ApoE4-mediated blood-brain barrier damage in Alzheimer's disease: Progress and prospects

Zhou, Xinru; Shi, Qiyuan; Zhang, Xinyue; Gu, Leyi; Li, Jinhua; Quan, Shengli; Zhao, Xiaojie; Qin, Li

doi:10.1016/j.brainresbull.2023.110670

Cited by 9 publications

(4 citation statements)

References 71 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

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“…For example, M1M3M4* haplotype containing risk factor apoE-ε4 and M1M3M6 haplotype containing risk factor apoE-ε3 were found to be associated with risk for AD in small human population (210 AD cases and 159 non-demented elderly controls) using our sister haplotypes and RD test. ApoE-ε3 ( Huang et al, 1995 ; DeMattos et al, 2001 ; Hopkins et al, 2002 ; Sen et al, 2012 ; Pedachenko et al, 2015 ; Mahan et al, 2022 ; Sepulveda-Falla et al, 2022 ; Mulgrave et al, 2023 ) and apoE-ε4 ( Ayyubova, 2023 ; Chen et al, 2023 ; Hamza et al, 2023 ; Koutsodendris et al, 2023 ; Pires and Rego, 2023 ; Sun and Xie, 2023 ; Zhou et al, 2023 ) have been verified to be risk factors for AD. Fallin et al (2001) however found that 3 haplotypes in configure 2 flanking M3 and M4 were significantly associated with risk for AD by using individual-others pairs.…”

Section: Discussionmentioning

confidence: 99%

Sister haplotypes and recombination disequilibrium: a new approach to identify associations of haplotypes with complex diseases

Liao,

Tan

2024

Front. Genet.

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Haplotype-based association analysis has several advantages over single-SNP association analysis. However, to date all haplotype-disease associations have not excluded recombination interference among multiple loci and hence some results might be confounded by recombination interference. Association of sister haplotypes with a complex disease, based on recombination disequilibrium (RD) was presented. Sister haplotypes can be determined by translating notation of DNA base haplotypes to notation of genetic genotypes. Sister haplotypes provide haplotype pairs available for haplotype-disease association analysis. After performing RD tests in control and case cohorts, a two-by-two contingency table can be constructed using sister haplotype pair and case-control pair. With this standard two-by-two table, one can perform classical Chi-square test to find statistical haplotype-disease association. Applying this method to a haplotype dataset of Alzheimer disease (AD), association of sister haplotypes containing ApoE3/4 with risk for AD was identified under no RD. Haplotypes within gene IL-13 were not associated with risk for breast cancer in the case of no RD and no association of haplotypes in gene IL-17A with risk for coronary artery disease were detected without RD. The previously reported associations of haplotypes within these genes with risk for these diseases might be due to strong RD and/or inappropriate haplotype pairs.

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“…In addition, cognitively normal ApoE4 carriers show significant age-related deficits in cerebral perfusion as they age, which increases the risk of AD ( Thambisetty et al, 2010 ; Liu et al, 2013 ). Carrying the ApoE4 also heightens the risk of pericyte dysfunction thereby reducing the critical role of pericytes in maintaining the integrity of the blood brain barrier (BBB) thereby allowing Aβ and other inflammatory molecules to penetrate the CNS, inducing neuroinflammation and accelerating AD in part via inhibition of the anti-inflammatory effects of the TREM2-DAP12 complex on microglia ( Armulik et al, 2010 ; Nishitsuji et al, 2011 ; Halliday et al, 2016 ; Fitz et al, 2021 ; Iannucci et al, 2021 ; Zhou et al, 2023 ). Data from ApoE4 carriers shows that the breakdown in the BBB starts in the medial temporal lobe, which is the part of the brain critical for cognitive function ( Montagne et al, 2020 ).…”

Section: Hypotheses and Drug Targetsmentioning

confidence: 99%

“…Risk is also higher in females who carry ApoE4 ( Riedel et al, 2016 ). Approximately 25% of the population express the ApoE4 genotype and it is a major contributor to LOAD ( Crean et al, 2011 ; Di Battista et al, 2016 ; Montagne et al, 2020 ), and lowers the clearance of Aβ ( Ma et al, 2018 ; Zhou et al, 2023 ), increases the transcription of AP-1, promotes tau phosphorylation ( Huang et al, 2017 ; Barthélemy et al, 2020 ), and neuroinflammation ( Fitz et al, 2021 ; Iannucci et al, 2021 ). Targeting ApoE4 offers another approach to the treatment of AD and a gene therapy trial directed at ApoE4 is currently being pursued (see Table 2 ).…”

Section: Hypotheses and Drug Targetsmentioning

confidence: 99%

Alzheimer’s disease and its treatment–yesterday, today, and tomorrow

Kim,

Al Jerdi,

MacDonald

et al. 2024

Front. Pharmacol.

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Alois Alzheimer described the first patient with Alzheimer’s disease (AD) in 1907 and today AD is the most frequently diagnosed of dementias. AD is a multi-factorial neurodegenerative disorder with familial, life style and comorbidity influences impacting a global population of more than 47 million with a projected escalation by 2050 to exceed 130 million. In the USA the AD demographic encompasses approximately six million individuals, expected to increase to surpass 13 million by 2050, and the antecedent phase of AD, recognized as mild cognitive impairment (MCI), involves nearly 12 million individuals. The economic outlay for the management of AD and AD-related cognitive decline is estimated at approximately 355 billion USD. In addition, the intensifying prevalence of AD cases in countries with modest to intermediate income countries further enhances the urgency for more therapeutically and cost-effective treatments and for improving the quality of life for patients and their families. This narrative review evaluates the pathophysiological basis of AD with an initial focus on the therapeutic efficacy and limitations of the existing drugs that provide symptomatic relief: acetylcholinesterase inhibitors (AChEI) donepezil, galantamine, rivastigmine, and the N-methyl-D-aspartate receptor (NMDA) receptor allosteric modulator, memantine. The hypothesis that amyloid-β (Aβ) and tau are appropriate targets for drugs and have the potential to halt the progress of AD is critically analyzed with a particular focus on clinical trial data with anti-Aβ monoclonal antibodies (MABs), namely, aducanumab, lecanemab and donanemab. This review challenges the dogma that targeting Aβ will benefit the majority of subjects with AD that the anti-Aβ MABs are unlikely to be the “magic bullet”. A comparison of the benefits and disadvantages of the different classes of drugs forms the basis for determining new directions for research and alternative drug targets that are undergoing pre-clinical and clinical assessments. In addition, we discuss and stress the importance of the treatment of the co-morbidities, including hypertension, diabetes, obesity and depression that are known to increase the risk of developing AD.

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ApoE4-mediated blood-brain barrier damage in Alzheimer's disease: Progress and prospects

Cited by 9 publications

References 71 publications

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

Sister haplotypes and recombination disequilibrium: a new approach to identify associations of haplotypes with complex diseases

Alzheimer’s disease and its treatment–yesterday, today, and tomorrow

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