Association of Acquired and Heritable Factors With Intergenerational Differences in Age at Symptomatic Onset of Alzheimer Disease Between Offspring and Parents With Dementia

• Authors: Gregory S. Day, Washington University in St. Louis; Carlos Cruchaga, Washington University in St. Louis; Thomas Wingo, Emory University; Suzanne E. Schindler, Washington University in St. Louis; Dean Coble, Washington University in St. Louis; John C. Morris, Washington University in St. Louis
• Journal Title: JAMA Network Open
• Volume: Volume 2, Number 10
• Publisher: JAMA Network | 2019-10-01
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1001/jamanetworkopen.2019.13491
• Subjects: Biology, Genetics; Psychology, Clinical
• Keywords: acquired factors; heritable factors; genetics; intergenerational difference; age at symptomatic onset; Alzheimer disease; family history; dementia; early onset

Abstract

Question What are the associations of acquired and heritable factors with intergenerational differences in age at symptomatic onset (AAO) of Alzheimer disease (AD) among offspring of parents with AD? Findings In this cohort study including 164 participants with symptomatic AD and a parental history of dementia, the factors of parental inheritance, more years of education, and retrospective determination of AAO were associated with an earlier-than-expected AAO of AD; parental history of early-onset dementia, APOE ε4 allele status, and hypertension were associated with a later-than-expected AAO of AD. Missense or frameshift variants within genes associated with AD pathogenesis were more common in participants with greater unexplained variability in intergenerational AAO of AD. Meaning Acquired and heritable factors were associated with a substantial proportion of variability in intergenerational AAO of AD.