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Missense mutations in the  LRRK2  gene were first identified as a pathogenic cause of Parkinson’s disease (PD) in 2004. Soon thereafter, a founder mutation in  LRRK2 , p.G2019S (rs34637584), was described, and it is now estimated that there are approximately 100,000 people worldwide carrying this risk variant. While the clinical presentation of  LRRK2  parkinsonism has been largely indistinguishable from sporadic PD, disease penetrance and age at onset can be quite variable. In addition, its neuropathological features span a wide range from nigrostriatal loss with Lewy body pathology, lack thereof, or atypical neuropathology, including a large proportion of cases with concomitant Alzheimer’s pathology, hailing  LRRK2  parkinsonism as the “Rosetta stone” of parkinsonian disorders, which provides clues to an understanding of the different neuropathological trajectories. These differences may result from interactions between the LRRK2 mutant protein and other proteins or environmental factors that modify LRRK2 function and, thereby, influence pathobiology. This review explores how potential genetic and biochemical modifiers of LRRK2 function may contribute to the onset and clinical presentation of  LRRK2  parkinsonism. We review which genetic modifiers of  LRRK2  influence clinical symptoms, age at onset, and penetrance, what  LRRK2  mutations are associated with pleomorphic  LRRK2  neuropathology, and which environmental modifiers can augment  LRRK2  mutant pathophysiology. Understanding how  LRRK2  function is influenced and modulated by other interactors and environmental factors—either increasing toxicity or providing resilience—will inform targeted therapeutic development in the years to come. This will allow the development of disease-modifying therapies for PD- and  LRRK2 -related neurodegeneration.

Genetic and Environmental Factors Influence the Pleomorphy of LRRK2 Parkinsonism