title: Blood methylomic signatures of presymptomatic dementia in elderly subjects with type 2 diabetes mellitus.
abstract: Due to an aging population, the incidence of dementia is steadily rising. The ability to identify early markers in blood, which appear before the onset of clinical symptoms is of considerable interest to allow early intervention, particularly in "high risk" groups such as those with type 2 diabetes. Here, we present a longitudinal study of genome-wide DNA methylation in whole blood from 18 elderly individuals with type 2 diabetes who developed presymptomatic dementia within an 18-month period following baseline assessment and 18 age-, sex-, and education-matched controls who maintained normal cognitive function. We identified a significant overlap in methylomic differences between groups at baseline and follow-up, with 8 CpG sites being consistently differentially methylated above our nominal significance threshold before symptoms at baseline and at 18 months follow up, after a diagnosis of presymptomatic dementia. Finally, we report a significant overlap between DNA methylation differences identified in converters, only after they develop symptoms of dementia, with differences at the same loci in blood samples from patients with clinically diagnosed Alzheimer's disease compared with unaffected control subjects.
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, Devon, UK. Electronic address: k.lunnon@exeter.ac.uk.
authors.forename: Katie
authors.initials: K
authors.lastname: Lunnon
authors.affiliation: MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College, London, London, UK.
authors.forename: Rebecca G
authors.initials: RG
authors.lastname: Smith
authors.affiliation: The Joseph Sagol Neuroscience Center, Sheba Medical Center, Ramat Gan, Israel.
authors.forename: Itzik
authors.initials: I
authors.lastname: Cooper
authors.affiliation: The Joseph Sagol Neuroscience Center, Sheba Medical Center, Ramat Gan, Israel; Department of Neurology, Sheba Medical Center, Ramat Gan, Israel.
authors.forename: Lior
authors.initials: L
authors.lastname: Greenbaum
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, Devon, UK; MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College, London, London, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Mill
authors.affiliation: The Joseph Sagol Neuroscience Center, Sheba Medical Center, Ramat Gan, Israel; Department of Psychiatry, The Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: michal.beeri@mssm.edu.
authors.forename: Michal Schnaider
authors.initials: MS
authors.lastname: Beeri
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000097:blood / Q000175:diagnosis; D015415:Biomarkers / Q000097:blood; D019175:DNA Methylation / Q000235:genetics*; D003704:Dementia / Q000175:diagnosis* / Q000209:etiology / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000150:complications / Q000235:genetics*; D003937:Diagnosis, Differential; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D055106:Genome-Wide Association Study; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D012306:Risk; D013997:Time Factors
chemical_list: D015415:Biomarkers
keywords: Alzheimer's disease (AD); Biomarker; Blood; DNA methylation; Dementia; Epigenetics; Type 2 diabetes