DNA Methylation Analysis of Candidate Genes Associated with Dementia in Peripheral Blood

Abstract

Aim: To investigate whether genes implicated in dementia pathogenesis are differently methylated in peripheral blood. Materials&methods: Participants included 160 cognitively healthy individuals aged 70+ years: 73 who were subsequently diagnosed with dementia and 87 controls matched on age, gender, education, smoking and baseline cognition. A total of 49 participants also provided blood samples at diagnosis. Blood DNA methylation of APOE, APP, BDNF, PIN1, SNCA and TOMM40 was examined. Results: A total of 56 of 299 probes were differentially methylated in dementia compared with controls and 39 probes prior to diagnosis. The greatest effect size was in APP (cg19423170, Δ-8.32%, adjusted p = 0.009 at diagnosis; cg19933173, Δ-4.18%, adjusted p <xs 0.0001 prediagnosis). Conclusion: Genes implicated in dementia pathogenesis show differential blood methylation in dementia, even prior to diagnosis.

Keywords::

• APOE
• APP
• BDNF
• biomarker
• blood
• dementia
• DNA methylation
• PIN1
• SNCA
• TOMM40

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/suppl/10.2217/epi-2020-0236

Acknowledgments

The authors acknowledge the dedicated and skilled staff in Australia and the USA involved in the ASPREE cohort. The authors also are most grateful to the ASPREE participants, who so willingly volunteered for this study and the general practitioners and staff of the medical clinics who cared for the participants.

Financial&competing interests disclosure

The work was supported by the National Institute on Aging and the National Cancer Institute at the National Institutes of Health (U01AG029824); the National Health and Medical Research Council (NHMRC) of Australia (334047 and 1127060); Monash University and the Victorian Cancer Agency. J Ryan is funded by an NHMRC Dementia Research Leader Fellowship (APP1135727). PD Fransquet is gratefully funded by RTP stipend PhD scholarship, awarded by Monash University and the Australian Government. A Murray reports receiving consulting fees from Alkahest, Inc. and reports grants from National Institute on Aging. RC Shah reports grants for clinical research regarding dementia and Alzheimer’s disease from National Institutes of Health, the Centers for Medicare and Medicaid Services, the Department of Defense and the Illinois Department of Public Health; being a noncompensated board member of the Alzheimer’s Association – Illinois Chapter; and, being the site principal investigator or subinvestigator for clinical trials for which his institution (Rush University Medical Center) is compensated (Amylyx Pharmaceuticals, Inc., Eli Lilly&Co., Inc., Genentech, Inc., Merck&Co, Inc., Navidea Biopharmaceuticals, Novartis Pharmaceuticals, Inc., Roche Holdings AG and Takeda Development Center Americas, Inc.). The funders had no role in the study design; collection, analysis and interpretation of data; writing of the report; and decision to submit the article for publication. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Data sharing statement

The authors certify that this manuscript reports original clinical trial data. The data that support the findings of this study are available from the ASPREE principle investigators, but restrictions apply to the availability of these data, which were used under license for the current study and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of the ASPREE principle investigators through the web site (www.ASPREE.org). Data will be shared with researchers assessed upon request, for use in epigenetic analysis. If approved data will be made available through a web-based data portal safe haven at Monash University, Australia.

Ethical conduct of research

The ASPREE study was approved by Monash Human Ethics Committee (2006/745M), all participants gave informed consent. This DNA methylation substudy was approved by The Alfred Human Ethics Committee (Project 448/16). The study was conducted in accordance with the Declaration of Helsinki 2008 revision, NHMRC Guidelines on Human Experimentation, the federal patient privacy (HIPAA) law, the International Conference of Harmonisation Guidelines for Good Clinical Practice and the Code of Federal Regulations.

Additional information

Funding

The work was supported by the National Institute on Aging and the National Cancer Institute at the National Institutes of Health (U01AG029824); the National Health and Medical Research Council (NHMRC) of Australia (334047 and 1127060); Monash University and the Victorian Cancer Agency. J Ryan is funded by an NHMRC Dementia Research Leader Fellowship (APP1135727). PD Fransquet is gratefully funded by RTP stipend PhD scholarship, awarded by Monash University and the Australian Government. A Murray reports receiving consulting fees from Alkahest, Inc. and reports grants from National Institute on Aging. RC Shah reports grants for clinical research regarding dementia and Alzheimer’s disease from National Institutes of Health, the Centers for Medicare and Medicaid Services, the Department of Defense and the Illinois Department of Public Health; being a noncompensated board member of the Alzheimer’s Association – Illinois Chapter; and, being the site principal investigator or subinvestigator for clinical trials for which his institution (Rush University Medical Center) is compensated (Amylyx Pharmaceuticals, Inc., Eli Lilly&Co., Inc., Genentech, Inc., Merck&Co, Inc., Navidea Biopharmaceuticals, Novartis Pharmaceuticals, Inc., Roche Holdings AG and Takeda Development Center Americas, Inc.). The funders had no role in the study design; collection, analysis and interpretation of data; writing of the report; and decision to submit the article for publication. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.