title: An Alzheimer's Disease Genetic Risk Score Predicts Longitudinal Thinning of Hippocampal Complex Subregions in Healthy Older Adults.
abstract: Variants at 21 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 the 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 2-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 (WRS) approach. Each score included APOE (apolipoprotein E), CLU (clusterin), PICALM (phosphatidylinositol binding clathrin assembly protein), and family history of AD. Both unweighted risk score (URS) and WRS correlated strongly with the percentage 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 control subjects can be useful to maximize the ability to detect an effect on a longitudinal neuroimaging endpoint, like hippocampal complex cortical thickness.
authors.affiliation: Neuroscience Interdepartmental Graduate Program, University of California, Los Angeles, Los Angeles, California 90095; Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, California 90095.
authors.forename: Theresa M
authors.identifier: 0000-0002-2036-3496
authors.initials: TM
authors.lastname: Harrison
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles , Los Angeles, California 90095.
authors.forename: Zanjbeel
authors.initials: Z
authors.lastname: Mahmood
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles , Los Angeles, California 90095.
authors.forename: Edward P
authors.initials: EP
authors.lastname: Lau
authors.affiliation: Staglin IMHRO Center for Cognitive Neuroscience, University of California, Los Angeles , Los Angeles, California 90095.
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Karacozoff
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles , Los Angeles, California 90095.
authors.forename: Alison C
authors.identifier: 0000-0002-8322-0118
authors.initials: AC
authors.lastname: Burggren
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, California 90095; Semel Institute for Neuroscience and Human Behaviors, University of California, Los Angeles, Los Angeles, California 90095; UCLA Longevity Center, University of California, Los Angeles, Los Angeles, California 90095.
authors.forename: Gary W
authors.initials: GW
authors.lastname: Small
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, California 90095; Staglin IMHRO Center for Cognitive Neuroscience, University of California, Los Angeles, Los Angeles, California 90095; Semel Institute for Neuroscience and Human Behaviors, University of California, Los Angeles, Los Angeles, California 90095.
authors.forename: Susan Y
authors.initials: SY
authors.lastname: Bookheimer
mesh_terms: D000375:Aging / Q000235:genetics* / Q000473:pathology* / Q000523:psychology; D000544:Alzheimer Disease / Q000000981:diagnostic imaging* / Q000235:genetics* / Q000523:psychology; D001057:Apolipoproteins E / Q000235:genetics; D002986:Clinical Trials as Topic; D051152:Clusterin / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D006624:Hippocampus / Q000000981:diagnostic imaging* / Q000473:pathology; D006801:Humans; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008297:Male; D008609:Mental Status Schedule; D008875:Middle Aged; D034041:Monomeric Clathrin Assembly Proteins / Q000235:genetics; D020412:Multifactorial Inheritance; D015999:Multivariate Analysis; D009483:Neuropsychological Tests; D009929:Organ Size; D062706:Prodromal Symptoms; D044465:White People
chemical_list: D001057:Apolipoproteins E; C495242:CLU protein, human; D051152:Clusterin; D034041:Monomeric Clathrin Assembly Proteins; C439003:PICALM protein, human
keywords: clinical trials; normal aging; polygenic risk score; preclinical Alzheimer's disease; structural MRI