AACG Oral 11: DISCOVERING THE NON-PENETRANT: IDENTIFICATION OF COGNITIVELY HEALTHY APOE E4 HOMOZYGOTES

摘要

APOE ε4/ε4 homozygosity is the strongest genetic risk factor for late onset Alzheimer's disease (LOAD), increasing lifetime risk from 11% for males and 14% for females to 51% and 68%, respectively. In some cases, however, ε4 homozygotes live well beyond the expected age of onset without developing typical signs and symptoms, suggesting protection or reduced penetrance to increased genetic risk. These protected or 'resilient' individuals are difficult to find and validate, given genetic testing of healthy elderly individuals is rare. Even rarer is the availability of detailed pheno-typic and cognitive function data alongside an APOE ε4 genotype to confirm the absence of cognitive decline. Here we present a scalable screening approach to identify cognitively healthy APOE ε4 homozygotes among ~15,000 elderly participants of the ASPirin in Reducing Events in the Elderly (ASPREE) biobank. We present the baseline characteristics of 22 such individuals aged over 75 years who were identified through our first round of screening of 2,200 ASPREE biobank participants. We present demographic and clinical characteristics of these resilient individuals who had no prior diagnosis of dementia at study enrolment and a score of >77 in the Modified Mini-Mental State Examination (3MS). A cohort of unaffected APOE ε4 homozygotes will be formed to enable future studies of penetrance and genetic resilience, an approach that will be expanded to other genes used in predictive testing. This is the first step in studying the genetic and environmental factors in individuals who do not develop disease despite a significant genetic predisposition.