<i>APOE</i> ε4 carriers may undergo synaptic damage conferring risk of Alzheimer's disease

Sun, Xiaoyan; Dong, Chuanhui; Levin, Bonnie; Crocco, Elizabeth; Loewenstein, David; Zetterberg, Henrik; Blennow, Kaj; Wright, Clinton B.

doi:10.1016/j.jalz.2016.05.003

Cited by 32 publications

(23 citation statements)

References 36 publications

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“…The same trend was observed for the MCI group but there was no statistically significant difference between the groups, which may be due to low number of patients included. This is in agreement with a previous study and shows that the number of copies of the ε4 allele may be associated with synaptic dysfunction which is reflected in the CSF as higher Ng concentrations [47]. One explanation could be that ADD patients with two copies of the ε4 allele have an increased plaque load compared to patients with no ε4 allele [11].…”

Section: Discussionsupporting

confidence: 92%

Cerebrospinal fluid neurogranin concentration in neurodegeneration: relation to clinical phenotypes and neuropathology

et al. 2018

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Neurogranin (Ng) is a post-synaptic protein that previously has been shown to be a biomarker for synaptic function when measured in cerebrospinal fluid (CSF). The CSF concentration of Ng is increased in Alzheimer’s disease dementia (ADD), and even in the pre-dementia stage. In this prospective study, we used an enzyme-linked immunosorbent assay that quantifies Ng in CSF to test the performance of Ng as a marker of synaptic function. In 915 patients, CSF Ng was evaluated across several different neurodegenerative diseases. Of these 915 patients, 116 had a neuropathologically confirmed definitive diagnosis and the relation between CSF Ng and topographical distribution of different pathologies in the brain was evaluated. CSF Ng was specifically increased in ADD compared to eight other neurodegenerative diseases, including Parkinson’s disease (p < 0.0001), frontotemporal dementia (p < 0.0001), and amyotrophic lateral sclerosis (p = 0.0002). Similar results were obtained in neuropathologically confirmed cases. Using a biomarker index to evaluate whether CSF Ng contributed diagnostic information to the core AD CSF biomarkers (amyloid β (Aβ), t-tau, and p-tau), we show that Ng significantly increased the discrimination between AD and several other disorders. Higher CSF Ng levels were positively associated with greater Aβ neuritic plaque (Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) neuritic plaque score, p = 0.0002) and tau tangle pathology (Braak neurofibrillary tangles staging, p = 0.0007) scores. In the hippocampus and amygdala, two brain regions heavily affected in ADD with high expression of Ng, CSF Ng was associated with plaque (p = 0.0006 and p < 0.0001), but not with tangle, α-synuclein, or TAR DNA-binding protein 43 loads. These data support that CSF Ng is increased specifically in ADD, that high CSF Ng concentrations likely reflect synaptic dysfunction and that CSF Ng is associated with β-amyloid plaque pathology.Electronic supplementary materialThe online version of this article (10.1007/s00401-018-1851-x) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 92%

Cerebrospinal fluid neurogranin concentration in neurodegeneration: relation to clinical phenotypes and neuropathology

et al. 2018

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“…Conversely, the ε2 allele is associated with nearly 50% lower risk of AD [4]. The mechanisms underlying the relationship between APOE ε4 and AD are thought to be complex [5], involving β-amyloid (Aβ) peptide clearance [6] as well as a direct role on neuronal death [7,8] and on phosphorylation of tau [9]. Beyond individual genetic susceptibilities, increasing age is the main risk factor of AD [10].…”

Section: Introductionmentioning

confidence: 99%

Age and the association between apolipoprotein E genotype and Alzheimer disease: A cerebrospinal fluid biomarker–based case–control study

et al. 2020

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“…10 Neurogranin (NG), a postsynaptic protein, has been reported to be significantly increased in the CSF of patients with mild cognitive impairment (MCI) and AD. [11][12][13] In addition, CSF NG levels can predict progression of MCI to AD dementia. 14 In animals, knockdown of NG inhibits long-term potentiation (LTP) and cognition, 15 while upregulation enhances LTP and cognition.…”

Section: Introductionmentioning

confidence: 99%

<p>Association of Clusterin Levels in Cerebrospinal Fluid with Synaptic Degeneration Across the Alzheimer’s Disease Continuum</p>

Wang¹,

Zhang²,

Zhu³

et al. 2020

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Although emerging evidence has suggested that clusterin is involved in the pathogenesis of Alzheimer's disease (AD), the association of clusterin with synaptic degeneration in living human is unclear. In the present study, we aimed to examine the association of CSF clusterin levels with synaptic degeneration in individuals with different severities of cognitive impairment. Patients and Methods: In the present study, we compared levels of clusterin in CSF among individuals with normal cognition (NC), mild cognitive impairment (MCI), and AD. Further, linear regression models were performed to examine the association of CSF clusterin with neurogranin (NG, reflecting synaptic degeneration) with adjustment of several potential confounders. Results: We found that CSF clusterin levels were positively correlated with NG in the NC and MCI groups, but not the AD group. In all subjects, linear regression models suggested that clusterin levels were positively associated with NG levels independent of age, gender, apolipoprotein E4 (APOE4) genotype, clinical diagnosis, and CSF Aβ42 levels. Conclusion: Our data indicated that clusterin was associated with CSF NG levels among older individuals with different severities of cognitive impairment.

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APOE ε4 carriers may undergo synaptic damage conferring risk of Alzheimer's disease

Cited by 32 publications

References 36 publications

Cerebrospinal fluid neurogranin concentration in neurodegeneration: relation to clinical phenotypes and neuropathology

Cerebrospinal fluid neurogranin concentration in neurodegeneration: relation to clinical phenotypes and neuropathology

Age and the association between apolipoprotein E genotype and Alzheimer disease: A cerebrospinal fluid biomarker–based case–control study

<p>Association of Clusterin Levels in Cerebrospinal Fluid with Synaptic Degeneration Across the Alzheimer’s Disease Continuum</p>

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