Dynamic changes of CSF sTREM2 in preclinical Alzheimer’s disease: the CABLE study

Ma, Lingzhi; Tan, Lan; Bi, Yan‐Lin; Shen, Xue‐Ning; Xu, Wei; Ma, Ya‐Hui; Li, Hongqi; Dong, Qiang; Yu, Jin‐Tai

doi:10.1186/s13024-020-00374-8

Cited by 63 publications

(61 citation statements)

References 45 publications

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“…Therefore, in this study, CSF biomarker positive participants were defined as having CSF Aβ42 levels in the lower one-third of the distribution of participants (A+: ≤120.71 pg/mL) or having p-tau (T+: ≥39.15 pg/mL) or t-tau ( N +: ≥184.19 pg/mL) levels in the upper one-third of the distribution. This method for establishing cut-offs was also used in previous studies, yielding reasonable results 22 , 32 .…”

Section: Methodsmentioning

confidence: 74%

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Association between methylation of BIN1 promoter in peripheral blood and preclinical Alzheimer’s disease

Tan

et al. 2021

Transl Psychiatry

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The bridging integrator 1 (BIN1) gene is the second most important susceptibility gene for late-onset Alzheimer’s disease (LOAD) after apolipoprotein E (APOE) gene. To explore whether the BIN1 methylation in peripheral blood changed in the early stage of LOAD, we included 814 participants (484 cognitively normal participants [CN] and 330 participants with subjective cognitive decline [SCD]) from the Chinese Alzheimer’s Biomarker and LifestylE (CABLE) database. Then we tested associations of methylation of BIN1 promoter in peripheral blood with the susceptibility for preclinical AD or early changes of cerebrospinal fluid (CSF) AD-related biomarkers. Results showed that SCD participants with significant AD biological characteristics had lower methylation levels of BIN1 promoter, even after correcting for covariates. Hypomethylation of BIN1 promoter were associated with decreased CSF Aβ42 (p = 0.0008), as well as increased p-tau/Aβ42 (p = 0.0001) and t-tau/Aβ42 (p < 0.0001) in total participants. Subgroup analysis showed that the above associations only remained in the SCD subgroup. In addition, hypomethylation of BIN1 promoter was also accompanied by increased CSF p-tau (p = 0.0028) and t-tau (p = 0.0130) in the SCD subgroup, which was independent of CSF Aβ42. Finally, above associations were still significant after correcting single nucleotide polymorphic sites (SNPs) and interaction of APOE ɛ4 status. Our study is the first to find a robust association between hypomethylation of BIN1 promoter in peripheral blood and preclinical AD. This provides new evidence for the involvement of BIN1 in AD, and may contribute to the discovery of new therapeutic targets for AD.

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Section: Methodsmentioning

confidence: 74%

“…The CABLE database is an ongoing large independent cohort study initiated in 2017. It aimed to determine the genetic and environmental modifiers of AD biomarkers and their utility in early diagnosis in the northern Chinese Han population 21 , 22 . All participants in CABLE were enrolled at Qingdao Municipal Hospital, Shandong Province, China.…”

Section: Methodsmentioning

confidence: 99%

Association between methylation of BIN1 promoter in peripheral blood and preclinical Alzheimer’s disease

Tan

et al. 2021

Transl Psychiatry

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“…Why CSF sTREM2 was not signi cantly associated with Aβ 42 in our sample is unknown. Given the early appearance of Aβ 42 and its plateau in the prodromal stage of AD, giving way to the increase in P-tau, sTREM2 may be closely linked with Aβ-triggered tau phosphorylation occurring after Aβ 42 accumulation [11,28] . Tau aggregations might affect the microglial activation state, suppressing Aβ clearance and producing neurodegeneration [29,30] .…”

Section: Discussionmentioning

confidence: 99%

The Relationship of Soluble TREM2 to Other Biomarkers of Sporadic Alzheimer’s Disease

Park

Lee

Kim

et al. 2021

Preprint

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Microglial activation is a central player in the pathophysiology of Alzheimer’s disease (AD). The soluble fragment of triggering receptor expressed on myeloid cells 2 (sTREM2) can serve as a marker for microglial activation and has been shown to be overexpressed in AD. However, the relationship of sTREM2 with other AD biomarkers has not been extensively studied. We investigated the relationship between cerebrospinal fluid (CSF) sTREM2 and other AD biomarkers and examined the correlation of plasma sTREM2 with CSF sTREM2 in a cohort of individuals with AD and without AD.Participants were consecutively recruited from Asan Medical Center from 2018 to 2020. Subjects were stratified by their amyloid positivity and clinical status. Along with other AD biomarkers, sTREM2 level was measured in the plasma as well as CSF.In 101 patients with either amyloid-positive or negative status, CSF sTREM2 was closely associated with CSF T-tau and P-tau and not with Abeta42. CSF sTREM2 levels were found to be strongly correlated with CSF neurofilament light chain. The comparison of CSF and plasma sTREM2 levels tended to have an inverse correlation. Plasma sTREM2 and P-tau levels were oppositely influenced by age.Our results suggest that neuroinflammation may be closely associated with tau-induced neurodegeneration.

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“…Third, in transgenic mouse models overproducing Aβ the knockout of TREM2 expression accelerates amyloid plaque seeding 17 and the plaques have increased protofibrillar halos and hotspots 3,16,18 , indicating that either TREM2 or sTREM2 inhibit plaque formation. Fourth, in the earliest pre-symptomatic stages of AD, at the time of Aβ deposition, sTREM2 levels in cerebrospinal fluid (CSF) are lower than in healthy controls 10,19 , consistent with sTREM2 being an endogenous inhibitor of Aβ deposition. However, the CSF Aβ levels rise in the early symptomatic stages of AD, and then decline again at later stages of AD 11,12 .…”

Section: Introductionmentioning

confidence: 88%

Wild-type sTREM2 blocks Aβ aggregation and neurotoxicity, while the Alzheimer’s R47H mutant does the opposite

Vilalta

Zhou

Sévalle

et al. 2020

Preprint

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Missense mutations (e.g. R47H) of the microglial receptor TREM2 increase risk of Alzheimer’s disease (AD), and the soluble ectodomain of wild-type TREM2 (sTREM2) appears to protect in vivo, but the underlying mechanisms are unclear. We show that Aβ oligomers bind to TREM2, inducing shedding of sTREM2. Wild-type sTREM2 inhibits Aβ oligomerization, fibrillization and neurotoxicity, and disaggregates preformed Aβ oligomers and protofibrils. In contrast, the R47H AD-risk variant of sTREM2 is less able to bind and disaggregate oligomeric Aβ, but rather promotes Aβ protofibril formation and neurotoxicity. Thus, in addition to mediating phagocytosis, wild-type TREM2 may protect against amyloid pathology by Aβ-induced release of sTREM2 that blocks Aβ aggregation and neurotoxicity; while R47H sTREM2 promotes Aβ aggregation into neurotoxic forms, which may explain why the R47H variant gene increases AD risk several fold.

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Dynamic changes of CSF sTREM2 in preclinical Alzheimer’s disease: the CABLE study

Cited by 63 publications

References 45 publications

Association between methylation of BIN1 promoter in peripheral blood and preclinical Alzheimer’s disease

Association between methylation of BIN1 promoter in peripheral blood and preclinical Alzheimer’s disease

The Relationship of Soluble TREM2 to Other Biomarkers of Sporadic Alzheimer’s Disease

Wild-type sTREM2 blocks Aβ aggregation and neurotoxicity, while the Alzheimer’s R47H mutant does the opposite

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