APOE ε4 is associated with higher levels of CSF SNAP-25 in prodromal Alzheimer’s disease

Wang, Shanshan; Zhang, Jie; Pan, Tengwei; Initiative, for Alzheimer’s Disease Neuroimaging

doi:10.1016/j.neulet.2018.08.029

Cited by 27 publications

(20 citation statements)

References 33 publications

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“…Subtypes and 5 showed high levels of CSF markers for neuronal and synaptic injury such as VILIP-1 and SNAP-25 ( Figures 5A and 5B). The levels of these markers gradually increased with the dose of APOE ε4, consistent with the findings of recent studies reporting associations between these markers and APOE ε4 [30,31]. On the other hand, the levels of the inflammation marker YKL-40 in the CSF were increased only in subtype 5 among the subtypes except for subtype 4 (Figure 5D).…”

Section: Discussionsupporting

confidence: 90%

Identification of Mild Cognitive Impairment Subtypes Predicting Conversion to Alzheimer’s Disease Using a Heterogeneous Mixture Learning

Kikuchi¹,

Kobayashi²,

Itoh³

et al. 2020

Preprint

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BackgroundMild cognitive impairment (MCI) is a high-risk condition for conversion to dementias, including Alzheimer's disease (AD) dementia. However, individuals with MCI show heterogeneity in patterns of pathology, and MCI does not always convert to AD dementia. Detailed subtyping of MCI and accurate prediction of the patients in whom MCI will convert to AD dementia may support new trial designs and enable evaluation of the efficacy of drugs within small numbers of patients during clinical trials. MethodsWe constructed a decision tree model by the heterogeneous mixture learning (HML) method, integrating cerebrospinal fluid (CSF) biomarker data, structural MRI data, APOE genotype data, and a recorded age at examination. The decision tree model was applied to predict conversion to AD dementia and to identify subtypes of MCI. After the test performances of HML models were assessed, MCI subjects were classified into some subtypes based on a decision tree. Then, we characterized each MCI subtype in terms of the degree of CSF biomarker abnormalities and brain atrophy, declines of cognitive functions, and gene expression alterations derived from peripheral blood samples.ResultsWe identified five subtypes of MCI using the HML approach and categorized them into three groups: those similar to CN subjects with low conversion rates; those with intermediate conversion rates; and those similar to patients with AD with high conversion rates. Furthermore, the subtypes with intermediate conversion rates were separated into the subtype with CSF biomarker abnormalities or the subtype with brain atrophy. The results from the CSF inflammation marker and gene expression analysis suggested the occurrence of aberrant inflammatory immune responses in the CSF and blood of the subjects in the subtypes with CSF biomarker abnormalities. ConclusionThe subtypes that were identified in this study exhibited varying conversion rates to AD as well as differing levels of biological features. Focusing on specific subtypes in which conversion to AD can be predicted with the most accuracy could enable more efficient clinical trials to be conducted.

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Section: Discussionsupporting

confidence: 90%

Identification of Mild Cognitive Impairment Subtypes Predicting Conversion to Alzheimer’s Disease Using a Heterogeneous Mixture Learning

Kikuchi¹,

Kobayashi²,

Itoh³

et al. 2020

Preprint

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“… 149 SNAP-25 has, in various studies using both enzyme-linked immunosorbent assay (ELISA) and mass spectrometry-based assays, shown to have significantly higher CSF levels in AD, even at a very early stages. 7 , 150 - 152 Increased CSF levels of SNAP-25 have also been found in patients with PD 153 and patients with sporadic CJD. 154 In addition, SNAP-25 has been associated with several psychiatric diseases such as attention deficiency hyperactivity disorder (ADHD), schizophrenia, and bipolar disorder.…”

