Lower DNA methylation levels in CpG island shores of CR1, CLU, and PICALM genes in the blood of Alzheimer’s disease patients

AbstractThe aim of the present study was to (1) investigate the relationship between late onset AD and DNA methylation levels in the top six Alzheimer’s disease (AD)-related genes in blood and (2) examine its applicability to the diagnosis of AD. We examined methylation differences at CpG island shores in the top six genes using Sanger sequencing, and one of two groups of 48 AD patients and 48 elderly controls was used for a test or replication analysis. We found that methylation levels in three out of the six genes, CR1, CLU, and PICALM, were lower in AD subjects. The combination of CLU methylation levels and the APOE genotype classified AD patients with AUC=0.84 and 0.80 in the test and replication analyses, respectively. Our results implicate methylation differences at the CpG island shores of AD-related genes in the onset of AD and suggest their diagnostic value.

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Superior Frontal Gyrus TOMM40-APOE Locus DNA Methylation in Alzheimer’s Disease

Journal of Alzheimer s Disease Reports ◽

10.3233/adr-201000 ◽

2021 ◽

pp. 1-8

Author(s):

Natalia Bezuch ◽

Steven Bradburn ◽

Andrew C. Robinson ◽

Neil Pendleton ◽

Antony Payton ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Dna Methylation ◽

Fluid Intelligence ◽

Cpg Island ◽

Amyloid Β ◽

Superior Frontal Gyrus ◽

Protein Levels ◽

Apoe Protein ◽

Apoe Locus

Background: The APOE ɛ4 allele is the strongest known genetic risk factor for sporadic Alzheimer’s disease (AD). The neighboring TOMM40 gene has also been implicated in AD due to its close proximity to APOE. Objective: Here we tested whether methylation of the TOMM40-APOE locus may influence ApoE protein levels and AD pathology. Methods: DNA methylation levels across the TOMM40-APOE locus and ApoE levels were measured in superior frontal gyrus tissues of 62 human brains genotyped for APOE and scored for AD neuropathology. Results: Methylation levels within the TOMM40 CpG island in the promoter or APOE CpG island in Exon 4 did not differ between APOE ɛ4 carriers versus non-carriers. However, APOE ɛ4 carriers had significantly higher methylation the APOE promoter compared with non-carriers. Although DNA methylation at TOMM40, APOE promoter region, or APOE did not differ between AD pathological groups, there was a negative association between TOMM40 methylation and CERAD scores. ApoE protein concentrations did not significantly different between APOE ɛ4 carriers and non-carriers, or between AD pathological groups. Finally, there was no correlation between ApoE protein concentrations and DNA methylation levels. Conclusion: APOE gene methylation may not be affected by genotype, relate to AD pathology or ApoE protein levels in the superior frontal gyrus, though, DNA methylation at the ApoE promoter differed between genotype. DNA methylation at TOMM40 associated with amyloid-β plaques and longitudinal fluid intelligence. In sum, these results suggest a complicated regulation of the TOMM40-APOE locus in the brain in controlling ApoE protein levels and AD neuropathology.

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Integrated DNA methylation and gene expression profiling across multiple brain regions implicate novel genes in Alzheimer’s disease

10.1101/430603 ◽

2018 ◽

Author(s):

Stephen A. Semick ◽

Rahul A. Bharadwaj ◽

Leonardo Collado-Torres ◽

Ran Tao ◽

Joo Heon Shin ◽

...

Keyword(s):

Gene Expression ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Dna Methylation ◽

Neurodegenerative Disorder ◽

Late Onset ◽

Brain Regions ◽

Epigenetic Mechanism ◽

Novel Genes ◽

Age Related

AbstractBackgroundLate-onset Alzheimer’s disease (AD) is a complex age-related neurodegenerative disorder that likely involves epigenetic factors. To better understand the epigenetic state associated with AD represented as variation in DNA methylation (DNAm), we surveyed 420,852 DNAm sites from neurotypical controls (N=49) and late-onset AD patients (N=24) across four brain regions (hippocampus, entorhinal cortex, dorsolateral prefrontal cortex and cerebellum).ResultsWe identified 858 sites with robust differential methylation, collectively annotated to 772 possible genes (FDR<5%, within 10kb). These sites were overrepresented in AD genetic risk loci (p=0.00655), and nearby genes were enriched for processes related to cell-adhesion, immunity, and calcium homeostasis (FDR<5%). We analyzed corresponding RNA-seq data to prioritize 130 genes within 10kb of the differentially methylated sites, which were differentially expressed and had expression levels associated with nearby DNAm levels (p<0.05). This validated gene set includes previously reported (e.g. ANK1, DUSP22) and novel genes involved in Alzheimer’s disease, such as ANKRD30B.ConclusionsThese results highlight DNAm changes in Alzheimer’s disease that have gene expression correlates, implicating DNAm as an epigenetic mechanism underlying pathological molecular changes associated with AD. Furthermore, our framework illustrates the value of integrating epigenetic and transcriptomic data for understanding complex disease.

