DNA Methylation in the Apolipoprotein-A1 Gene is Associated with Episodic Memory Performance in Healthy Older Individuals

Article type: Research Article

Authors: Lazarus, Jessica^{a; b} | Mather, Karen A.^c | Armstrong, Nicola J.^d | Song, Fei^{c; e; f} | Poljak, Anne^{b; c; e} | Thalamuthu, Anbupalam^c | Lee, Teresa^{c; f} | Kochan, Nicole A.^{c; f} | Brodaty, Henry^{c; g} | Wright, Margaret J.^h | Ames, David^{i; j} | Sachdev, Perminder S.^{c; f} | Kwok, John B.J.^{a; b; *}

Affiliations: [a] Neuroscience Research Australia, Sydney, NSW, Australia | [b] School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia | [c] Centre for Healthy Brain Aging, School of Psychiatry, University of New South Wales, Sydney, NSW, Australia | [d] School of Mathematics and Statistics, University of Sydney, Sydney, NSW, Australia | [e] Bioanalytical Mass Spectrometry Facility, University of New South Wales, Sydney, Australia | [f] Neuropsychiatric Institute (NPI), Prince of Wales Hospital, Sydney, NSW, Australia | [g] Dementia Collaborative Research Centre – Assessment and Better Care, University of New South Wales, Sydney, NSW, Australia | [h] QIMR Berghofer Medical Research Institute, Brisbane, Australia | [i] Department of Psychiatry, University of Melbourne, Australia | [j] National Ageing Research Institute, Melbourne, Australia

Correspondence: [*] Correspondence to: John B.J. Kwok, Neuroscience Research Australia, Barker St, Randwick, Sydney, NSW 2031, Australia. Tel.: +61 2 9399 1837; Fax: +61 2 9399 1005; E-mail: [email protected].

Abstract: Background:DNA methylation variation has been implicated in memory, cognitive performance, and dementia. Plasma apolipoprotein-A1 (ApoA1) levels may act as a biomarker of age-associated cognitive performance and decline. Objectives:To estimate the heritability of plasma ApoA1 protein levels; to examine DNA methylation variation within the APOA1 gene; and to investigate whether APOA1 methylation is associated with plasma ApoA1 levels and episodic memory performance. Method:Heritability of ApoA1 protein levels in Older Australian Twins Study (OATS) was assessed using structural equation modelling. APOA1 methylation levels were assayed in two cohorts of cognitively normal older individuals. The methylation status of 12 CpGs in 24 twin pairs from OATS was assayed using the Illumina 450K methylation array. Candidate CpGs were assayed in 454 individuals from Sydney Memory and Ageing Study (Sydney MAS) using pyrosequencing. Regression analyses assessed associations between APOA1 methylation levels, ApoA1 plasma levels, and memory performance. Results:No significant heritability was observed for ApoA1 protein levels. APOA1 candidate-gene analyses revealed CpG sites associated with memory performance in the twin study (p < 0.050). Replication of an association between methylation of a specific CpG (cg03010018) in APOA1 and memory performance was observed in Sydney MAS (β = −0.145, p = 0.010). Methylation of this CpG site was also significantly correlated with ApoA1 protein levels (β = 0.161, p = 0.019). However, no relationship between a composite memory domain score and methylation was observed (p = 0.389). Conclusion:Findings demonstrated that epigenetic control of APOA1 expression and DNA methylation levels are associated with episodic memory performance in older adults.

Keywords: Aging, apolipoprotein A1, DNA methylation, epigenomics, episodic memory

DOI: 10.3233/JAD-141314

Journal: Journal of Alzheimer's Disease, vol. 44, no. 1, pp. 175-182, 2015