A comprehensive analysis of methods for assessing polygenic burden on Alzheimer’s disease pathology and risk beyond APOE

Abstract

Genome-wide association studies have identified dozens of loci that alter the risk to develop Alzheimer’s disease. However, with the exception of the APOE-ε4 allele, most variants bear only little individual effect and have, therefore, limited diagnostic and prognostic value. Polygenic risk scores aim to collate the disease risk distributed across the genome in a single score. Recent works have demonstrated that polygenic risk scores designed for Alzheimer’s disease are predictive of clinical diagnosis, pathology confirmed diagnosis and changes in imaging biomarkers. Methodological innovations in polygenic risk modelling include the polygenic hazard score, which derives effect estimates for individual single nucleotide polymorphisms from survival analysis, and methods that account for linkage disequilibrium between genomic loci. In this work, using data from the Alzheimer’s disease neuroimaging initiative, we compared different approaches to quantify polygenic disease burden for Alzheimer’s disease and their association (beyond the APOE locus) with a broad range of Alzheimer’s disease-related traits: cross-sectional CSF biomarker levels, cross-sectional cortical amyloid burden, clinical diagnosis, clinical progression, longitudinal loss of grey matter and longitudinal decline in cognitive function. We found that polygenic scores were associated beyond APOE with clinical diagnosis, CSF-tau levels and, to a minor degree, with progressive atrophy. However, for many other tested traits such as clinical disease progression, CSF amyloid, cognitive decline and cortical amyloid load, the additional effects of polygenic burden beyond APOE were of minor nature. Overall, polygenic risk scores and the polygenic hazard score performed equally and given the ease with which polygenic risk scores can be derived; they constitute the more practical choice in comparison with polygenic hazard scores. Furthermore, our results demonstrate that incomplete adjustment for the APOE locus, i.e. only adjusting for APOE-ε4 carrier status, can lead to overestimated effects of polygenic scores due to APOE-ε4 homozygous participants. Lastly, on many of the tested traits, the major driving factor remained the APOE locus, with the exception of quantitative CSF-tau and p-tau measures.

Association between polygenic risk score of Alzheimer’s disease and plasma phosphorylated tau in individuals from the Alzheimer’s Disease Neuroimaging Initiative

“…Possible explanations are differences in diagnostic/disease stage, and sometimes also differences in genetic variants included in the PRSs. Importantly, our results in plasma replicate a previous report in CSF within the same cohort [ 16 ]. Moreover, we included three versions of PRSs and they performed relatively similar.…”

“…So far, studies of the relation between AD-PRSs and plasma p-tau181 are lacking. Previous CSF-based results of most relevance for comparison with our plasma-based results are those presented in a recent study of polygenic burden on AD pathology in ADNI [ 16 ]. Similar to our finding, the authors reported that CSF p-tau181 was independently (after correction for APOE ) associated with the 31-SNP polygenic hazard score (PHS) (including APOE effects) used in our study.…”

“…Moreover, we included three versions of PRSs and they performed relatively similar. We also included the PHS, which was the polygenic score that performed best in relation to CSF biomarkers in the ADNI-study by Altmann et al [ 16 ].…”

“…Analyses of the association between AD-PRS and CSF biomarkers have shown somewhat mixed results. The most recent study in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort reports that CSF t-tau and p-tau were associated with polygenic scores after correcting for APOE ε4 status, while the association seen with CSF Aβ42 was driven by APOE ε4 homozygotes [ 16 ].…”

Editorial

“…The papers we have published so far cover a broad range of topics in neurology, psychiatry and neuroscience from cell and animal models of diseases to human cohort studies. The new cover figure for volume 2 comes from Altmann et al (2019) who have found that polygenic risk score excluding the APOE4 locus associates with clinical diagnosis and biomarkers. The images show regional associations between amyloid PET tracer uptake and polygenic risk scores in the Alzheimer’s Disease Neuroimaging Initiative cohorts.…”