Peripheral DNA methylation of candidate Alzheimer’s disease risk genes and its associations with cognition, brain volume and amyloid-β burden
11 affiliations
- 1Centre for Precision Health, Edith Cowan University, 270 Joondalup Drive, Joondalup, WA 6027 Australia
- 2Collaborative Genomics and Translation Group, School of Medical and Health Sciences, Edith Cowan University, 270 Joondalup Drive, Joondalup, WA 6027 Australia
- 3Australian E-Health Research Centre, CSIRO, Underwood Ave, Floreat, WA 6010 Australia
- 4Australian E-Health Research Centre, CSIRO, 296 Herston Rd, Herston, QLD 4006 Australia
- 5Department of Molecular Imaging and Therapy and Centre for PET, Austin Health, 145 Studley Rd, Heidelberg, VIC 3084 Australia
- 6Australian E-Health Research Centre, CSIRO, 351 Royal Parade, Parkville, VIC 3052 Australia
- 7School of Psychological Sciences and Turner Institute for Brain and Mental Health, Monash University, Level 5, 18 Innovation Walk, Clayton Campus, Clayton, VIC 3800 Australia
- 8Florey Institute of Neuroscience and Mental Health, The University of Melbourne, 30 Royal Parade, Parkville, VIC 3052 Australia
- 9Cogstate Ltd, 367 Collins Street, Melbourne, VIC 3000 Australia
- 10Department of Psychiatry, University of Pittsburgh, 3811 O’Hara Street, Pittsburgh, PA 15213 USA
- 11Curtin Medical School, Curtin University, Kent St, Bentley, WA 6102 Australia
Abstract
Alzheimer’s disease (AD) is a growing major public health issue, affecting millions of people worldwide. Genome-wide association studies (GWAS) have identified over 50 loci associated with late-onset AD risk. However, most disease-associated variants are located in noncoding regions of the genome, making it difficult to elucidate exactly how disease risk is affected. Variants within noncoding regions can modulate disease risk through mechanisms such as gene expression regulation, which can be regulated by DNA methylation, which has, in recent years, been implicated in dementia and AD. This study utilised data from two well-characterised longitudinal studies, the Australian Imaging, Biomarker and Lifestyle (AIBL) study (n = 565) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI; n = 533), and aimed to investigate the association between peripheral blood DNA methylation at CpG sites located in previously implicated AD-risk genes and cognition, MRI volumetric measures and brain Aβ-amyloid (Aβ) burden. Analyses were undertaken across the preclinical to prodromal population as well as within subsets classified by clinical diagnosis and Aβ burden using two methods: all CpG sites within a candidate gene and a representative site from each gene region with the greatest variance (mean absolute deviation; MAD). We identified numerous associations in the AIBL cohort that remained significant after correction for the false discovery rate, although only one novel site was validated in the ADNI cohort. This was located within the gene body region of CR1 (cg00416522) and was associated with ventricle volume in cognitively unimpaired individuals with high brain Aβ burden. While this study’s results contribute to a growing literature that supports the role of epigenetic modifications in ageing and AD-related traits, they suggest that there are limited associations of peripheral DNA methylation with cognitive and neuroimaging traits in the a priori AD-risk genes that were screened in this study. Future meta-analyses across studies with larger cohort sizes and phenotypically rich datasets will help to confirm this finding and potentially elucidate further associations, while unbiased approaches are warranted and may uncover novel peripheral DNA methylation associations.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1038/s41598-026-64935-5.
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BibTeX
@article{milicic2026peripheral,
title = {{Peripheral DNA methylation of candidate Alzheimer’s disease risk genes and its associations with cognition, brain volume and amyloid-β burden}},
author = {Lidija Milicic and Michael Vacher and Pierrick Bourgeat and Vincent Doré and Rosita Shishegar and Paul Maruff and Colin L. Masters and Christopher C. Rowe and Victor L. Villemagne and Tenielle Porter and Simon M. Laws and Australian Imaging Biomarkers and Lifestyle (AIBL) Study and Alzheimer’s Disease Neuroimaging Initiative (ADNI)},
journal = {Scientific Reports},
year = {2026},
month = aug,
doi = {10.1038/s41598-026-64935-5},
url = {https://doi.org/10.1038/s41598-026-64935-5},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Peripheral DNA methylation of candidate Alzheimer’s disease risk genes and its associations with cognition, brain volume and amyloid-β burden
AU - Lidija Milicic
AU - Michael Vacher
AU - Pierrick Bourgeat
AU - Vincent Doré
AU - Rosita Shishegar
AU - Paul Maruff
AU - Colin L. Masters
AU - Christopher C. Rowe
AU - Victor L. Villemagne
AU - Tenielle Porter
AU - Simon M. Laws
AU - Australian Imaging Biomarkers and Lifestyle (AIBL) Study
AU - Alzheimer’s Disease Neuroimaging Initiative (ADNI)
PY - 2026
DA - 2026/08/03
JO - Scientific Reports
DO - 10.1038/s41598-026-64935-5
UR - https://doi.org/10.1038/s41598-026-64935-5
AB - Alzheimer’s disease (AD) is a growing major public health issue, affecting millions of people worldwide. Genome-wide association studies (GWAS) have identified over 50 loci associated with late-onset AD risk. However, most disease-associated variants are located in noncoding regions of the genome, making it difficult to elucidate exactly how disease risk is affected. Variants within noncoding regions can modulate disease risk through mechanisms such as gene expression regulation, which can be regulated by DNA methylation, which has, in recent years, been implicated in dementia and AD. This study utilised data from two well-characterised longitudinal studies, the Australian Imaging, Biomarker and Lifestyle (AIBL) study (n = 565) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI; n = 533), and aimed to investigate the association between peripheral blood DNA methylation at CpG sites located in previously implicated AD-risk genes and cognition, MRI volumetric measures and brain Aβ-amyloid (Aβ) burden. Analyses were undertaken across the preclinical to prodromal population as well as within subsets classified by clinical diagnosis and Aβ burden using two methods: all CpG sites within a candidate gene and a representative site from each gene region with the greatest variance (mean absolute deviation; MAD). We identified numerous associations in the AIBL cohort that remained significant after correction for the false discovery rate, although only one novel site was validated in the ADNI cohort. This was located within the gene body region of CR1 (cg00416522) and was associated with ventricle volume in cognitively unimpaired individuals with high brain Aβ burden. While this study’s results contribute to a growing literature that supports the role of epigenetic modifications in ageing and AD-related traits, they suggest that there are limited associations of peripheral DNA methylation with cognitive and neuroimaging traits in the a priori AD-risk genes that were screened in this study. Future meta-analyses across studies with larger cohort sizes and phenotypically rich datasets will help to confirm this finding and potentially elucidate further associations, while unbiased approaches are warranted and may uncover novel peripheral DNA methylation associations. Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1038/s41598-026-64935-5.
SN - 2045-2322
ER -