression occurs through the sMCI-to-mMCI sequence as a result of the extension of initial pathological processes. To support this hypothesis, we assess myelin content with a Magnetization Transfer Ratio (MTR) in 21 sMCI and 21 mMCI patients and in 42 age-, sex-, and education-matched controls. A conjunction analysis revealed MTR reduction shared by sMCI and mMCI groups in the medial temporal lobe and posterior structures including white matter (WM: splenium, posterior corona radiata) and gray matter (GM: hippocampus; parahippocampal and lingual gyri). A disjunction analysis showed the spread of demyelination to prefrontal WM and insula GM in executive mMCI. Our findings suggest that demyelination starts in the structures affected by neurofibrillary pathology; its presence correlates with the clinical picture and indicates the method of MCI-to-AD progression. In vivo staging of preclinical AD can be developed in terms of WM/GM demyelination.     

7-Deoxy-trans-dihydronarciclasine Reduces β-Amyloid and Ameliorates Memory Impairment in a Transgenic Model of Alzheimer’s Disease

The critical pathological feature of Alzheimer’s disease (AD) is the accumulation of β-amyloid (Aβ), the main constituent of amyloid plaques. β-amyloid precursor protein (APP) undergoes amyloidogenic cleavage by β- and γ-secretase generating Aβ at endosomes or non-amyloidogenic processing by α-secretase precluding the production of Aβ at the plasma membrane. Recently, several natural products have been widely researched on the prevention of Aβ accumulation for AD treatment. We previously reported that Lycoris chejuensis K. Tae et S. Ko (CJ), which originated from Jeju Island in Korea, improved the disrupted memory functions and reduced Aβ production in vivo. Here, we further explored the effect of its active component, 7-deoxy-trans-dihydronarciclasine (coded as E144), on Aβ generation and the underlying mechanism. Our results showed that E144 reduced the level of APP, especially its mature form, in HeLa cells overexpressing human APP with the Swedish mutation. Concomitantly, E144 decreased the levels of Aβ, sAPPβ, sAPPα, and C-terminal fragment. In addition, administration of E144 normalized the behavioral deficits in Tg2576 mice, an APP transgenic mouse model of AD. E144 also decreased the Aβ and APP levels in the cerebral cortex of Tg2576 mice. Thus, we propose that E144 could be a potential drug candidate for an anti-amyloid disease-modifying AD therapy.     

Cerebral Metabolic Differences Associated with Cognitive Impairment in Parkinson’s Disease

PurposeTo characterize cerebral glucose metabolism associated with different cognitive states in Parkinson’s disease (PD) using ¹⁸F-fluorodeoxyglucose (FDG) and Positron Emission Tomography (PET).MethodsThree groups of patients were recruited in this study including PD patients with dementia (PDD; n = 10), with mild cognitive impairment (PD-MCI; n = 20), and with no cognitive impairment (PD-NC; n = 30). The groups were matched for age, sex, education, disease duration, motor disability, levodopa equivalent dose and Geriatric Depression Rating Scale (GDS) score. All subjects underwent a FDG-PET study. Maps of regional metabolism in the three groups were compared using statistical parametric mapping (SPM5).ResultsPD-MCI patients exhibited limited areas of hypometabolism in the frontal, temporal and parahippocampal gyrus compared with the PD-NC patients (p < 0.01). PDD patients had bilateral areas of hypometabolism in the frontal and posterior parietal-occipital lobes compared with PD-MCI patients (p < 0.01), and exhibited greater metabolic reductions in comparison with PD-NC patients (p < 0.01).ConclusionsCompared with PD-NC patients, hypometabolism was much higher in the PDD patients than in PD-MCI patients, mainly in the posterior cortical areas. The result might suggest an association between posterior cortical hypometabolism and more severe cognitive impairment. PD-MCI might be important for early targeted therapeutic intervention and disease modification.     

