scholarly journals Longitudinal data in peripheral blood confirm that PM20D1 is a quantitative trait locus (QTL) for Alzheimer’s disease and implicate its dynamic role in disease progression

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Qi Wang ◽  
Yinghua Chen ◽  
Benjamin Readhead ◽  
Kewei Chen ◽  
Yi Su ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Dna Methylation ◽  
Longitudinal Data ◽  
Disease Progression ◽  
Peripheral Blood ◽  
Early Stage ◽  
Underlying Mechanism ◽  
Methylation Data ◽  
Brain Tissues

Abstract Background While Alzheimer’s disease (AD) remains one of the most challenging diseases to tackle, genome-wide genetic/epigenetic studies reveal many disease-associated risk loci, which sheds new light onto disease heritability, provides novel insights to understand its underlying mechanism and potentially offers easily measurable biomarkers for early diagnosis and intervention. Methods We analyzed whole-genome DNA methylation data collected from peripheral blood in a cohort (n = 649) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and compared the DNA methylation level at baseline among participants diagnosed with AD (n = 87), mild cognitive impairment (MCI, n = 175) and normal controls (n = 162), to identify differentially methylated regions (DMRs). We also leveraged up to 4 years of longitudinal DNA methylation data, sampled at approximately 1 year intervals to model alterations in methylation levels at DMRs to delineate methylation changes associated with aging and disease progression, by linear mixed-effects (LME) modeling for the unchanged diagnosis groups (AD, MCI and control, respectively) and U-shape testing for those with changed diagnosis (converters). Results When compared with controls, patients with MCI consistently displayed promoter hypomethylation at methylation QTL (mQTL) gene locus PM20D1. This promoter hypomethylation was even more prominent in patients with mild to moderate AD. This is in stark contrast with previously reported hypermethylation in hippocampal and frontal cortex brain tissues in patients with advanced-stage AD at this locus. From longitudinal data, we show that initial promoter hypomethylation of PM20D1 during MCI and early stage AD is reversed to eventual promoter hypermethylation in late stage AD, which helps to complete a fuller picture of methylation dynamics. We also confirm this observation in an independent cohort from the Religious Orders Study and Memory and Aging Project (ROSMAP) Study using DNA methylation and gene expression data from brain tissues as neuropathological staging (Braak score) advances. Conclusions Our results confirm that PM20D1 is an mQTL in AD and demonstrate that it plays a dynamic role at different stages of the disease. Further in-depth study is thus warranted to fully decipher its role in the evolution of AD and potentially explore its utility as a blood-based biomarker for AD.

scholarly journals Association of peripheral blood DNA methylation levels with Alzheimer’s disease progression

2021 ◽  
Vol 17 (S5) ◽  
Author(s):  
Qingqin S. Li ◽  
Aparna Vasanthakumar ◽  
Justin W. Davis ◽  
Kenneth Idler ◽  
Kwangsik Nho ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Dna Methylation ◽  
Disease Progression ◽  
Peripheral Blood

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

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hao Hu ◽  
Lan Tan ◽  
Yan-Lin Bi ◽  
Wei Xu ◽  
Lin Tan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Peripheral Blood ◽  
Late Onset ◽  
Early Stage ◽  
Susceptibility Gene ◽  
Subjective Cognitive Decline ◽  
Preclinical Ad ◽  
T Tau ◽  
New Evidence

AbstractThe 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.

scholarly journals THE APOE-ε4 ALLELE AND AGE SYNERGISTICALLY DRIVE DISEASE PROGRESSION IN ALZHEIMER’S DISEASE

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S943-S943
Author(s):  
Luca Kleineidam ◽  
Andrea R Zammit ◽  
Alyssa DeVito ◽  
Richard B Lipton ◽  
Oliver Peters ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Disease Progression ◽  
Underlying Mechanism ◽  
Additive Models ◽  
Tau Pathology ◽  
Case Control Studies ◽  
Cross Sectional ◽  
Apoe Ε4 ◽  
Ε4 Allele

Abstract The Apolipoprotein E (APOE)-ε4 allele is the strongest genetic risk factor for Alzheimer’s disease (AD) and other neurodegenerative dementias. Cross-sectional case-control studies suggest that the effect of APOE-ε4 decreases in old age. However, since APOE- ε4 is associated with mortality, these studies might be prone to bias due to selective survival. Therefore, we used multi-state-modeling in longitudinal cohort studies to examine the effect of APOE-ε4 on the transition through cognitive states (i.e. cognitively normal, mild cognitive impairment (MCI) and dementia) while taking death as a competing risk into account. Results from the German AgeCoDe study (n=3000, aged 75-101 years) showed that APOE-ε4 increases the risk for cognitive deterioration in all disease stages. Contrary to results from cross-sectional studies, the effect of APOE-ε4 on the transition from MCI to dementia increased with increasing age (HR=1.044, 95%-CI=1.001-1090). The direction of this effect was confirmed in a smaller sample from the Einstein Aging Study (n=744, HR=1.032, 95%-CI=0.949-1.122). To examine the pathophysiological basis of these results, generalized additive models were used to study AD biomarkers in the liquor of 1045 patients with MCI or AD-dementia. Here, increased amyloid (Abeta1-42) pathology was associated with increased tau pathology (pTau181), consistent with the amyloid-cascade-hypothesis. Interestingly, higher age and presence of the APOE-ε4 synergistically lowered the amount of amyloid required to exacerbate tau pathology (interaction p=0.012). Taken together, our results suggest that the effect of APOE-ε4 on disease progression increases with advancing age. An altered neuroinflammatory response to neurodegeneration should be further explored as potential underlying mechanism.

