Polygenic risk score analysis of pathologically confirmed Alzheimer disease

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Polygenic risk score (PRS) analysis enhances the predictability of the diagnosis of Alzheimer disease (AD) over the use of just the apolipoprotein E (APOE) locus.1 In a recent PRS analysis, we showed that the area under the curve (AUC) in the recent genome‐wide association study (GWAS) was 0.79.1 However, the study samples in these cohorts were largely comprised of clinical cases of AD, and the diagnostic accuracy of these is not perfect, as recent clinical trial failures have highlighted.2 In addition, the majority of controls used in GWASs are sampled from a general population and are often underaged to develop AD. This diagnostic uncertainty has also been demonstrated by the observation of c9orf72 expansions (a locus causing frontotemporal dementia) within some of the clinical AD cohorts used in the generation of the GWAS and AD sequencing data.3
Having a better understanding of the diagnostic utility of PRS is of importance for two reasons: first, because it enables the accurate assessment of how much risk for disease there is still left to be found, and this is important in setting research goals; and second, because this type of analysis could be used in the refinement of inclusion criteria for clinical trials and eventually in clinical health care recommendations.
We have previously reported a GWAS in clinically characterized and neuropathologically confirmed samples of AD and matched controls4: in this analysis, we apply PRS to these pathological data to determine whether some of the “missing heritability” of AD is due to clinical misdiagnosis.

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