Superior Frontal Gyrus Locus DNA Methylation in Alzheimer's Disease

Overview

Journal J Alzheimers Dis Rep

Publisher IOS Press

Date 2021 Jun 11

PMID 34113784

Citations 4

Authors

Natalia Bezuch

Steven Bradburn

Andrew C Robinson

Neil Pendleton

Antony Payton

Chris Murgatroyd

Affiliations

Soon will be listed here.

Abstract

Background: The ɛ4 allele is the strongest known genetic risk factor for sporadic Alzheimer's disease (AD). The neighboring gene has also been implicated in AD due to its close proximity to .

Objective: Here we tested whether methylation of the locus may influence ApoE protein levels and AD pathology.

Methods: DNA methylation levels across the locus and ApoE levels were measured in superior frontal gyrus tissues of 62 human brains genotyped for and scored for AD neuropathology.

Results: Methylation levels within the CpG island in the promoter or CpG island in Exon 4 did not differ between ɛ4 carriers versus non-carriers. However, ɛ4 carriers had significantly higher methylation the promoter compared with non-carriers. Although DNA methylation at , promoter region, or did not differ between AD pathological groups, there was a negative association between methylation and CERAD scores. ApoE protein concentrations did not significantly different between ɛ4 carriers and non-carriers, or between AD pathological groups. Finally, there was no correlation between ApoE protein concentrations and DNA methylation levels.

Conclusion: 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 associated with amyloid-β plaques and longitudinal fluid intelligence. In sum, these results suggest a complicated regulation of the locus in the brain in controlling ApoE protein levels and AD neuropathology.

Citing Articles

Pan-Cancer Analysis of the Prognostic and Immunological Role of TOMM40 to Identify Its Function in Breast Cancer.

Zhou Y, Wei X, Jia L, Li W, Zhang S, Zhao Y Biochem Genet. 2024; .

PMID: 38649557 DOI: 10.1007/s10528-024-10794-6.

Association of gene polymorphisms with serum lipid levels and the risk of type 2 diabetes mellitus in the Chinese Han population of central China.

Zeng Y, Wen S, Huan L, Xiong L, Zhong B, Wang P PeerJ. 2023; 11:e15226.

PMID: 37123009 PMC: 10135405. DOI: 10.7717/peerj.15226.

Genetic Variants Cause Neuroinflammation in Alzheimer's Disease.

Chen Y, Chang S, Lee Y, Ho W, Huang Y, Wu Y Int J Mol Sci. 2023; 24(4).

PMID: 36835494 PMC: 9962462. DOI: 10.3390/ijms24044085.

Alzheimer's Disease: An Updated Overview of Its Genetics.

Andrade-Guerrero J, Santiago-Balmaseda A, Jeronimo-Aguilar P, Vargas-Rodriguez I, Cadena-Suarez A, Sanchez-Garibay C Int J Mol Sci. 2023; 24(4).

PMID: 36835161 PMC: 9966419. DOI: 10.3390/ijms24043754.

References

Omoumi A, Fok A, Greenwood T, Sadovnick A, Feldman H, Hsiung G . Evaluation of late-onset Alzheimer disease genetic susceptibility risks in a Canadian population. Neurobiol Aging. 2013; 35(4):936.e5-12. DOI: 10.1016/j.neurobiolaging.2013.09.025. View

Fennema-Notestine C, Panizzon M, Thompson W, Chen C, Eyler L, Fischl B . Presence of ApoE ε4 allele associated with thinner frontal cortex in middle age. J Alzheimers Dis. 2011; 26 Suppl 3:49-60. PMC: 3302177. DOI: 10.3233/JAD-2011-0002. View

Mirra S, HEYMAN A, McKeel D, SUMI S, Crain B, Brownlee L . The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer's disease. Neurology. 1991; 41(4):479-86. DOI: 10.1212/wnl.41.4.479. View

Li W, Qin W, Liu H, Fan L, Wang J, Jiang T . Subregions of the human superior frontal gyrus and their connections. Neuroimage. 2013; 78:46-58. DOI: 10.1016/j.neuroimage.2013.04.011. View

Roses A, Lutz M, Crenshaw D, Grossman I, Saunders A, Gottschalk W . TOMM40 and APOE: Requirements for replication studies of association with age of disease onset and enrichment of a clinical trial. Alzheimers Dement. 2013; 9(2):132-6. DOI: 10.1016/j.jalz.2012.10.009. View

