From polygenic scores to precision medicine in Alzheimer’s Disease: A systematic review

Background: Late-onset Alzheimer’s Disease (AD) is highly heritable. The effect of many common genetic variants, single nucleotide polymorphisms (SNPs) confer risk. Variants are clustered in areas of biology, notably immunity and inflammation, cholesterol metabolism, endocytosis and ubiquitination. Polygenic scores (PRS), which weight the sum of an individual’s risk alleles, have been used to draw inferences about the pathological processes underpinning AD. Objective: This paper aims to systematically review how AD PRS are being used to study a range of outcomes and phenotypes related to neurodegeneration. Methods: We searched the literature from July 2008-July 2018 following PRISMA guidelines. Results: 57 studies met criteria. The AD PRS can distinguish AD cases from controls. The ability of AD PRS to predict conversion from Mild Cognitive Impairment (MCI) to AD was less clear. There was strong evidence of association between AD PRS and cognitive impairment. AD PRS were correlated with a number of biological phenotypes associated with AD pathology, such as neuroimaging changes and amyloid and tau measures. Pathway-specific polygenic scores were also associated with AD-related biologically relevant phenotypes. Conclusion: PRS can predict AD effectively and are associated with cognitive impairment. There is also evidence of association between AD PRS and other phenotypes relevant to neurodegeneration. The associations between pathway specific polygenic scores and phenotypic changes may allow us to define the biology of the disease in individuals and indicate who may benefit from specific treatments. Longitudinal cohort studies are required to test the ability of PGS to delineate pathway-specific disease activity