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Background: Lipid metabolism changes occur in early Alzheimer's disease (AD) patients. Yet little is known about metabolic gene changes in early AD cortex. Methods: The lipid metabolic genes selected from two datasets (GSE39420 and GSE118553) were analyzed with enrichment analysis. Protein–protein interaction network construction and correlation analyses were used to screen core genes. Literature analysis and molecular docking were applied to explore potential therapeutic drugs. Results: 60 lipid metabolic genes differentially expressed in early AD patients’ cortex were screened. Bioinformatics analyses revealed that up-regulated genes were mainly focused on mitochondrial fatty acid oxidation and mediating the activation of long-chain fatty acids, phosphoproteins, and cholesterol metabolism. Down-regulated genes were mainly focused on lipid transport, carboxylic acid metabolic process, and neuron apoptotic process. Literature reviews and molecular docking results indicated that ACSL1, ACSBG2, ACAA2, FABP3, ALDH5A1, and FFAR4 were core targets for lipid metabolism disorder and had a high binding affinity with compounds including adenosine phosphate, oxidized Photinus luciferin, BMS-488043, and candidate therapeutic drugs especially bisphenol A, benzo(a)pyrene, ethinyl estradiol. Conclusions: AD cortical lipid metabolism disorder was associated with the dysregulation of the PPAR signaling pathway, glycerophospholipid metabolism, adipocytokine signaling pathway, fatty acid biosynthesis, fatty acid degradation, ferroptosis, biosynthesis of unsaturated fatty acids, and fatty acid elongation. Candidate drugs including bisphenol A, benzo(a)pyrene, ethinyl estradiol, and active compounds including adenosine phosphate, oxidized Photinus luciferin, and BMS-488043 have potential therapeutic effects on cortical lipid metabolism disorder of early AD.

Background: Among the protective factors for cognitive decline related to aging and Alzheimer's disease, education level is one of the most prominent. However, the mechanisms underlying the protective effects of education on cognition remain to be elucidated. In this study, we aimed to systematically assess the role of Functional Connectivity (FC) of resting-state brain networks playing in the cognition-protection effect of education. Methods: Data from a battery of neuropsychological tests and functional magnetic resonance imaging in resting-state were acquired in 77 cognitively normal elderly participants from local communities in Beijing, China. Six resting-state networks related to primary function or complex cognition were extracted through independent component analysis. We then explored the relationships between education level, cognition, and FC of these networks. Results: We found that education level was positively associated with a wide range of complex cognitive domains including general mental status, episodic memory, language, attention, executive function and visuospatial processing, and it showed significantly negative correlations with FC of multiple areas in the Default Mode Network (DMN) and Left Frontal-parietal Network (LFP) which are related to complex cognition. And regional connectivity of DMN was significantly negatively correlated with episodic memory performance. Further mediation analysis suggested that higher education level was associated with higher episodic memory performance through lower regional connectivity of DMN. Conclusion: Our findings indicate that inhibitory modulation in the resting-state brain networks related to complex cognition is one of the main routes through which education exerts its protective effects on cognition in normal aging.

Background: As a risk factor for Alzheimer's disease (AD), type 2 diabetes mellitus (T2DM) itself causes cognitive impairment and has higher prevalence of mild cognitive impairment (MCI). Objective: The aim of this study was to explore the cognition especially the episodic memory difference, the DMN functional connectivity and DMN-related white matter integrity in patients with both T2DM and amnestic MCI (T2DM-MCI) as compared to patients with T2DM only. Methods: Focusing especially on T2DM population, we investigated the default mode network (DMN) through resting-state functional magnetic resonance imaging among 22 elderly T2DM-MCI patients and 24 elderly T2DM patients. Including primarily the bilateral cingulum, hippocampus and uncinate fasciculus, these DMN white matter fibers were also closely associated with episodic memory and the integrity of them was also investigated using diffusion tensor imaging in 19 elderly T2DM-MCI patients and 23 elderly T2DM patients. Results: Compared with the patients with T2DM, the T2DM-MCI patients performed worse in several areas of cognition besides episodic memory, and showed stronger DMN functional connectivity in the left precuneus and weaker functional connectivity in the left calcarine, as well as decreased integrity of the left cingulate bundle and bilateral uncinate fasciculus. Furthermore, a correlation analysis indicated that higher left calcarine connectivity was associated with better episodic memory performance among the overall group. Conclusion: Our results demonstrated that T2DM patients with comorbid amnestic MCI had abnormal functional connectivity patterns and decreased white matter integrity, which could potentially serve as AD or AD risk biomarkers for early detection of those elderly individuals with T2DM.

Background: Evidence demonstrates that the T allele of the single-nucleotide polymorphism rs405509 as the apolipoprotein E (APOE) promoter is a risk factor for Alzheimer’s disease (AD). However, it is unclear the APOE-rs405509 interaction effect on brain spontaneous activity. Methods: We analyzed the interaction of the rs405509 TT allele and the APOE 4 allele on cognitive performances measured using neuropsychological tests and brain default mode network (DMN) defined by independent component analysis using based on resting-state functional magnetic resonance imaging data among the non-demented elderly people. Results: Significant interaction was found between rs405509 and APOE on general mental status, memory and attention (p<0.05). Functional network analysis showed a significantly APOE-rs405509 interaction on anterior cingulate gyrus, medial frontal region and precuneus at anterior and posterior DMN (False Discovery Rate p<0.05). Additionally, significant correlations were found between cognitive performance and DMN connectivity (p<0.05). Conclusion: The data indicates that the APOE-rs405509 interaction impairs elderly’s cognitive performance through brain functional network.

Silent lacunar infarct (SLI) is a risk factor for dementia. This study investigated the white matter integrity abnormality and its relationship to the cognition impairments in SLI patients.

Previous studies have demonstrated that Alzheimer’s disease (AD) and amnestic mild cognitive impairment (aMCI) exhibited anatomical and functional abnormalities in the anterior cingulate cortex (ACC) and accumulating evidence supported the hypothesis that changes in the ACC predict the progression from aMCI to AD. In this study, we aimed to explore how the two functional and structural heterogeneous sub-regions of ACC, namely the dorsal ACC (dACC) and the ventral ACC (vACC), changed in aMCI and whether the structural connectivity affects the functional connectivity between the two ACC subregions. To investigate this hypothesis, we studied resting-state fMRI and DTI images in a group of 24 aMCIs and 29 healthy controls. The dACC exhibited a significantly increased functional connectivity in the Salience Network (SN) and a decreased functional connectivity with the vACC in aMCI. The DTI results showed that the bilateral cingulum fibers were the most damaged tracts in aMCI and that the fractional anisotrophy of the left anterior cingulum was significantly correlated with the functional connectivity between the two ACC sub-regions. In conclusion, this study revealed the pathological changes in the intrinsic functional connectivity of the ACC within SN, as well as the connectivity between the dACC and vACC in aMCI. Our study also revealed that disrupted white matter integrity of the anterior regions of the cingulum was associated with the alterations in subregional connectivity in the ACC.

Objective: To investigate effects and functional mechanism of compound Congrongyizhi Capsule (CCRC), a Chinese medicine, on cognitive functions against amnestic mild cognitive impairment (aMCI) patients with functional magnetic resonance imaging (fMRI) based on n-back task. Methods: Forty-one aMCI participants from hospital and local communities in Beijing and randomly divided into treatment (16 patients with CCRC capsule treatment), placebo (12 patients with placebo capsules) and control group (13 patients with no treatment). The duration of intervention lasted for 3 months. Neuropsychological tests and fMRI were applied to assess cognitive ability and brain activation changes after three months treatment. Results: Drug group (n=16) presented increased significance in the MMSE (P=0.008) and digit span (P<0.001) tests, while other scores of neuropsychological tests showed no statistical significance. fMRI results showed an increased brain negative activation in drug group during performing the n-back working-memory task in posterior cingulate (PCC), inferior frontal gyrus and lingual gyrus regions after 3 months; placebo and control group did not show the same effect. Meanwhile, there were negative correlations between left PCC activation levels and changed values of MMSE and digit span separately since increased negative activation was associated with better performance on the scores of MMSE and Digit Span tests. Conclusions: CCRC can increase negative activation degree of PCC under performing working memory tasks while this modulation are associated with better performance on the MMSE and Digit Span.

Patients with amnestic mild cognitive impairment (aMCI) often display deficits in episodic memory. Amnestic MCI is now recognized as a prodromal form of Alzheimers disease. Various aMCI clinical subtypes have been identified as ingle-domain (SD) or multi-domain (MD). The various subtypes represent heterogeneous syndrome indicating the probability of progression to AD, impaired cognitive domains and so on. To examine the characteristics of brain regions of aMCI subtypes is likely to be important for early diagnosis and prediction to AD. This study investigated brain functional activation and hippocampal atrophy during a visually complex scene encoding in 20 individuals with aMCI-SD, 14 individuals with aMCI-MD and 25 healthy controls. During the encoding task, aMCI-MD patients had reduced activation in right superior medial frontal, right inferior and middle temporal, right middle occipital and left inferior frontal regions compared to controls. The different active brain regions between aMCI-MD and aMCI-SD patients are the right middle occipital and left middle cingulum regions. The aMCI-MD group had significantly lower left hippocampus volumes compared to the aMCI-SD group and controls, but there was no difference between aMCI-SD patients and the control group in terms of left hippocampus atrophy. The findings provide evidence that aMCI may represent a heterogeneous group. The aMCI-MD patients displayed more severe hippocampcal atrophy and fMRI activation changes than aMCI-SD. The aMCIMD may represent a more advanced prodromal stage of AD.