Predicting risk of Alzheimer’s disease using polygenic risk scores developed for Parkinson’s disease

Background and Objectives The two most common neurodegenerative diseases are Alzheimer’s disease (AD) and Parkinson’s disease (PD), both related to age and affect millions of people across the world, especially as life expectancy increases in certain countries. Here, we explore the potential predictiveness of the genetic risk of AD and PD separately and then the extent of the underlying shared genetics of AD and PD. Methods The population genetic risk estimates for AD and PD were derived using a previously developed population specific polygenic risk score (psPRS) and regression-based SNP filtering method. To test the overlap between AD and PD, we ran a regression of the AD psPRSs versus the population PD prevalences for both the filtered and unfiltered AD PRS and vice versa. We then assessed gene-gene interaction and pathway involvement using the Alzheimer’s KnowledgeBase (AlzKB) and STRINGdb, respectively. Results The unfiltered PD psPRS was moderately predictive, while the AD psPRS was not. After filtering, both the AD and PD, psPRSs improved to strongly predictive, explained most of the genetic variation. The ability of the unfiltered AD psPRS to predict PD, and vice versa, is poor. However, the filtered AD, and PD, psPRS were highly predictive. Discussion Our results suggest that there is a correlation between AD, and PD, specific allele frequency and prevalence, as well as an overlap of AD and PD generally. However, the AD psPRS is a better predictor of PD, than the PD psPRS is of AD. Our results call for further research into the general overlap of Alzheimer’s disease and Parkinson’s disease, despite the previous lack of evidence. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by R01 LM010098, U19 AG074865 and U01 AG066833. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The source data were openly available before this study. We used data from 1000 Genomes accessed through Ensembl (http://useast.ensembl.org/index.html) and the GWAS catalog (https://www.ebi.ac.uk/gwas/efotraits/MONDO\_0004975, https://www.ebi.ac.uk/gwas/efotraits/MONDO\_0005180). Additionally, we used data from AlzKB (https://alzkb.ai/) and the STRINGdb (https://string-db.org/). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript.