ApoE4-Mediated Blood Brain Barrier Damage in Alzheimer's Disease: Progress and Prospects

Zhou, Xinru; Shi, Qiyuan; Zhang, Xinyue; Gu, Leyi; Li, Hongxing; Ju, Yue; Hu, Min; Zhao, Xiaojie; Qin, Li

doi:10.2139/ssrn.4120190

Cited by 2 publications

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“…In the central nervous system, APOE protein plays a crucial role in maintaining and repairing neurons [36]. CSF APOE ε4 has been implicated in inducing AD through bloodbrain barrier damage [37]. Previous research has indicated that low plasma APOE levels may be associated with various aspects of AD pathology, while high plasma APOE levels appear bene cial for neurodegenerative diseases [38,39], which aligns with our ndings.…”

Section: Discussionsupporting

confidence: 86%

Novel Plasma Protein Biomarkers: A Time-Dependent predictive model for Alzheimer's Disease

Zhuang,

Yang,

Ren

et al. 2023

Preprint

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Background The accurate prediction of Alzheimer's disease (AD) is crucial for the efficient management of its progression. The objective of this research is to construct a new risk predictive model utilizing novel plasma protein biomarkers for predicting AD incidence in the future and analyze their potential biological correlation with AD incidence. Methods A cohort of 440 participants aged 60 years and older from the Alzheimer's Disease Neuroimaging Initiative (ADNI) longitudinal cohort was utilized. The baseline plasma proteomics data was employed to conduct Cox regression, LASSO regression, and cross-validation to identify plasma protein signatures predictive of AD risk. Subsequently, a multivariable Cox proportional hazards model based on these signatures was constructed. The performance of the risk prediction model was evaluated using time-dependent receiver operating characteristic (t-ROC) curves and Kaplan-Meier curves. Additionally, we analyzed the correlations between protein signature expression in plasma and predicted AD risk, the time of AD onset, the expression of protein signatures in cerebrospinal fluid (CSF), the expression of CSF biomarkers, and APOE ε4 genotypes. Results We identified seven protein signatures (APOE, CGA, CRP, CCL26, CCL20, NRCAM, and PYY) that independently predicted AD incidence in the future. The risk prediction model demonstrated area under the ROC curve (AUC) values of 0.77, 0.76, and 0.77 for predicting AD incidence at 4, 6, and 8 years, respectively. Furthermore, the model remained stable in the range of the 3rd to the 12th year (ROC ≥ 0.75). The low-risk group, as defined by the model, exhibited a significantly later AD onset compared to the high-risk group (P < 0.0001). Moreover, all protein signatures exhibited significant correlations with AD risk (P < 0.001) and the time of AD onset (P < 0.01). There was no strong correlation between the protein expression levels in plasma and CSF, as well as AD CSF biomarkers. APOE, CGA, and CRP exhibited significantly lower expression levels in APOE ε4 positive individuals (P < 0.05). Conclusion Our research has successfully identified protein signatures in plasma as potential risk biomarkers that can independently predict AD incidence in the future. Notably, this risk prediction model has demonstrated commendable predictive performance and stability over time. These findings underscore the promising utility of plasma protein signatures in dynamically predicting the risk of Alzheimer's disease, thereby facilitating early screening and intervention strategies.

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Section: Discussionsupporting

confidence: 86%

Novel Plasma Protein Biomarkers: A Time-Dependent predictive model for Alzheimer's Disease

Zhuang,

Yang,

Ren

et al. 2023

Preprint

View full text Add to dashboard Cite

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“…ApoE ε4 is one of the most significant genetic risk factors for late-onset AD, associated with cognitive impairment and neuroinflammation ( 49, 50 ). Overexpression of APOE4 decreases blood-brain barrier (BBB) integrity ( 51 ) and myeloid-producing apoE modulates antigen presentation to activate T cells ( 52 ). These observations indicate ApoE ε4 may play a role in T cell homing to the brain and activation during AD pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

ApoE ε4-dependent alteration of CXCR3⁺CD127⁺CD4⁺T cells is associated with elevated plasma neurofilament light chain in Alzheimer’s disease

Hu,

Chen,

et al. 2024

Preprint

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Recent findings indicate a correlation between the peripheral adaptive immune system and neuroinflammation in Alzheimer’s disease (AD). To characterize the composition of adaptive immune cells in the peripheral blood of AD patients, we utilized single-cell mass cytometry (CyTOF) to profile peripheral blood mononuclear cells (PBMCs). Concurrently, we assessed the concentration of proteins associated with AD and neuroinflammation in the plasma of the same subjects. We found that the abundance of proinflammatory CXCR3+CD127+Type 1 T helper (Th1) cells in AD patients was negatively correlated with the abundance of neurofilament light chain (NfL) protein. This correlation is apolipoprotein E (ApoE) ε4-dependent. Analyzing public single-cell RNA-sequencing (scRNA-seq) data, we found that, contrary to the scenario in the peripheral blood, the cell frequency of CXCR3+CD127+Th1 cells in the cerebrospinal fluid (CSF) of AD patients was increased compared to healthy controls (HCs). Moreover, the proinflammatory capacity of CXCR3+CD127+Th1 cells in the CSF of AD patients was further increased compared to HCs. These results reveal an association of a peripheral T-cell change with neuroinflammation in AD and suggest that dysregulation of peripheral adaptive immune responses, particularly involving CXCR3+CD127+Th1 cells, may potentially be mediated by factors such as ApoE ε4 genotype.One sentence summaryAn apolipoprotein E (ApoE) ε4-dependent alteration of CD4 T cell subpopulation in peripheral blood is associated with neuroinflammation in patients with Alzheimer’s disease.

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ApoE4-Mediated Blood Brain Barrier Damage in Alzheimer's Disease: Progress and Prospects

Cited by 2 publications

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Novel Plasma Protein Biomarkers: A Time-Dependent predictive model for Alzheimer's Disease

Novel Plasma Protein Biomarkers: A Time-Dependent predictive model for Alzheimer's Disease

ApoE ε4-dependent alteration of CXCR3⁺CD127⁺CD4⁺T cells is associated with elevated plasma neurofilament light chain in Alzheimer’s disease

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ApoE4-Mediated Blood Brain Barrier Damage in Alzheimer's Disease: Progress and Prospects

Cited by 2 publications

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Novel Plasma Protein Biomarkers: A Time-Dependent predictive model for Alzheimer's Disease

Novel Plasma Protein Biomarkers: A Time-Dependent predictive model for Alzheimer's Disease

ApoE ε4-dependent alteration of CXCR3+CD127+CD4+T cells is associated with elevated plasma neurofilament light chain in Alzheimer’s disease

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ApoE ε4-dependent alteration of CXCR3⁺CD127⁺CD4⁺T cells is associated with elevated plasma neurofilament light chain in Alzheimer’s disease