Plasma GFAP, NfL and pTau 181 detect preclinical stages of dementia

Ingannato, Assunta; Bagnoli, Silvia; Mazzeo, Salvatore; Giacomucci, Giulia; Bessi, Valentina; Ferrari, Camilla; Sorbi, Sandro; Nacmias, Benedetta

doi:10.3389/fendo.2024.1375302

Cited by 3 publications

References 54 publications

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The association between rs6859 inNECTIN2gene and Alzheimer’s disease is partly mediated by pTau

Lathika Rajendrakumar,

Arbeev,

Bagley

et al. 2024

Preprint

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IntroductionEmerging evidence suggests a connection between vulnerability to infections and Alzheimer’s disease (AD). The nectin cell adhesion molecule 2(NECTIN2)gene coding for a membrane component of adherens junctions is involved in response to infection, and its single nucleotide polymorphism (SNP) rs6859 was significantly associated with AD risk in several human cohorts. It is unclear, however, how exactly rs6859 influences the development of AD pathology. The aggregation of hyperphosphorylated tau protein (pTau) is a key pathological feature of neurodegeneration in AD, which may be induced by infections, among other factors, and potentially influenced by genes involved in both AD and vulnerability to infections, such asNECTIN2.Materials and methodsWe conducted a causal mediation analysis (CMA) on a sample of 708 participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). The relationship between rs6859 and Alzheimer’s disease (AD), with AD (yes/no) as the outcome and pTau-181 levels in the cerebrospinal fluid (CSF) acting as a mediator in this association, was assessed. Adjusted estimates from the probit and linear regression models were used in the CMA model, where an additive model considered an increase in dosage of the rs6859 A allele (AD risk factor).ResultsThe increase in dose of allele A of the SNP rs6859 resulted in about 0.144 increase per standard deviation (SD) of pTau-181 (95% CI: 0.041, 0.248, p<0.01). When included together in the probit model, the change in A allele dose and each standard deviation change in pTau-181 predicted 6.84% and 9.79% higher probabilities for AD, respectively. In the CMA, the proportion of the average mediated effect was 17.05% and was higher for the risk allele homozygotes (AA), at 19.40% (95% CI: 6.20%, 43.00%, p<0.01). The sensitivity analysis confirmed the evidence of a robust mediation effect.ConclusionThis study reported a new causal relationship between pTau-181 and AD. We found that the association between rs6859 in theNECTIN2gene and AD is partly mediated by pTau-181 levels in CSF. The rest of this association may be mediated by other factors. Further research, using other biomarkers, is needed to uncover the remaining mechanisms of the association between theNECTIN2gene and AD.

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The association between rs6859 inNECTIN2gene and Alzheimer’s disease is partly mediated by pTau

Lathika Rajendrakumar,

Arbeev,

Bagley

et al. 2024

Preprint

View full text Add to dashboard Cite

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Deformability of Heterogeneous Red Blood Cells in Aging and Related Pathologies

Prudinnik,

Kussanova,

Vorobjev

et al. 2024

Aging and disease

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Aging is interrelated with changes in red blood cell parameters and functionality. In this article, we focus on red blood cells (RBCs) and provide a review of the known changes associated with the characterization of RBC deformability in aging and related pathologies. The biophysical parameters complement the commonly used biochemical parameters and may contribute to a better understanding of the aging process. The power of the deformability measurement approach is well established in clinical settings. Measuring RBCs' deformability has the advantage of relative simplicity, and it reflects the complex effects developing in erythrocytes during aging. However, aging and related pathological conditions also promote heterogeneity of RBC features and have a certain impact on the variance in erythrocyte cell properties. The possible applications of deformability as an early biophysical biomarker of pathological states are discussed, and modulating PIEZO1 as a therapeutic target is suggested. The changes in RBCs' shape can serve as a proxy for deformability evaluation, leveraging single-cell analysis with imaging flow cytometry and artificial intelligence algorithms. The characterization of biophysical parameters of RBCs is in progress in humans and will provide a better understanding of the complex dynamics of aging.

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The association between rs6859 in NECTIN2 gene and Alzheimer’s disease is partly mediated by pTau

Rajendrakumar,

Arbeev,

Bagley

et al. 2024

Front. Aging Neurosci.

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IntroductionEmerging evidence suggests a connection between vulnerability to infections and Alzheimer’s disease (AD). The nectin cell adhesion molecule 2 (NECTIN2) gene coding for a membrane component of adherens junctions is involved in response to infections, and its single nucleotide polymorphism (SNP) rs6859 was significantly associated with AD risk in several human cohorts. It is unclear, however, how exactly rs6859 influences the development of AD pathology. The aggregation of hyperphosphorylated tau protein (pTau) is a key pathological feature of neurodegeneration in AD, which may be induced by infections, among other factors, and potentially influenced by genes involved in both AD and vulnerability to infections, such as NECTIN2.Materials and methodsWe conducted a causal mediation analysis (CMA) on a sample of 708 participants in the Alzheimer’s disease Neuroimaging Initiative (ADNI). The relationship between rs6859 and Alzheimer’s disease (AD), with AD (yes/no) as the outcome and pTau-181 levels in the cerebrospinal fluid (CSF) acting as a mediator in this association, was assessed. Adjusted estimates from the probit and linear regression models were used in the CMA model, where an additive model considered an increase in dosage of the rs6859 A allele (AD risk factor).ResultsThe increase in dose of allele A of the SNP rs6859 resulted in about 0.144 increase per standard deviation (SD) of pTau-181 (95% CI: 0.041, 0.248, p < 0.01). When included together in the probit model, the change in A allele dose and each standard deviation change in pTau-181 predicted 6.84% and 9.79% higher probabilities for AD, respectively. In the CMA, the proportion of the average mediated effect was 17.05% and was higher for the risk allele homozygotes (AA), at 19.40% (95% CI: 6.20%, 43.00%, p < 0.01). The sensitivity analysis confirmed the evidence of a robust mediation effect.ConclusionThis study reported a new potential causal relationship between pTau-181 and AD. We found that the association between rs6859 in the NECTIN2 gene and AD is partly mediated by pTau-181 levels in CSF. The rest of this association may be mediated by other factors. Our finding sheds light on the complex interplay between genetic susceptibility, protein aggregation, and neurodegeneration in AD. Further research, using other biomarkers, is needed to uncover the remaining mechanisms of the association between the NECTIN2 gene and AD.

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Plasma GFAP, NfL and pTau 181 detect preclinical stages of dementia

Cited by 3 publications

References 54 publications

The association between rs6859 inNECTIN2gene and Alzheimer’s disease is partly mediated by pTau

The association between rs6859 inNECTIN2gene and Alzheimer’s disease is partly mediated by pTau

Deformability of Heterogeneous Red Blood Cells in Aging and Related Pathologies

The association between rs6859 in NECTIN2 gene and Alzheimer’s disease is partly mediated by pTau

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