Is Peripheral BDNF Promoter Methylation a Preclinical Biomarker of Dementia?

Article type: Research Article

Authors: Fransquet, Peter D.^{a; b} | Ritchie, Karen^{c; d} | Januar, Vania^b | Saffery, Richard^b | Ancelin, Marie-Laure^c | Ryan, Joanne^{a; b; c; *}

Affiliations: [a] Biological Neuropsychiatry and Dementia Unit, School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia | [b] Epigenetics Group, Murdoch Childrens Research Institute, Royal Children’s Hospital, University of Melbourne, Parkville, Victoria, Australia | [c] Inserm U1061, Hospital La Colombiere & University Montpellier, Montpellier, France | [d] Center for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom

Correspondence: [*] Correspondence to: Joanne Ryan, School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia. Tel.: +61 3 9903 0200; E-mail: joanne.ryan@monash.edu.

Abstract: Brain-derived neurotrophic factor (BDNF) has been implicated in dementia. Preliminary evidence suggests that BDNF DNA methylation may be a diagnostic biomarker of dementia, but the potential pre-clinical utility remains unclear. Participants in the ESPRIT study were assessed for cognitive function and dementia (DSM-IV criteria) over 14 years. BDNF exon 1 promoter methylation was measured in blood at baseline (n = 769) and buccal samples during follow-up (n = 1062). Genotyping was carried out for several common BDNF SNPs, including Val66Met (rs6265) and APOE ɛ4. Multivariable logistic regression analyses determined the association between BDNF methylation and both prevalent and incident dementia. Adjustment for gender, age, education, APOE ɛ4 genotype, body mass index, depression, and type 2 diabetes, as well as possible effect modification by gender and genetic variation were also investigated. Weak evidence of an association between lower blood methylation and dementia was observed at one of 11 sites investigated (Δ–0.5%, 95% CI:–0.9,–0.04, p = 0.03, p = 0.22 adjusted for multiple comparisons). Buccal methylation at two other sites was associated with 14-year incident dementia cases prior to adjustment for multiple comparisons only, and the effect sizes were small (Δ+0.3%, OR:1.57, SE:0.30, p = 0.02, p = 0.14 adjusted and Δ–1.5%, OR:0.85, SE:0.06, p = 0.03, p = 0.14 adjusted). Genetic variation in the BDNF gene did not modify these associations, and no gender-specific effects were observed. There was only a weak correlation between blood and buccal BDNF log-methylation at two sites (both r=–0.11). There was no strong evidence that blood or buccal BDNF exon 1 promoter DNA methylation is associated with prevalent or incident dementia, and reported associations would not remain after adjustment for multiple testing.

Keywords: BDNF, biomarkers, blood, dementia, DNA methylation, epigenetics

DOI: 10.3233/JAD-190738

Journal: Journal of Alzheimer's Disease, vol. 73, no. 2, pp. 645-655, 2020