Ginsennoside Rd Attenuates Cognitive Dysfunction in a Rat Model of Alzheimer’s Disease

Alzheimer??s disease is a neurodegenerative disease characterized by the production of ??-amyloid proteins and hyperphosphorylation of tau protein. Inflammation and apoptotic severity were highly correlated with earlier age at onset of Alzheimer??s disease and were also associated with cognitive decline. This study aims to examine whether the traditional Chinese medicine ginsennoside Rd could prevent cognitive deficit and take neuroprotective effects in ??-amyloid peptide 1?C40-induced rat model of Alzheimer??s disease. To produce Alzheimer??s disease animal model, aggregated ??-amyloid peptide 1?C40 injected into hippocampus bilaterally. Ginsennoside Rd protected their cognitive impairment and improved their memory function by daily intraperitoneal injection for 30?days consecutively. In addition, ginsennoside Rd alleviated the inflammation induced by ??-amyloid peptide 1?C40. Furthermore, ginsennoside Rd played a role in the down-regulation of caspase-3 proteins and reduced the apoptosis that normally followed ??-amyloid peptide 1?C40 injection. The results of this study showed that the pretreatment of ginsennoside Rd had neuroprotective effects in ??-amyloid peptide 1?C40-induced AD model rat.     

Atrophic Patterns of the Frontal-Subcortical Circuits in Patients with Mild Cognitive Impairment and Alzheimer’s Disease

Atrophy of the cortical thickness and gray matter volume are regarded as sensitive markers for the early clinical diagnosis of Alzheimer’s disease (AD). This study aimed to investigate differences in atrophy patterns in the frontal-subcortical circuits between MCI and AD, assess whether these differences were essential for the pathologic basis of cognitive impairment. A total of 131 individuals were recruited, including 45 with cognitively normal controls (CN), 46 with MCI, and 40 with AD. FreeSurfer software was used to perform volumetric measurements of the frontal-subcortical circuits from 3.0T magnetic resonance (MR) scans. Data revealed that both MCI and AD subjects had a thinner cortex in the left caudal middle frontal gyrus and the left lateral orbitofrontal gyrus compared with CN individuals. The left lateral orbitofrontal gyrus was also thinner in AD compared with MCI patients. There were no statistically significant differences in the cortical mean curvature among the three groups. Both MCI and AD subjects exhibited smaller bilateral hippocampus volumes compared with CN individuals. The volumes of the bilateral hippocampus and the right putamen were also smaller in AD compared with MCI patients. Logistic regression analyses revealed that the left lateral orbitofrontal gyrus and bilateral hippocampus were risk factors for cognitive impairment. These current results suggest that atrophy was heterogeneous in subregions of the frontal-subcortical circuits in MCI and AD patients. Among these subregions, the reduced thickness of the left lateral orbitofrontal and the smaller volume of the bilateral hippocampus seemed to be markers for predicting cognitive impairment.     

Fibrinogen Induces Microglia-Mediated Spine Elimination and Cognitive Impairment in an Alzheimer’s Disease Model

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Changes in White Matter Integrity before Conversion from Mild Cognitive Impairment to Alzheimer’s Disease

Background

Mild cognitive impairment (MCI) may represent an early stage of dementia conferring a particularly high annual risk of 15–20% of conversion to Alzheimer’s disease (AD). Recent findings suggest that not only gray matter (GM) loss but also a decline in white matter (WM) integrity may be associated with imminent conversion from MCI to AD.

Objective

In this study we used Voxel-based morphometry (VBM) to examine if gray matter loss and/or an increase of the apparent diffusion coefficient (ADC) reflecting mean diffusivity (MD) are an early marker of conversion from MCI to AD in a high risk population.

Method

Retrospective neuropsychological and clinical data were collected for fifty-five subjects (MCI converters n = 13, MCI non-converters n = 14, healthy controls n = 28) at baseline and one follow-up visit. All participants underwent diffusion weighted imaging (DWI) and T1-weighted structural magnetic resonance imaging scans at baseline to analyse changes in GM density and WM integrity using VBM.

Results

At baseline MCI converters showed impaired performance in verbal memory and naming compared to MCI non-converters. Further, MCI converters showed decreased WM integrity in the frontal, parietal, occipital, as well as the temporal lobe prior to conversion to AD. Multiple regression analysis showed a positive correlation of gray matter atrophy with specific neuropsychological test results.

Conclusion

Our results suggest that additionally to morphological changes of GM a reduced integrity of WM indicates an imminent progression from MCI stage to AD. Therefore, we suggest that DWI is useful in the early diagnosis of AD.     

Reduced CSF Water Influx in Alzheimer’s Disease Supporting the β-Amyloid Clearance Hypothesis

Objective

To investigate whether water influx into cerebrospinal fluid (CSF) space is reduced in Alzheimer’s patients as previously shown in the transgenic mouse model for Alzheimer’s disease.

