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The molecular modifiers underlying this variability remain poorly understood.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      To investigate whether dysfunctional alternative polyadenylation (APA), a key post\u2010transcriptional regulatory process, modulates the penetrance of\n                      <jats:italic>LRRK2<\/jats:italic>\n                      variants in PD.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Using RNA\u2010seq data from 905 participants in the Parkinson's Progression Markers Initiative (PPMI), we quantified dysfunctional APA based on the percentage of distal polyadenylation site usage index (PDUI). Dysfunctional APA associated with\n                      <jats:italic>LRRK2<\/jats:italic>\n                      variants was assessed in healthy controls (HCs) and PD patients, with a focus on PD\u2010specific APA. We further identified dysfunctional APA that distinguishes symptomatic from asymptomatic\n                      <jats:italic>LRRK2<\/jats:italic>\n                      variant carriers and evaluated its associations with immune cell composition and symptom severity. A sensitivity analysis using an APA\u2010based score was conducted to assess whether the G2019S variant drives dysfunctional APA in\n                      <jats:italic>LRRK2<\/jats:italic>\n                      carriers.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      PD patients exhibited over twice the number of dysfunctional APA events associated with\n                      <jats:italic>LRRK2<\/jats:italic>\n                      variants compared with HCs. PD\u2010specific APA events were involved in immune disorders, amyloid fiber formation, and ubiquitin\u2010specific processing proteases, all implicated in PD pathogenesis. Fourteen dysfunctional APA events distinguished symptomatic from asymptomatic\n                      <jats:italic>LRRK2<\/jats:italic>\n                      carriers, correlated with immune cell composition, and were associated with PD symptom severity. The G2019S variant largely recapitulates the global dysfunctional APA pattern observed in\n                      <jats:italic>LRRK2<\/jats:italic>\n                      variant carriers and validated in an independent replication cohort.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Dysfunctional APA is a potential modifier of\n                      <jats:italic>LRRK2<\/jats:italic>\n                      variant penetrance, contributing to PD onset. \u00a9 2025 International Parkinson and Movement Disorder Society.\n                    <\/jats:p>\n                  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