scholarly journals Differential Expression of mRNAs in the Brain Tissues of Patients with Alzheimer’s Disease Based on GEO Expression Profile and Its Clinical Significance

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Guowei Ma ◽  
Mingyan Liu ◽  
Ke Du ◽  
Xin Zhong ◽  
Shiqiang Gong ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Differential Expression ◽  
Brain Tissue ◽  
Peripheral Blood ◽  
Bioinformatics Analysis ◽  
Venn Diagram ◽  
Ad Prevention ◽  
The Brain ◽  
Brain Tissues

Background. Early diagnosis of Alzheimer’s disease (AD) is an urgent point for AD prevention and treatment. The biomarkers of AD still remain indefinite. Based on the bioinformatics analysis of mRNA differential expressions in the brain tissues and the peripheral blood samples of Alzheimer’s disease (AD) patients, we investigated the target mRNAs that could be used as an AD biomarker and developed a new effective, practical clinical examination program. Methods. We compared the AD peripheral blood mononuclear cells (PBMCs) expression dataset (GEO accession GSE4226 and GSE18309) with AD brain tissue expression datasets (GEO accessions GSE1297 and GSE5281) from GEO in the present study. The GEO gene database was used to download the appropriate gene expression profiles to analyze the differential mRNA expressions between brain tissue and blood of AD patients and normal elderly. The Venn diagram was used to screen out the differential expression of mRNAs between the brain tissue and blood. The protein-protein interaction network map (PPI) was used to view the correlation between the possible genes. GO (gene ontology) and KEGG (Kyoto Gene and Genomic Encyclopedia) were used for gene enrichment analysis to determine the major affected genes and the function or pathway. Results. Bioinformatics analysis revealed that there were differentially expressed genes in peripheral blood and hippocampus of AD patients. There were 4958 differential mRNAs in GSE18309, 577 differential mRNAs in GSE4226 in AD PBMCs sample, 7464 differential mRNAs in GSE5281, and 317 differential mRNAs in GSE129 in AD brain tissues, when comparing between AD patients and healthy elderly. Two mRNAs of RAB7A and ITGB1 coexpressed in hippocampus and peripheral blood were screened. Furthermore, functions of differential genes were enriched by the PPI network map, GO, and KEGG analysis, and finally the chemotaxis, adhesion, and inflammatory reactions were found out, respectively. Conclusions. ITGB1 and RAB7A mRNA expressions were both changed in hippocampus and PBMCs, highly suggested being used as an AD biomarker with AD. Also, according to the results of this analysis, it is indicated that we can test the blood routine of the elderly for 2-3 years at a frequency of 6 months or one year. When a patient continuously detects the inflammatory manifestations, it is indicated as a potentially high-risk AD patient for AD prevention.

scholarly journals Sulfhydration of AKT triggers Tau-phosphorylation by activating glycogen synthase kinase 3β in Alzheimer’s disease

2020 ◽  
Vol 117 (8) ◽  
pp. 4418-4427
Author(s):  
Tanusree Sen ◽  
Pampa Saha ◽  
Tong Jiang ◽  
Nilkantha Sen
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Glycogen Synthase ◽  
Early Stage ◽  
Underlying Mechanism ◽  
Glycogen Synthase Kinase ◽  
Synaptic Dysfunction ◽  
Glycogen Synthase Kinase 3Β ◽  
Phosphorylated Akt ◽  
Postmortem Brains

In Alzheimer’s disease (AD), human Tau is phosphorylated at S199 (hTau-S199-P) by the protein kinase glycogen synthase kinase 3β (GSK3β). HTau-S199-P mislocalizes to dendritic spines, which induces synaptic dysfunction at the early stage of AD. The AKT kinase, once phosphorylated, inhibits GSK3β by phosphorylating it at S9. In AD patients, the abundance of phosphorylated AKT with active GSK3β implies that phosphorylated AKT was unable to inactivate GSK3β. However, the underlying mechanism of the inability of phosphorylated AKT to phosphorylate GSK3β remains unknown. Here, we show that total AKT and phosphorylated AKT was sulfhydrated at C77 due to the induction of intracellular hydrogen sulfide (H2S). The increase in intracellular H2S levels resulted from the induction of the proinflammatory cytokine, IL-1β, which is a pathological hallmark of AD. Sulfhydrated AKT does not interact with GSK3β, and therefore does not phosphorylate GSK3β. Thus, active GSK3β phosphorylates Tau aberrantly. In a transgenic knockin mouse (AKT-KI+/+) that lacked sulfhydrated AKT, the interaction between AKT or phospho-AKT with GSK3β was restored, and GSK3β became phosphorylated. In AKT-KI+/+ mice, expressing the pathogenic human Tau mutant (hTau-P301L), the hTau S199 phosphorylation was ameliorated as GSK3β phosphorylation was regained. This event leads to a decrease in dendritic spine loss by reducing dendritic localization of hTau-S199-P, which improves cognitive dysfunctions. Sulfhydration of AKT was detected in the postmortem brains from AD patients; thus, it represents a posttranslational modification of AKT, which primarily contributes to synaptic dysfunction in AD.

Sign in / Sign up

Export Citation Format

Share Document