Abstract
BackgroundAlzheimer’s disease (AD) is an international health concern that has a devastating effect on patients and families. While several genetic risk factors for AD have been identified much of the genetic variance in AD remains unexplained. There are limited published assessments of the familiality of Alzheimer’s disease. Here we present the largest genealogy-based analysis of AD to date.MethodsWe assessed the familiality of AD in The Utah Population Database (UPDB), a population-based resource linking electronic health data repositories for the state with the computerized genealogy of the Utah settlers and their descendants. We searched UPDB for significant familial clustering of AD to evaluate the genetic contribution to disease. We compared the Genealogical Index of Familiality (GIF) between AD individuals and randomly selected controls and estimated the Relative Risk (RR) for a range of family relationships. Finally, we identified pedigrees with a significant excess of AD deaths.ResultsThe GIF analysis showed that pairs of individuals dying from AD were significantly more related than expected. This excess of relatedness was observed for both close and distant relationships. RRs for death from AD among relatives of individuals dying from AD were significantly increased for both close and more distant relatives. Multiple pedigrees had a significant excess of AD deaths.ConclusionsThese data strongly support a genetic contribution to the observed clustering of individuals dying from AD. This report is the first large population-based assessment of the familiality of AD mortality and provides the only reported estimates of relative risk of AD mortality in extended relatives to date. The high-risk pedigrees identified show a true excess of AD mortality (not just multiple cases) and are greater in depth and width than published AD pedigrees. The presence of these high-risk pedigrees strongly supports the possibility of rare predisposition variants not yet identified.
Highlights
Alzheimer’s disease (AD) is the most common dementing disease and a pressing international healthcare concern affecting 24 to 35 million people worldwide
Case Classification AD as a coded cause-of-death first appeared in the International Classification of Disease (ICD) Revision 9, and AD appears in ICD Revision 10 We only considered individuals to have had AD if their death certificate included AD as a primary or contributing cause-of-death, as shown in Table
Almost 4,000 individuals in the Utah Population Database (UPDB) with at least 3 generations of genealogy data and at least 12 of their 14 immediate ancestors included in the UPDB have a cause-ofdeath of AD on their death certificate
Summary
Alzheimer’s disease (AD) is the most common dementing disease and a pressing international healthcare concern affecting 24 to 35 million people worldwide. Results: The GIF analysis showed that pairs of individuals dying from AD were significantly more related than expected This excess of relatedness was observed for both close and distant relationships. This report is the first large population-based assessment of the familiality of AD mortality and provides the only reported estimates of relative risk of AD mortality in extended relatives to date. The high-risk pedigrees identified show a true excess of AD mortality (not just multiple cases) and are greater in depth and width than published AD pedigrees. The presence of these high-risk pedigrees strongly supports the possibility of rare predisposition variants not yet identified
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