Our results indicate that APOE and other previously validated loci for AD affect clinical diagnosis of AD and neuroimaging measures associated with disease. These findings suggest that sequence variants that modulate AD risk in recent GWASs may act through their influence on neuroimaging measures. Furthermore, our genetic analysis of neuroimaging traits identified BIN1 and CNTN5 as genes of heightened interest for their relationship with AD, prioritizing these targets for further study.
Among non-APOE AD loci that have emerged from GWASs, only the CR1 locus was significantly associated with disease status. Failure to extend previous findings for CLU and PICALM is likely because of the limited sample size of the ADNI cohort. Nonetheless, our genetic risk score was associated in a dose-dependent manner with clinical diagnosis and clearly outperformed individual SNP models. This finding is consistent with a biological role for at least some, if not all, of the incorporated loci. Interestingly, the inclusion of previously un-validated loci at BIN1 and CNTN5 (albeit supported by P < 1 × 10−5 in the previous GWASs) did not degrade the performance of the genetic score, further supporting a role for these loci in AD.
The genetic risk score quartiles correlated with every examined neuroimaging trait, consistent with the underlying hypothesis that these traits are, at least in part, determined by genome sequence at these loci. This finding offers parallel evidence that the included genes influence biological processes underlying development of AD.
Among GWAS-validated loci, APOE, PICALM, and CR1 genotypes influenced neuroimaging measures, whereas CLU did not. The robust effect of APOE was seen across all measures except WML volume, whereas the effect of PICALM was restricted to hippocampal volume and ECT, and the effect of CR1 was restricted to ECT. These findings raise the possibility that the biological effects of these genes may be relatively confined to 1 neuroimaging trait and hence may offer clues to the mechanisms through which particular genetic variants might influence AD risk.
Two loci, identified as GWAS-promising in previous AD studies, showed association with neuroimaging measures. CNTN5
variation was associated with WML, ECT, parahippocampal gyrus thickness, and TPT, whereas BIN1
was associated with ECT and TPT. These genes encode proteins involved in neurite growth,32
presynaptic cyto-skeleton structure integrity,31
and fission of synaptic vesicles.33
Brain-specific isoforms and expression patterns have been reported for BIN34
Although our results for these loci can only be considered preliminary, they may help prioritize targets for future genetic studies and GWASs in AD, particularly given their association with neuroimaging correlates of AD and disease status.
The crucial limitations of our study arise from its small sample size. Because of restricted power, we were forced to constrain our analysis to SNPs and loci with high prior probabilities of association with AD and imaging traits, based on their status as either validated (APOE, CLU, PICALM, and CR1) or promising (CNTN5 and BIN1) genetic risk factors. Our power also limits the conclusions we can draw about observed differential genetic effects on neuroimaging traits. For example, although the absence of an effect of CR1 on hippocampal volume may reflect important biology, it is also possible that an effect could be detected with increased power.
In summary, we have shown that established and candidate AD genes have a role in 6 neuroimaging traits linked to AD. Furthermore, 2 promising genes from prior AD GWASs, CNTN5 and BIN1, are also associated with these neuroimaging measures, which heightens their interest as novel AD loci. These genes may act selectively, influencing only 1 or a few established AD-related MRI measures. Future studies are required to replicate and expand these findings.