<i>APOE</i> DNA methylation is altered in Lewy body dementia

Tulloch, Jessica; Leong, Lesley; Chen, Sunny; Keene, C. Dirk; Millard, Steven P.; López, Oscar L.; Kofler, Julia; Kaye, Jeffrey; Woltjer, Randy; Nelson, Peter T.; Neltner, Janna H.; Jicha, Gregory A.; Galasko, Douglas; Masliah, Eliezer; Leverenz, James B.; Yu, Chang; Tsuang, Debby W.

doi:10.1016/j.jalz.2018.02.005

Cited by 19 publications

(16 citation statements)

References 22 publications

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“…Cases were classified as having AD neuropathology if Braak Stage for neurofibrillary tangles was IV, V, or VI and CERAD neuritic plaque score was “moderate" or “frequent.” Coexistent LBD was classified based on the presence of α‐synuclein immunohistochemistry positive inclusions consistent with “limbic” or “neocortical” Lewy body pathology 35,36 …”

Section: Methodsmentioning

confidence: 99%

Cognitive tests aid in clinical differentiation of Alzheimer's disease versus Alzheimer's disease with Lewy body disease: Evidence from a pathological study

Azar

Chapman

et al. 2020

Alzheimer's & Dementia

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Introduction Clinical differentiation between Alzheimer's disease (AD) and AD with Lewy body disease (LBD) is relatively imprecise. The current study examined pathologically confirmed group differences in neuropsychological functioning, and the classification ability of specific tests. Methods Fifty‐one participants with postmortem diagnoses of AD (n = 34) and AD plus LBD (n = 17) were drawn from the Predictors Study. One‐way analyses of variance (ANOVAs) and χ2 analyses examined group differences in neuropsychological performance. Binary logistic regressions examined predictive utility of specific tests for pathological diagnosis. Results Individuals with AD had better visuoconstruction (P = .006), phonemic fluency (P = .08), and processing speed than AD plus LBD (P = .013). No differences were found in memory, naming, semantic fluency, or set‐switching. Processing speed and visuoconstruction predicted pathologic group (P = .03). Discussion Processing speed and visuoconstruction predicted postmortem diagnosis of AD versus AD plus LBD. Current results offer guidance in the selection and interpretation of neuropsychological tests to be used in the differential diagnosis of early dementia.

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Section: Methodsmentioning

confidence: 99%

Cognitive tests aid in clinical differentiation of Alzheimer's disease versus Alzheimer's disease with Lewy body disease: Evidence from a pathological study

Azar

Chapman

et al. 2020

Alzheimer's & Dementia

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“…The APOE gene contains a CpG island approximately 4000 bp downstream to exon 1 ( Figure 1 ), which has not been studied so far in the context of LBD [ 113 ]. Additionally, the presence of a second CpG island in exon 4 has also been reported [ 114 ].…”

Section: Epigenetics In Lewy Body Diseasesmentioning

confidence: 99%

“…Exon 4 contains the two SNPs (rs7412, rs429358) that define the common APOE genotype comprising alleles ε2, ε3, and ε4, and the presence of the ε4 allele corresponds to a higher CpG density in this region [ 115 ]. Although this CpG island presents hypomethylation in the frontal cortex of DLB and AD brains [ 113 ], APOE mRNA expression does not correlate with the methylation status of the CpG island of exon 4 [ 115 ].…”

Section: Epigenetics In Lewy Body Diseasesmentioning

confidence: 99%

“…DNA modifications represent a highly promising biomarker for neurodegenerative disorders [ 145 ]. As discussed above, DNA methylation in LBD has been primarily investigated within selected candidate genes [ 85 , 86 , 113 , 116 , 117 , 146 , 147 , 148 ]. However, global DNA methylation abnormalities in PD and DLB brains have been identified in several epigenome-wide studies (see Figure 2 ) [ 122 , 130 , 131 , 142 , 149 , 150 , 151 , 152 , 153 , 154 , 155 ].…”

Section: Epigenetic Pattern As Lbd Biomarkermentioning

confidence: 99%

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Epigenetics in Lewy Body Diseases: Impact on Gene Expression, Utility as a Biomarker, and Possibilities for Therapy

Urbizu

Beyer

2020

IJMS

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Lewy body disorders (LBD) include Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). They are synucleinopathies with a heterogeneous clinical manifestation. As a cause of neuropathological overlap with other neurodegenerative diseases, the establishment of a correct clinical diagnosis is still challenging, and clinical management may be difficult. The combination of genetic variation and epigenetic changes comprising gene expression-modulating DNA methylation and histone alterations modifies the phenotype, disease course, and susceptibility to disease. In this review, we summarize the results achieved in the deciphering of the LBD epigenome. To provide an appropriate context, first LBD genetics is briefly outlined. Afterwards, a detailed review of epigenetic modifications identified for LBD in human cells, postmortem, and peripheral tissues is provided. We also focus on the difficulty of identifying epigenome-related biomarker candidates and discuss the results obtained so far. Additionally, epigenetic changes as therapeutic targets, as well as different epigenome-based treatments, are revised. The number of studies focusing on PD is relatively limited and practically inexistent for DLB. There is a lack of replication studies, and some results are even contradictory, probably due to differences in sample collection and analytical techniques. In summary, we show the current achievements and directions for future research.

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“…Individuals carrying one ε4 allele are 3-4 times more likely to be diagnosed with AD than non-carriers, and the risk of developing AD increases by 12-15 times for those with two ε4 alleles [96,97]. Increasing evidence indicates that genetic polymorphisms of APOE ε4 are closely related to multiple types of dementia, such as Lewy body dementia (LBD) [98,99] and Parkinson disease dementia [100,101], suggesting a possible overlap in the mechanisms of different types of dementia in relation to APOE gene polymorphism. Although APOE is widely involved in the regulation of cholesterol metabolism, lipid transport, and APP production/metabolism [89,102,103], the best-established relationships are APOE variants and Aβ formation [104], accumulation [105] and plaque deposition in the brain [106,107].…”

Section: Apoe Genementioning

confidence: 99%

The Genetics of Alzheimer’s Disease in the Chinese Population

Gan

Zhang

Lee

2020

IJMS

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Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive cognitive dysfunction and behavioral impairment. In China, the number of AD patients is growing rapidly, which poses a considerable burden on society and families. In recent years, through the advancement of genome-wide association studies, second-generation gene sequencing technology, and their application in AD genetic research, more genetic loci associated with the risk for AD have been discovered, including KCNJ15, TREM2, and GCH1, which provides new ideas for the etiology and treatment of AD. This review summarizes three early-onset AD causative genes (APP, PSEN1, and PSEN2) and some late-onset AD susceptibility genes and their mutation sites newly discovered in China, and briefly introduces the potential mechanisms of these genetic susceptibilities in the pathogenesis of AD, which would help in understanding the genetic mechanisms underlying this devastating disease.

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APOE DNA methylation is altered in Lewy body dementia

Abstract: Given that npLBD and npAD postmortem brains shared a similar reduction in APOE methylation, it is possible that an aberrant epigenetic change in APOE is linked to risk for both diseases.

Cited by 19 publications

References 22 publications

Cognitive tests aid in clinical differentiation of Alzheimer's disease versus Alzheimer's disease with Lewy body disease: Evidence from a pathological study

Cognitive tests aid in clinical differentiation of Alzheimer's disease versus Alzheimer's disease with Lewy body disease: Evidence from a pathological study

Epigenetics in Lewy Body Diseases: Impact on Gene Expression, Utility as a Biomarker, and Possibilities for Therapy

The Genetics of Alzheimer’s Disease in the Chinese Population

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