Age at onset of Alzheimer's disease is highly variable, and its modifiers (genetic or environmental) could act through epigenetic changes, such as DNA methylation at CpG sites. DNA methylation is also linked to ageing-the strongest Alzheimer's disease risk factor. DNA methylation age can be calculated using age-related CpGs and might reflect biological ageing. We conducted a clinical, genetic and epigenetic investigation of a unique Ashkenazi Jewish family with monozygotic triplets, two of whom developed Alzheimer's disease at ages 73 and 76, while the third at age 85 has no cognitive complaints or deficits in daily activities. One of their offspring developed Alzheimer's disease at age 50. Targeted sequencing of 80 genes associated with neurodegeneration revealed that the triplets and the affected offspring are heterozygous carriers of the risk APOE ε4 allele, as well as rare substitutions in APP (p.S198P), NOTCH3 (p.H1235L) and SORL1 (p.W1563C). In addition, we catalogued 52 possibly damaging rare variants detected by NeuroX array in affected individuals. Analysis of family members on a genome-wide DNA methylation chip revealed that the DNA methylation age of the triplets was 6-10 years younger than chronological age, while it was 9 years older in the offspring with early-onset Alzheimer's disease, suggesting accelerated ageing.
Keywords: Alzheimer's disease; DNA methylation; ageing; monozygotic triplets.
© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: email@example.com.
The effect of APOE and other common genetic variants on the onset of Alzheimer's disease and dementia: a community-based cohort study.Lancet Neurol. 2018 May;17(5):434-444. doi: 10.1016/S1474-4422(18)30053-X. Epub 2018 Mar 16. Lancet Neurol. 2018. PMID: 29555425
Rare Genetic Variant in SORL1 May Increase Penetrance of Alzheimer's Disease in a Family with Several Generations of APOE-ɛ4 Homozygosity.J Alzheimers Dis. 2017;56(1):63-74. doi: 10.3233/JAD-160091. J Alzheimers Dis. 2017. PMID: 27911290 Free PMC article.
The Contribution and Therapeutic Potential of Epigenetic Modifications in Alzheimer's Disease.Front Neurosci. 2018 Sep 19;12:649. doi: 10.3389/fnins.2018.00649. eCollection 2018. Front Neurosci. 2018. PMID: 30283297 Free PMC article. Review.
DNA methylation in the APOE genomic region is associated with cognitive function in African Americans.BMC Med Genomics. 2018 May 8;11(1):43. doi: 10.1186/s12920-018-0363-9. BMC Med Genomics. 2018. PMID: 29739406 Free PMC article.
Dementia -- Caring, Ethics, Ethnical and Economical Aspects: A Systematic Review [Internet].Stockholm: Swedish Council on Health Technology Assessment (SBU); 2008 Jun. SBU Assessment No. 172. Swedish Council on Health Technology Assessment (SBU). 2008. PMID: 28876770 Free Books & Documents. Review.