BackgroundGenome-wide association studies (GWAS) have indicated moderate genetic overlap between Alzheimer’s disease (AD) and related dementias (ADRD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS), neurodegenerative disorders traditionally considered etiologically distinct. However, the specific genetic variants and loci underlying this overlap remain almost entirely unknown.MethodsWe leveraged state-of-the-art GWAS for ADRD, PD, and ALS. For each pair of disorders, we examined each of the GWAS hits for one disorder and tested whether they were also significant for the other disorder, applying Bonferroni correction for the number of variants tested. This approach rigorously controls the family-wise error rate for both disorders, analogously to genome-wide significance.ResultsEleven loci with GWAS hits for one disorder were also associated with one or both of the other disorders: one with all three disorders (theMAPT/KANSL1locus), five with ADRD and PD (nearLCORL,CLU,SETD1A/KAT8,WWOX, andGRN), three with ADRD and ALS (nearGPX3,HS3ST5/HDAC2/MARCKS, andTSPOAP1), and two with PD and ALS (nearGAK/TMEM175andNEK1). Two of these loci (LCORLandNEK1) were associated with an increased risk of one disorder but decreased risk of another. Colocalization analysis supported a shared causal variant between ADRD and PD at theCLU,WWOX, andLCORLloci, between ADRD and ALS at theTSPOAP1locus, and between PD and ALS at theNEK1andGAK/TMEM175loci. To address the concern that ADRD is an imperfect proxy for AD and that the ADRD and PD GWAS have overlapping participants (nearly all of which are from the UK Biobank), we confirmed that all our ADRD associations had nearly identical odds ratios in an AD GWAS that excluded the UK Biobank, and all but one remained nominally significant (p< 0.05) for AD.ConclusionsIn one of the most comprehensive investigations to date of pleiotropy between neurodegenerative disorders, we identify eleven genetic risk loci shared among ADRD, PD, and ALS. These loci support lysosomal/autophagic dysfunction (GAK/TMEM175,GRN,KANSL1), neuroinflammation/immunity (TSPOAP1), oxidative stress (GPX3,KANSL1), and the DNA damage response (NEK1) as transdiagnostic processes underlying multiple neurodegenerative disorders.