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Leveraging DNA methylation quantitative-trait loci to characterize the relationship between metabolic traits and Alzheimer’s disease

10.21203/rs.3.rs-38215/v1 ◽

2020 ◽

Author(s):

Di Liu ◽

Zhiyuan Yu ◽

Weijie Cao ◽

Youxin Wang ◽

Qun Meng

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Dna Methylation ◽

Quantitative Trait Loci ◽

Quantitative Trait ◽

Sensitivity Analyses ◽

Metabolic Traits ◽

Trait Loci ◽

The Relationship ◽

Methylation Quantitative Trait Loci

Abstract Background: The relationship between DNA methylation, common metabolic risk and Alzheimer’s disease (AD) is not well understood.Methods: Summary statistics integrating DNA methylation quantitative trait loci (mQTLs) and several genome-wide association study data were used. Network with bidirectional mendelian randomization (MR) analysis was performed to examine the causal association among metabolic traits, DNA methylation and AD.Results: Our study showed that cis-mQTLs determined DNA methylation to higher total cholesterol (TC) was associated with higher AD risk (β [95% CI] =0.007 [0.002-0.013], P=0.005). The findings were robust in sensitivity analyses with different instrumental variables. We found no evidence to support causal associations of cis-mQTLs determined obesity and T2D with AD, and vice versa.Conclusion: Overall, our study showed that the cis-mQTLs determined DNA methylation to higher TC was associated with higher AD risk, whereas the relation of cis-mQTLs determined AD and metabolic dysregulation was unlikely to be causal.

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Identification of epigenome-wide DNA methylation differences between carriers of APOE ε4 and APOE ε2 alleles

Genome Medicine ◽

10.1186/s13073-020-00808-4 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Rosie M. Walker ◽

Kadi Vaher ◽

Mairead L. Bermingham ◽

Stewart W. Morris ◽

Andrew D. Bretherick ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Dna Methylation ◽

Late Onset ◽

Meta Analysis ◽

Density Lipoprotein ◽

Differentially Methylated Region ◽

Carrier Status ◽

Ε4 Allele ◽

Methylation Patterns

Abstract Background The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late onset Alzheimer’s disease, whilst the ε2 allele confers protection. Previous studies report differential DNA methylation of APOE between ε4 and ε2 carriers, but associations with epigenome-wide methylation have not previously been characterised. Methods Using the EPIC array, we investigated epigenome-wide differences in whole blood DNA methylation patterns between Alzheimer’s disease-free APOE ε4 (n = 2469) and ε2 (n = 1118) carriers from the two largest single-cohort DNA methylation samples profiled to date. Using a discovery, replication and meta-analysis study design, methylation differences were identified using epigenome-wide association analysis and differentially methylated region (DMR) approaches. Results were explored using pathway and methylation quantitative trait loci (meQTL) analyses. Results We obtained replicated evidence for DNA methylation differences in a ~ 169 kb region, which encompasses part of APOE and several upstream genes. Meta-analytic approaches identified DNA methylation differences outside of APOE: differentially methylated positions were identified in DHCR24, LDLR and ABCG1 (2.59 × 10−100 ≤ P ≤ 2.44 × 10−8) and DMRs were identified in SREBF2 and LDLR (1.63 × 10−4 ≤ P ≤ 3.01 × 10−2). Pathway and meQTL analyses implicated lipid-related processes and high-density lipoprotein cholesterol was identified as a partial mediator of the methylation differences in ABCG1 and DHCR24. Conclusions APOE ε4 vs. ε2 carrier status is associated with epigenome-wide methylation differences in the blood. The loci identified are located in trans as well as cis to APOE and implicate genes involved in lipid homeostasis.

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Genome-wide DNA methylation profiling in nonagenarians suggests an effect of PM20D1 in late onset Alzheimer’s disease

CNS Spectrums ◽

10.1017/s109285292100105x ◽

2021 ◽

pp. 1-27

Author(s):

Carolina Coto-Vílchez ◽

José Jaime Martínez-Magaña ◽

L. Mora-Villalobos ◽

D. Valerio ◽

Alma Delia Genis-Mendoza ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Dna Methylation ◽

Late Onset ◽

Genome Wide ◽

Dna Methylation Profiling ◽

Methylation Profiling

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P1-053: Genome-wide analysis of DNA methylation differentiates late-onset Alzheimer's disease from dementia with Lewy bodies

