Epigenetic scores of blood-based proteins as biomarkers of general cognitive function and brain health

Background Blood-based biomarkers of brain health could provide a cost-effective contribution to detecting individuals at risk of dementia. Epigenetic scores (EpiScores) for blood protein levels have previously associated with several disease outcomes and measures of brain health, however this has typically been limited to single EpiScore analyse. Results Using 84 protein EpiScores as candidate biomarkers, associations with general cognitive function (both cross-sectionally and longitudinally) were tested in three independent cohorts: Generation Scotland (GS), and the Lothian Birth Cohorts of 1921 and 1936 (LBC1921 and LBC1936, respectively). A meta-analysis of general cognitive functioning results in all three cohorts identified 18 EpiScore associations (absolute meta-analytic standardised estimates ranged from 0.03 to 0.14, median of 0.04, FDR P<0.05). Several associations were also observed between EpiScores and global brain volumetric measures in the LBC1936. An EpiScore for the S100A9 protein (a known Alzheimer disease biomarker) was associated with general cognitive functioning (meta-analytic standardised beta: -0.06, P = 1.3 x 10-9), and with time-to-dementia in GS (Hazard ratio: 1.24, 95% confidence interval 1.08 - 1.44, P = 0.003), but not in LBC1936 (Hazard ratio: 1.11, P = 0.32). Conclusions EpiScores might make a contribution to the risk profile of poor general cognitive function and global brain health, and risk of dementia, however these scores require replication in further studies. ### Competing Interest Statement R.E.M is an advisor to the Epigenetic Clock Development Foundation, and Optima partners. R.F.H. has received consultant fees from Illumina and Optima partners. D.A.G. has received consultant fees from, and is currently employed in part-time capacity, by Optima Partners. D.L.McC. and is currently employed in part-time capacity, by Optima Partners. All other authors declare no competing interest. ### Funding Statement This research was funded in whole, or in part, by the Wellcome Trust \[104036/Z/14/Z, 21843/Z/15/Z, 108890/Z/15/Z]. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission H.M.S and D.A.G. are students on the Translational Neuroscience PhD programme funded by Wellcome [21843/Z/19/Z, 108890/Z/15/Z]. R.F.H is supported through a MRC IEU Short-term Fellowship. R.E.M is supported by Alzheimers Society major project grant AS-PG-19b-010. Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates (CZD/16/6) and the Scottish Funding Council (HR03006). Genotyping and DNA methylation profiling of the GS samples was carried out by the Genetics Core Laboratory at the Edinburgh Clinical Research Facility, Edinburgh, Scotland and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award STratifying Resilience and Depression Longitudinally (STRADL; Reference 104036/Z/14/Z). The DNA methylation data assayed for Generation Scotland was partially funded by a 2018 NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation (Ref: 27404; awardee: Dr David M Howard) and by a JMAS SIM fellowship from the Royal College of Physicians of Edinburgh (Awardee: Dr Heather C Whalley). LBC1921 was supported by the UKs Biotechnology and Biological Sciences Research Council (BBSRC), The Royal Society, and The Chief Scientist Office of the Scottish Government. LBC1936 is supported by the BBSRC, and the Economic and Social Research Council [BB/W008793/1\] (which supports SEH), Age UK (Disconnected Mind project), the Milton Damerel Trust, and the University of Edinburgh. SRC is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (221890/Z/20/Z). Methylation typing in the LBCs was supported by Centre for Cognitive Ageing and Cognitive Epidemiology (Pilot Fund award), Age UK, The Wellcome Trust Institutional Strategic Support Fund, The University of Edinburgh, and The University of Queensland. JMW is supported by the Dementia Research Institute funded by the UK Medical Research Council, Alzheimers Society and Alzheimers Research UK. MVH is supported by the Row Fogo Charitable Trust; SMM is supported by Age UK and the BBSRC. KMG was supported by an MRC University Unit grant to the MRC Human Genetics Unit. DSM PhD Fellowship was funded by the Royal College of Psychiatrists and the Masonic Charitable Foundation. JPB is supported by a MRC UKRI Programme Grant MR/X003434/1. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All components of Generation Scotland (GS) received ethical approval from the NHS Tayside Committee on Medical Research Ethics (REC Reference Number: 05/S1401/89). GS has also been granted Research Tissue Bank status by the East of Scotland Research Ethics Service (REC Reference Number: 20-ES-0021), providing generic ethical approval for a wide range of uses within medical research. Ethics permission for the Lothian Birth Cohort 1936 (LBC1936) was obtained from the Multi-Centre Research Ethics Committee for Scotland (Wave 1: MREC/01/0/56), the Lothian Research Ethics Committee (Wave 1: LREC/2003/2/29), and the Scotland A Research Ethics Committee (Waves 2, 3, 4 & 5: 07/MRE00/58). Ethics permission for the Lothian Birth Cohort 1921 (LBC1921) was obtained from the Lothian Research Ethics Committee (Wave 1: LREC/1998/4/183; Wave 2: LREC/2003/7/23; Wave 3: LREC1702/98/4/183) and the Scotland A Research Ethics Committee (Wave 4: 10/S1103/6; Wave 5: 10/MRE00/87). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The source datasets from the cohorts that were analysed during the current study are not publicly available due to them containing information that could compromise participant consent and confidentiality. Data can be obtained from the data owners. Instructions for accessing Generation Scotland data can be found here: https://www.ed.ac.uk/generation-scotland/for-researchers/access; the GS Access Request Form can be downloaded from this site. Completed request forms must be sent to access@generationscotland.org to be approved by the Generation Scotland Access Committee. According to the terms of consent for GS participants, access to data must be reviewed by the GS Access Committee. Instructions for accessing Lothian Birth Cohort data, alongside a Data Request Form template, Data Summary Tables and Data Dictionaries can be found here: https://www.ed.ac.uk/lothian-birth-cohorts/data-access-collaboration.