Liu C, Liu C, Kanekiyo T, Xu H, Bu G . Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol. 2013; 9(2):106-18. PMC: 3726719. DOI: 10.1038/nrneurol.2012.263. View

Liu J, Zhao W, Ware E, Turner S, Mosley T, Smith J . DNA methylation in the APOE genomic region is associated with cognitive function in African Americans. BMC Med Genomics. 2018; 11(1):43. PMC: 5941603. DOI: 10.1186/s12920-018-0363-9. View

Shao Y, Shaw M, Todd K, Khrestian M, DAleo G, Barnard P . DNA methylation of TOMM40-APOE-APOC2 in Alzheimer's disease. J Hum Genet. 2018; 63(4):459-471. PMC: 6466631. DOI: 10.1038/s10038-017-0393-8. View

Valant V, Keenan B, Anderson C, Shulman J, Devan W, Ayres A . TOMM40 in Cerebral Amyloid Angiopathy Related Intracerebral Hemorrhage: Comparative Genetic Analysis with Alzheimer's Disease. Transl Stroke Res. 2013; 3(Suppl 1):102-12. PMC: 4054941. DOI: 10.1007/s12975-012-0161-1. View

10.

Gourley D, Pasha E, Kaur S, Haley A, Tanaka H . Association of Dementia and Vascular Risk Scores With Cortical Thickness and Cognition in Low-risk Middle-aged Adults. Alzheimer Dis Assoc Disord. 2020; 34(4):313-317. DOI: 10.1097/WAD.0000000000000392. View

11.

Aarons T, Bradburn S, Robinson A, Payton A, Pendleton N, Murgatroyd C . Dysregulation of BDNF in Prefrontal Cortex in Alzheimer's Disease. J Alzheimers Dis. 2019; 69(4):1089-1097. DOI: 10.3233/JAD-190049. View

12.

Payton A, Sindrewicz P, Pessoa V, Platt H, Horan M, Ollier W . A TOMM40 poly-T variant modulates gene expression and is associated with vocabulary ability and decline in nonpathologic aging. Neurobiol Aging. 2016; 39:217.e1-7. DOI: 10.1016/j.neurobiolaging.2015.11.017. View

13.

Davies G, Harris S, Reynolds C, Payton A, Knight H, Liewald D . A genome-wide association study implicates the APOE locus in nonpathological cognitive ageing. Mol Psychiatry. 2012; 19(1):76-87. PMC: 7321835. DOI: 10.1038/mp.2012.159. View

14.

Hyman B, Phelps C, Beach T, Bigio E, Cairns N, Carrillo M . National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease. Alzheimers Dement. 2012; 8(1):1-13. PMC: 3266529. DOI: 10.1016/j.jalz.2011.10.007. View

15.

Thal D, Rub U, Orantes M, Braak H . Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology. 2002; 58(12):1791-800. DOI: 10.1212/wnl.58.12.1791. View

16.

Braak H, Braak E . Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991; 82(4):239-59. DOI: 10.1007/BF00308809. View

17.

Riddell D, Zhou H, Atchison K, Warwick H, Atkinson P, Jefferson J . Impact of apolipoprotein E (ApoE) polymorphism on brain ApoE levels. J Neurosci. 2008; 28(45):11445-53. PMC: 6671315. DOI: 10.1523/JNEUROSCI.1972-08.2008. View

18.

Tulloch J, Leong L, Thomson Z, Chen S, Lee E, Keene C . Glia-specific APOE epigenetic changes in the Alzheimer's disease brain. Brain Res. 2018; 1698:179-186. PMC: 6388639. DOI: 10.1016/j.brainres.2018.08.006. View

19.

Minta K, Brinkmalm G, Janelidze S, Sjodin S, Portelius E, Stomrud E . Quantification of total apolipoprotein E and its isoforms in cerebrospinal fluid from patients with neurodegenerative diseases. Alzheimers Res Ther. 2020; 12(1):19. PMC: 7020540. DOI: 10.1186/s13195-020-00585-7. View

20.

Cao J, El Gaamouch F, Meabon J, Meeker K, Zhu L, Zhong M . ApoE4-associated phospholipid dysregulation contributes to development of Tau hyper-phosphorylation after traumatic brain injury. Sci Rep. 2017; 7(1):11372. PMC: 5595858. DOI: 10.1038/s41598-017-11654-7. View