Alzheimer s & Dementia ◽

10.1016/j.jalz.2013.05.274 ◽

2013 ◽

Vol 9 ◽

pp. P171-P172

Author(s):

Crystal Humphries ◽

Patrice L. Whitehead ◽

Deborah Mash ◽

Gary Beecham ◽

Margaret Pericak-Vance ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Dna Methylation ◽

Dementia With Lewy Bodies ◽

Late Onset ◽

Lewy Bodies ◽

Genome Wide Analysis ◽

Genome Wide

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P02.255 The relationship between alzheimer's disease, early onset and late-onset depression in the elderly assessed in a family study

European Psychiatry ◽

10.1016/s0924-9338(00)94663-7 ◽

2000 ◽

Vol 15 (S2) ◽

pp. 390s-390s

Author(s):

R. Heun ◽

A. Papassotiropoulos ◽

F. Jessen ◽

W. Maier ◽

J.C.S. Breitner

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Early Onset ◽

Family Study ◽

Late Onset ◽

The Elderly ◽

The Relationship

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The Pathogenesis of Alzheimer's Disease: A Reevaluation of the “Amyloid Cascade Hypothesis”

International Journal of Alzheimer s Disease ◽

10.4061/2011/630865 ◽

2011 ◽

Vol 2011 ◽

pp. 1-6 ◽

Cited By ~ 20

Author(s):

R. A. Armstrong

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Late Onset ◽

Senile Plaques ◽

Amyloid Cascade Hypothesis ◽

Amyloid A ◽

Molecular Determinants ◽

Relationship Of ◽

The Relationship ◽

Amyloid Cascade

The most influential theory to explain the pathogenesis of Alzheimer's disease (AD) has been the “Amyloid Cascade Hypothesis” (ACH) first formulated in 1992. The ACH proposes that the deposition ofβ-amyloid (Aβ) is the initial pathological event in AD leading to the formation of senile plaques (SPs) and then to neurofibrillary tangles (NFTs) death of neurons, and ultimately dementia. This paper examines two questions regarding the ACH: (1) is there a relationship between the pathogenesis of SPs and NFTs, and (2) what is the relationship of these lesions to disease pathogenesis? These questions are examined in relation to studies of the morphology and molecular determinants of SPs and NFTs, the effects of gene mutation, degeneration induced by head injury, the effects of experimentally induced brain lesions, transgenic studies, and the degeneration of anatomical pathways. It was concluded that SPs and NFTs develop independently and may be the products rather than the causes of neurodegeneration in AD. A modification to the ACH is proposed which may better explain the pathogenesis of AD, especially of late-onset cases of the disease.

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Identification of epigenome-wide DNA methylation differences between carriers of APOE ε4 and APOE ε2

10.1101/815035 ◽

2019 ◽

Author(s):

Rosie M. Walker ◽

Kadi Vaher ◽

Mairead L. Bermingham ◽

Stewart W. Morris ◽

Andrew D. Bretherick ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Dna Methylation ◽

Late Onset ◽

Meta Analysis ◽

Density Lipoprotein ◽

Differentially Methylated Region ◽

Carrier Status ◽

Ε4 Allele ◽

Methylation Patterns

AbstractBACKGROUNDThe Apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late onset Alzheimer’s disease, while the ε2 allele confers protection. Previous studies report differential DNA methylation of APOE between ε4 and ε2 carriers, but associations with epigenome-wide methylation have not previously been characterised.METHODSUsing the EPIC array, we investigated epigenome-wide differences in whole blood DNA methylation patterns between Alzheimer’s disease-free APOE ε4 (n=2469) and ε2 (n=1118) carriers from the two largest single-cohort DNA methylation samples profiled to date. Using a discovery, replication and meta-analysis study design, methylation differences were identified using epigenome-wide association analysis and differentially methylated region (DMR) approaches. Results were explored using pathway and methylation quantitative trait loci (meQTL) analyses.RESULTSWe obtained replicated evidence for DNA methylation differences in a ~169kb region, which encompasses part of APOE and several upstream genes. Meta-analytic approaches identified DNA methylation differences outside of APOE: differentially methylated positions were identified in DHCR24, LDLR and ABCG1 (2.59 x 10−100≤P≤2.44 x 10−8) and DMRs were identified in SREBF2 and LDLR (1.63 x 10−4≤P≤3.01 x 10−2). Pathway and meQTL analyses implicated lipid-related processes and high density lipoprotein cholesterol was identified as a partial mediator of the methylation differences in ABCG1 and DHCR24.CONCLUSIONSAPOE ε4 vs. ε2 carrier status is associated with epigenome-wide methylation differences in the blood. The loci identified are located in trans as well as cis to APOE and implicate genes involved in lipid homeostasis.

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