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

Ming Zhang^{1

2

3}, Allison A Dilliott⁴, Roaa Khallaf⁵, John F Robinson⁴, Robert A Hegele⁴, Michael Comishen⁵, Christine Sato³, Giuseppe Tosto^{6

7

8}, Christiane Reitz^{6

8

9}, Richard Mayeux^{6

7

8

9

10}, Peter St George-Hyslop³, Morris Freedman^{11

12}, Ekaterina Rogaeva³

Affiliations

¹ First Rehabilitation Hospital, School of Medicine, Tongji University, Shanghai, China.
² Collaborative Innovation Center for Brain Science, Tongji University, Shanghai, China.
³ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Ave, Toronto, ON, Canada.
⁴ Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
⁵ Department of Medicine, Division of Neurology, Baycrest Health Sciences, and University of Toronto, Toronto, ON, Canada.
⁶ Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, NY, USA.
⁷ The Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, NY, USA.
⁸ Department of Neurology, College of Physicians and Surgeons, Columbia University and the New York Presbyterian Hospital, 710 West 168th Street, New York, NY, USA.
⁹ Department of Epidemiology, Mailman School of Public Health, Columbia University, 722 West 168th Street, New York, NY, USA.
¹⁰ Department of Psychiatry, College of Physicians and Surgeons, Columbia University. 1051 Riverside Drive, New York, NY, USA.
¹¹ Department of Medicine, Division of Neurology, Baycrest Health Sciences, Mt. Sinai Hospital, and University of Toronto, Toronto, ON, Canada.
¹² Rotman Research Institute, Baycrest Health Sciences, Toronto, ON, Canada.

PMID: 31580390
PMCID: PMC6821163
DOI: 10.1093/brain/awz289

Case Reports

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

Ming Zhang et al. Brain. 2019.

. 2019 Nov 1;142(11):3375-3381.

doi: 10.1093/brain/awz289.

Authors

Affiliations

¹ First Rehabilitation Hospital, School of Medicine, Tongji University, Shanghai, China.
² Collaborative Innovation Center for Brain Science, Tongji University, Shanghai, China.
³ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Ave, Toronto, ON, Canada.
⁴ Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
⁵ Department of Medicine, Division of Neurology, Baycrest Health Sciences, and University of Toronto, Toronto, ON, Canada.
⁶ Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, NY, USA.
⁷ The Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, NY, USA.
⁸ Department of Neurology, College of Physicians and Surgeons, Columbia University and the New York Presbyterian Hospital, 710 West 168th Street, New York, NY, USA.
⁹ Department of Epidemiology, Mailman School of Public Health, Columbia University, 722 West 168th Street, New York, NY, USA.
¹⁰ Department of Psychiatry, College of Physicians and Surgeons, Columbia University. 1051 Riverside Drive, New York, NY, USA.
¹¹ Department of Medicine, Division of Neurology, Baycrest Health Sciences, Mt. Sinai Hospital, and University of Toronto, Toronto, ON, Canada.
¹² Rotman Research Institute, Baycrest Health Sciences, Toronto, ON, Canada.

PMID: 31580390
PMCID: PMC6821163
DOI: 10.1093/brain/awz289

Abstract

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.

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Figures

**Figure 1**
**Pedigree of the Ashkenazi family with monozygotic triplets.** Gender is masked. Age at time of sample collection is shown above the symbol. Age of onset, DNAm-age acceleration (AA) and genetic findings by ONDRISeq are indicated below the symbol.

See this image and copyright information in PMC

References

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

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

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