Methods

Ten normal young volunteers (young control, 21-30 years old), ten normal senior volunteers (senior control, 60-78 years old, MMSE ≥ 29), and ten Alzheimer’s disease (AD) patients (study group, 59-84 years old, MMSE: 13-19) participated in this study. All AD patients were diagnosed by neurologists specializing in dementia based on DSM-IV criteria. CSF dynamics were analyzed using positron emission tomography (PET) following an intravenous injection of 1,000 MBq [¹⁵O]H₂O synthesized on-line.

Results

Water influx into CSF space in AD patients, expressed as influx ratio, (0.755 ± 0.089) was significantly reduced compared to young controls (1.357 ± 0.185; p < 0.001) and also compared to normal senior controls (0.981 ± 0.253, p < 0.05). Influx ratio in normal senior controls was significantly reduced compared to young controls (p < 0.01).

Conclusion

Water influx into the CSF is significantly reduced in AD patients. β-amyloid clearance has been shown to be dependent on interstitial flow and CSF production. The current study indicates that reduction in water influx into the CSF may disturb the clearance rate of β-amyloid, and therefore be linked to the pathogenesis of AD.

Trial Registration

UMIN Clinical Trials Registry UMIN000011939     

Whole-brain Functional Networks in Cognitively Normal,Mild Cognitive Impairment,and Alzheimer’s Disease

The conceptual significance of understanding functional brain alterations and cognitive deficits associated with Alzheimer’s disease (AD) process has been widely established. However, the whole-brain functional networks of AD and its prodromal stage, mild cognitive impairment (MCI), are not well clarified yet. In this study, we compared the characteristics of the whole-brain functional networks among cognitively normal (CN), MCI, and AD individuals by applying graph theoretical analyses to [¹⁸F] fluorodeoxyglucose positron emission tomography (FDG-PET) data. Ninety-four CN elderly, 183 with MCI, and 216 with AD underwent clinical evaluation and FDG-PET scan. The overall small-world property as seen in the CN whole-brain network was preserved in MCI and AD. In contrast, individual parameters of the network were altered with the following patterns of changes: local clustering of networks was lower in both MCI and AD compared to CN, while path length was not different among the three groups. Then, MCI had a lower level of local clustering than AD. Subgroup analyses for AD also revealed that very mild AD had lower local clustering and shorter path length compared to mild AD. Regarding the local properties of the whole-brain networks, MCI and AD had significantly decreased normalized betweenness centrality in several hubs regionally associated with the default mode network compared to CN. Our results suggest that the functional integration in whole-brain network progressively declines due to the AD process. On the other hand, functional relatedness between neighboring brain regions may not gradually decrease, but be the most severely altered in MCI stage and gradually re-increase in clinical AD stages.     

Upregulation of BACE1 and β-Amyloid Protein Mediated by Chronic Cerebral Hypoperfusion Contributes to Cognitive Impairment and Pathogenesis of Alzheimer’s Disease

Chronic cerebral hypoperfusion (CCH) increases the risk of Alzheimer disease (AD) through several biologically plausible pathways, but the relationship between CCH and the development of AD remains uncertain. To investigate expression of APP, BACE1 and Aβ in the hippocampus of BCCAO rats and study pathophysiological mechanism of AD from CCH. CCH rat model was established by chronic bilateral common carotid artery occlusion (BCCAO). Behavior was evaluated after BCCAO with Morris water maze and open-field task. Expression of Aβ was measured by enzyme linked immunosorbent assay (ELISA). β-Amyloid precursor protein cleavage enzyme 1 (BACE1) and β-amyloid precursor protein (APP) were tested by ELISA, Western blotting and RT-PCR. Cognitive impairment occurred with CCH by Morris water maze test and open-field task. The BACE1 and Aβ level in BCCAO rats was more increased than sham-operation control rats (P < 0.01) but APP had no difference(P > 0.05). The expression of BACE1 and Aβ has no inter-grouop difference in BCCAO rats (P > 0.05). The level of BACE1 and Aβ had positive correlation with cognitive impairment (P < 0.01) while no correlation was observed between APP and cognitive impairment. Chronic cerebral ischemia contributes to cognitive impairment and vascular pathogenesis of Alzheimer’s disease that chronic cerebral hypoperfusion increases BACE1 and Aβ level in brain.     