Section: Fluid Biomarkers For Synapse Pathologymentioning

confidence: 99%

Fluid Biomarkers for Synaptic Dysfunction and Loss

et al. 2020

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Synapses are the site for brain communication where information is transmitted between neurons and stored for memory formation. Synaptic degeneration is a global and early pathogenic event in neurodegenerative disorders with reduced levels of pre- and postsynaptic proteins being recognized as a core feature of Alzheimer’s disease (AD) pathophysiology. Together with AD, other neurodegenerative and neurodevelopmental disorders show altered synaptic homeostasis as an important pathogenic event, and due to that, they are commonly referred to as synaptopathies. The exact mechanisms of synapse dysfunction in the different diseases are not well understood and their study would help understanding the pathogenic role of synaptic degeneration, as well as differences and commonalities among them and highlight candidate synaptic biomarkers for specific disorders. The assessment of synaptic proteins in cerebrospinal fluid (CSF), which can reflect synaptic dysfunction in patients with cognitive disorders, is a keen area of interest. Substantial research efforts are now directed toward the investigation of CSF synaptic pathology to improve the diagnosis of neurodegenerative disorders at an early stage as well as to monitor clinical progression. In this review, we will first summarize the pathological events that lead to synapse loss and then discuss the available data on established (eg, neurogranin, SNAP-25, synaptotagmin-1, GAP-43, and α-syn) and emerging (eg, synaptic vesicle glycoprotein 2A and neuronal pentraxins) CSF biomarkers for synapse dysfunction, while highlighting possible utilities, disease specificity, and technical challenges for their detection.

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“…Reduced gene expression patterns of genes related to synaptic vesicle trafficking have been found, which indicate that synapses in AD may not function effectively, even prior to visible structural alteration of neurons [166]. In contrast to the decrease of SNAP-25 found in human brains, SNAP-25 is found to be increased in the CSF of AD patients compared to age-matched controls [91,[108][109][110]. No studies were found measuring the difference of SNAP-25 in the blood of AD patients compared to healthy controls.…”

Section: Snap-25mentioning

confidence: 98%

Utility of Animal Models to Understand Human Alzheimer’s Disease, Using the Mastermind Research Approach to Avoid Unnecessary Further Sacrifices of Animals

Qin

Prins

Groeneveld

et al. 2020

IJMS

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To diagnose and treat early-stage (preclinical) Alzheimer’s disease (AD) patients, we need body-fluid-based biomarkers that reflect the processes that occur in this stage, but current knowledge on associated processes is lacking. As human studies on (possible) onset and early-stage AD would be extremely expensive and time-consuming, we investigate the potential value of animal AD models to help to fill this knowledge gap. We provide a comprehensive overview of processes associated with AD pathogenesis and biomarkers, current knowledge on AD-related biomarkers derived from on human and animal brains and body fluids, comparisons of biomarkers obtained in human AD and frequently used animal AD models, and emerging body-fluid-based biomarkers. In human studies, amyloid beta (Aβ), hyperphosphorylated tau (P-tau), total tau (T-tau), neurogranin, SNAP-25, glial fibrillary acidic protein (GFAP), YKL-40, and especially neurofilament light (NfL) are frequently measured. In animal studies, the emphasis has been mostly on Aβ. Although a direct comparison between human (familial and sporadic) AD and (mostly genetic) animal AD models cannot be made, still, in brain, cerebrospinal fluid (CSF), and blood, a majority of similar trends are observed for human AD stage and animal AD model life stage. This indicates the potential value of animal AD models in understanding of the onset and early stage of AD. Moreover, animal studies can be smartly designed to provide mechanistic information on the interrelationships between the different AD processes in a longitudinal fashion and may also include the combinations of different conditions that may reflect comorbidities in human AD, according to the Mastermind Research approach.

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APOE ε4 is associated with higher levels of CSF SNAP-25 in prodromal Alzheimer’s disease

Cited by 27 publications

References 33 publications

Identification of Mild Cognitive Impairment Subtypes Predicting Conversion to Alzheimer’s Disease Using a Heterogeneous Mixture Learning

Identification of Mild Cognitive Impairment Subtypes Predicting Conversion to Alzheimer’s Disease Using a Heterogeneous Mixture Learning

Fluid Biomarkers for Synaptic Dysfunction and Loss

Utility of Animal Models to Understand Human Alzheimer’s Disease, Using the Mastermind Research Approach to Avoid Unnecessary Further Sacrifices of Animals

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