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IC‐P‐045: Weighted and unweighted genetic risk scores are associated with longitudinal cortical thinning of hippocampal complex subregions
Author(s) -
Harrison Theresa M.,
Lau Edward P.,
Mahmood Zanjbeel,
Burggren Alison C.,
Small Gary W.,
Bookheimer Susan Y.
Publication year - 2015
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2015.06.065
Subject(s) - endophenotype , allele , cohort , odds ratio , entorhinal cortex , family history , medicine , psychology , oncology , hippocampal formation , demography , genetics , biology , neuroscience , cognition , gene , sociology
Background:To date, 21 genetic loci have been identified where specific variants increase an individual’s risk for sporadic, late-onset Alzheimer Disease (AD). An important unresolved question is whether or not polygenic risk scores that use combinations of these risk loci increase power to detect changes in neuroimaging endophenotypes for AD. Furthermore, the optimal method to create polygenic risk scores is an active field of research. Methods: In a preliminary study, we acquired high-resolution structural images of the hippocampus in 47 healthy, older subjects. For 14 of these subjects, longitudinal two-year follow-up datawere also available. Unweighted andweighted genetic AD-risk scores were calculated for each subject. The unweighted risk score (URS)was the sumof family history ofAD (0 if negative history or 1 if positive history),APOE4 alleles (0,1, or 2), CLU risk alleles (0,1, or 2) and PICALM risk alleles (0,1, or 2). The weighted risk scores (WRS) usedpublishedodds ratios (OR) toweight the relative contribution of these risk factors before summing: positive family history OR1⁄42, APOE4 OR1⁄43, CLU minor allele OR1⁄40.9, PICALM minor allele OR1⁄40.9. Results: For the cross-sectional cohort, both URS and WRS showed no relationship to thickness in any hippocampal subregion. For the longitudinal cohort, URS and WRS correlated strongly to percent change in thickness across the whole hippocampus (URS r1⁄4-0.85, p1⁄40.0001; WRS r1⁄4-0.63, p1⁄40.015), driven by strong relationships in the entorhinal cortex (URS r1⁄4-0.66, p1⁄40.01; WRS r1⁄4-0.73, p1⁄40.003) and CA23/dentate gyrus (URS r1⁄4-0.66, p1⁄40.01; WRS r1⁄4-0.65, p1⁄40.01), two anterior subregions. In a multiple regression including age and sex as predictors, models with URS (beta1⁄4-2.16, p1⁄40.0003) and WRS (beta1⁄47.01, p1⁄40.014) predicting percent change in thickness across the whole hippocampus were significant (URS model p1⁄40.009; WRS model p1⁄40.03). Conclusions: 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. Our findings also show that the relationships between our polygenic risk score and hippocampal thinning are not mediated by weighting risk score components with published ORs.