Free and Cued Recall Memory in Parkinson’s Disease Associated with Amnestic Mild Cognitive Impairment

The hypothesis has been advanced that memory disorders in individuals with Parkinson’s disease (PD) are related to either retrieval or consolidation failure. However, the characteristics of the memory impairments of PD patients with amnestic mild cognitive impairment have not been clarified. This study was aimed at investigating whether memory deficits in PD patients with amnestic mild cognitive impairment (PDaMCI) are due to failure of retrieval or consolidation processes. Sixteen individuals with PDaMCI, 20 with amnestic mild cognitive impairment without PD (aMCINPD), and 20 healthy controls were recruited. Participants were administered the Free and Cued Selective Reminding Test. An index of cueing was computed for each subject to capture the advantage in retrieval of cued compared to free recall. Individuals with PDaMCI performed worse than healthy controls on the free recall (p<0.01) but not the cued recall (p>0.10) task, and they performed better than aMCINPD subjects on both recall measures (p<0.01). The index of cueing of subjects with PD was comparable to that of healthy controls (p>0.10) but it was significantly higher than that of the aMCINPD sample (p<0.01). Moreover, PD patients’ performance on free recall trials was significantly predicted by scores on a test investigating executive functions (i.e., the Modified Card Sorting Test; p = 0.042). Findings of the study document that, in subjects with amnestic mild cognitive impairment associated to PD, episodic memory impairment is related to retrieval rather than to consolidation failure. The same data suggest that, in these individuals, memory deficits might be due to altered frontal-related executive functioning.     

Posterior Atrophy and Medial Temporal Atrophy Scores Are Associated with Different Symptoms in Patients with Alzheimer’s Disease and Mild Cognitive Impairment

Background

Whether the occurrence of posterior atrophy (PA) and medial temporal lobe atrophy (MTA) was correlated with cognitive and non-cognitive symptoms in Alzheimer’s disease (AD) and mild cognitive impairment (MCI) patients are unclear.

Methods

Patients with probable AD and MCI from a medical center outpatient clinic received attention, memory, language, executive function evaluation and Mini-Mental Status Examination (MMSE). The severity of dementia was rated by the Clinical Dementia Rating (CDR) Sum of Box (CDR-SB). The neuropsychiatric inventory (NPI) subscale of agitation/aggression and mood symptoms was also applied. Magnetic resonance imaging (MRI) was scored visually for the MTA, PA and white matter hyperintensity (WMH) scores.

Results

We recruited 129 AD and 31 MCI (mean age 78.8 years, 48% female) patients. MMSE scores, memory, language and executive function were all significantly decreased in individuals with AD than those with MCI (p < 0.01). MTA and PA scores reflected significant atrophy in AD compared to MCI; however, the WMH scores did not differ. The MTA scores were significantly correlated with the frontal, parieto-occipital and global WMH scores (p < 0.01) while the PA scores showed a correlation with the parieto-occipital and temporal WMH scores (p < 0.01). After adjusting for age, education, APOE4 gene and diagnostic group covariates, the MTA scores showed a significant association with MMSE and CDR-SB, while the right side PA scores were significantly associated with NPI-agitation/aggression subscales (p < 0.01).

Conclusion

Regional atrophy is related to different symptoms in patients with AD or MCI. PA score is useful as a complementary measure for non-cognitive symptom.     

Novel Detox Gel Depot Sequesters β-Amyloid Peptides in a Mouse Model of Alzheimer’s Disease

Alzheimer’s disease (AD), a debilitating neurodegenerative disease is caused by aggregation and accumulation of a 39–43 amino acid peptide (amyloid β or Aβ) in brain parenchyma and cerebrovasculature. The rational approach would be to use drugs that interfere with Aβ–Aβ interaction and disrupt polymerization. Peptide ligands capable of binding to the KLVFF (amino acids 16–20) region in the Aβ molecule have been investigated as possible drug candidates. Retro-inverso (RI) peptide of this pentapeptide, ffvlk, has been shown to bind artificial fibrils made from Aβ with moderate affinity. We hypothesized that a ‘detox gel’, which is synthesized by covalently linking a tetrameric version of RI peptide ffvlk to poly(ethylene glycol) polymer chains will act like a ‘sink’ to capture Aβ peptides from the surrounding environment. We previously demonstrated that this hypothesis works in an in vitro system. The present study extended this hypothesis to an in vivo mouse model of AD and determined the therapeutic effect of our detox gel. We injected detox gel subcutaneously to AD model mice and analyzed brain levels of Aβ-42 and improvement in memory parameters. The results showed a reduction of brain amyloid burden in detox gel treated mice. Memory parameters in the treated mice improved. No undesirable immune response was observed. The data strongly suggest that our detox gel can be used as an effective therapy to deplete brain Aβ levels. Considering recent abandonment of failed antibody based therapies, our detox gel appears to have the advantage of being a non-immune based therapy.     

