Genome-wide Survival Study Identifies PARL as a Novel Locus for Clinical Progression and Neurodegeneration in Alzheimer’s Disease

Variability exists in the trajectories of Alzheimer's disease (AD). We aimed to identify genetic modulators of clinical progression in AD.We conducted the first genome-wide survival study on AD using a two-stage approach. The discovery and replication stage separately included 1158 and 211,817 individuals without dementia from the Alzheimer's Disease Neuroimaging Initiative and the UK Biobank, respectively (325 and 1103 progressed in average follow-up of 4.33 and 8.63 years, respectively). Cox proportional hazards models were applied with time to AD dementia as the phenotype of clinical progression. A series of bioinformatic analyses and functional experiments was performed to validate the novel findings.We found that APOE and PARL, a novel locus tagged by rs6795172 (hazard ratio = 1.66, p = 1.45 × 10-9), were significantly associated with AD clinical progression and were successfully replicated. The novel locus was linked to accelerated cognitive changes, higher tau levels, and faster atrophy of AD-specific brain structures, which were also verified in UK Biobank neuroimaging follow-up. Gene analysis and summary data-based Mendelian randomization indicated PARL as the most functionally relevant gene in the locus. Expression quantitative trait locus analyses and dual-luciferase reporter assays confirmed that PARL expression could be regulated by rs6795172. Three different AD mouse models consistently showed decreased PARL expression accompanied by elevated tau levels, and in vitro experiments revealed that knockdown/overexpression of PARL inversely changed tau levels.Collectively, genetic, bioinformatic, and functional evidence suggests that PARL modulates clinical progression and neurodegeneration in AD. Targeting PARL may potentially modify AD progression and have implications for disease-modifying therapies.