PT - JOURNAL ARTICLE AU - Theresa M. Harrison AU - Zanjbeel Mahmood AU - Edward P. Lau AU - Alexandra M. Karacozoff AU - Alison C. Burggren AU - Gary W. Small AU - Susan Y. Bookheimer TI - An Alzheimer’s Disease Genetic Risk Score Predicts Longitudinal Thinning of Hippocampal Complex Subregions in Healthy Older Adults AID - 10.1523/ENEURO.0098-16.2016 DP - 2016 Jun 28 TA - eneuro PG - ENEURO.0098-16.2016 4099 - http://www.eneuro.org/content/early/2016/06/27/ENEURO.0098-16.2016.short 4100 - http://www.eneuro.org/content/early/2016/06/27/ENEURO.0098-16.2016.full AB - Variants at twenty-one genetic loci have been associated with an increased risk for Alzheimer’s disease (AD). An important unresolved question is whether multiple genetic risk factors can be combined to increase power to detect changes in neuroimaging biomarkers for AD. We acquired high-resolution structural images of the hippocampus in 66 healthy, older human subjects. For 45 of these subjects, longitudinal two-year follow-up data were also available. We calculated an additive AD genetic risk score for each participant and contrasted this with a weighted risk score approach. Each score included APOE, CLU, PICALM and family history of AD. Both unweighted (URS) and weighted (WRS) risk scores correlated strongly to percent change in thickness across the whole hippocampal complex (URS r=-0.40, p=0.003; WRS r=-0.25, p=0.048), driven by a strong relationship to entorhinal cortex thinning (URS r=-0.35, p=0.009; WRS r=-0.35, p=0.009). By contrast, at baseline the risk scores showed no relationship to thickness in any hippocampal complex subregion. These results provide compelling evidence that polygenic AD risk scores may be especially sensitive to structural change over time in regions affected early in AD, like the hippocampus and adjacent entorhinal cortex. This work also supports the paradigm of studying genetic risk for disease in healthy volunteers. Together, these findings will inform clinical trial design by supporting the idea that genetic prescreening in healthy controls can be useful to maximize the ability to detect an effect on a longitudinal neuroimaging endpoint, like hippocampal complex cortical thickness.Significance Statement: This is the first study to show a relationship between a genetic risk score (GRS) for Alzheimer’s disease (AD) and hippocampal thinning in healthy adults. We found that a GRS composed of AD risk factors that have been shown to relate to hippocampal structure or function in humans predicted thinning of the hippocampal complex. Our ability to interpret these findings is bolstered by the association of genetic risk with longitudinal atrophy as opposed to cross-sectional morphology, which might be driven by neurodevelopmental differences. This work has implications for clinical trials focused on preclinical subjects such that screening by polygenic risk might increase the ability to detect an effect of a drug in a trial where hippocampal integrity is an endpoint.