Diagnosed Mild Cognitive Impairment Due to Alzheimer’s Disease with PET Biomarkers of Beta Amyloid and Neuronal Dysfunction

The aim of this study is to identify mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) using amyloid imaging of beta amyloid (Aβ) deposition and FDG imaging of reflecting neuronal dysfunction as PET biomarkers. Sixty-eight MCI patients underwent cognitive testing, [11C]-PIB PET and [18F]-FDG PET at baseline and follow-up. Regions of interest were defined on co-registered MRI. PIB distribution volume ratio (DVR) was calculated using Logan graphical analysis, and the standardized uptake value ratio (SUVR) on the same regions was used as quantitative analysis for [18F]-FDG. Thirty (44.1%) of all 68 MCI patients converted to AD over 19.2±7.1 months. The annual rate of MCI conversion was 23.4%. A positive Aβ PET biomarker significantly identified MCI due to AD in individual MCI subjects with a sensitivity (SS) of 96.6% and specificity (SP) of 42.1%. The positive predictive value (PPV) was 56.8%. A positive Aβ biomarker in APOE ε4/4 carriers distinguished with a SS of 100%. In individual MCI subjects who had a prominent impairment in episodic memory and aged older than 75 years, an Aβ biomarker identified MCI due to AD with a greater SS of 100%, SP of 66.6% and PPV of 80%, compared to FDG biomarker alone or both PET biomarkers combined. In contrast, when assessed in precuneus, both Aβ and FDG biomarkers had the greatest level of certainty for MCI due to AD with a PPV of 87.8%. The Aβ PET biomarker primarily defines MCI due to AD in individual MCI subjects. Furthermore, combined FDG biomarker in a cortical region of precuneus provides an added diagnostic value in predicting AD over a short period.     

Oridonin Attenuates Synaptic Loss and Cognitive Deficits in an Aβ1–42-Induced Mouse Model of Alzheimer’s Disease

Synaptic loss induced by beta-amyloid (Aβ) plays a critical role in the pathophysiology of Alzheimer’s disease (AD), but the mechanisms underlying this process remain unknown. In this study, we found that oridonin (Ori) rescued synaptic loss induced by Aβ_1–42in vivo and in vitro and attenuated the alterations in dendritic structure and spine density observed in the hippocampus of AD mice. In addition, Ori increased the expression of PSD-95 and synaptophysin and promoted mitochondrial activity in the synaptosomes of AD mice. Ori also activated the BDNF/TrkB/CREB signaling pathway in the hippocampus of AD mice. Furthermore, in the Morris water maze test, Ori reduced latency and searching distance and increased the number of platform crosses in AD mice. These data suggest that Ori might prevent synaptic loss and improve behavioral symptoms in Aβ_1–42-induced AD mice.     

Disrupted Functional Brain Connectivity and Its Association to Structural Connectivity in Amnestic Mild Cognitive Impairment and Alzheimer’s Disease

Although anomalies in the topological architecture of whole-brain connectivity have been found to be associated with Alzheimer’s disease (AD), our understanding about the progression of AD in a functional connectivity (FC) perspective is still rudimentary and few study has explored the function-structure relations in brain networks of AD patients. By using resting-state functional MRI (fMRI), this study firstly investigated organizational alternations in FC networks in 12 AD patients, 15 amnestic mild cognitive impairment (aMCI) patients, and 14 age-matched healthy aging subjects and found that all three groups exhibit economical small-world network properties. Nonetheless, we found a decline of the optimal architecture in the progression of AD, represented by a more localized modular organization with less efficient local information transfer. Our results also show that aMCI forms a boundary between normal aging and AD and represents a functional continuum between healthy aging and the earliest signs of dementia. Moreover, we revealed a dissociated relationship between the overall FC and structural connectivity (SC) in AD patients. In this study, diffusion tensor imaging tractography was used to map the structural network of the same individuals. The decreased FC-SC coupling may be indicative of more stringent and less dynamic brain function in AD patients. Our findings provided insightful implications for understanding the pathophysiological mechanisms of brain dysfunctions in aMCI and AD patients and demonstrated that functional disorders can be characterized by multimodal neuroimaging-based metrics.