Genetic and epigenetic study of an Alzheimer's disease family with monozygotic triplets

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 e4 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.