Abstract
Background
Pathogenic LRRK2 gene variants are a major genetic risk factor for both familial and sporadic Parkinson’s dissease (PD), opening an unattended window into disease mechanisms and potential therapies. Investigating the influence of pathogenic variants in LRRK2 gene on brain structure is a crucial step toward enabling early diagnosis and personalized treatment. Yet, despite its significance, the ways in which LRRK2 genotype affects brain structure remain largely unexplored. Work in this domain is plagued by small sample sizes and differences in cohort composition, which can obscure genuine distinctions among clinical subgroups.
Methods
In this study, we overcome such important limitations by combining explicit modeling of population background variation and pattern matching. Specifically, we leverage a cohort of 603 participants (including 370 with a PD diagnosis) to examine MRI-detectable cortical atrophy patterns associated with the LRRK2 pathogenic variants in people with PD and carriers without Parkinson’s symptoms.
Results
LRRK2 PD patients exhibit milder cortical thinning compared to sporadic PD, with notable preservation in temporal and occipital regions, suggesting a distinct pattern of neurodegeneration. Non-manifesting LRRK2 carriers show no significant cortical atrophy, indicating no structural signs of subclinical PD. We further analyze the relationship between aggregated alpha-synuclein in cerebrospinal fluid and atrophy. We find that those with evidence of aggregated alpha-synuclein experienced pronounced neurodegeneration and increased cortical thinning, possibly defining another aggressive PD subtype.
Conclusions
Our findings highlight genetic avenues for distinguishing PD subtypes, which could lead to more targeted treatment approaches and a more complete understanding of Parkinson’s disease progression.
Plain language summary
Parkinson’s disease is a brain disorder that affects movement, thinking, and daily functioning. While most cases have no clear cause, some people carry rare changes in a gene called LRRK2. Another important factor is a brain protein called alpha-synuclein, which can build up in harmful ways. In this study, we used brain scans from a large international project to understand how these genetic and protein markers relate to brain changes. We found that people with LRRK2 mutations had less brain damage than those with typical Parkinson’s disease, even when they had similar symptoms. This suggests that some people may have natural protection in the brain. Our findings could help doctors better understand different forms of Parkinson’s and guide more personalized treatments in the future.
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Data availability
Data used in the preparation of this article were obtained in May 2023 from the Parkinson’s Progression Markers Initiative (PPMI) database (www.ppmi-info.org/access-data-specimens/download-data), RRID:SCR_006431. Researchers can request access to PPMI imaging, genetic, and clinical data by submitting a data use agreement at the PPMI website. For up-to-date information on the study, visit www.ppmi-info.org. All numerical data underlying the graphs and charts in the main figures are provided as individual Excel files in the Supplementary Data: source data for Figs. 1–5 are available in Supplementary Data 1–5, respectively. Code used for analysis is available as described in the Code Availability section.
Code availability
The processing scripts and custom analysis software used in this work are available in a publicly accessible GitHub repository, along with examples of key visualizations in the paper: https://github.com/jakubkopal/LRRK2-MRI.
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Acknowledgements
PPMI—a public-private partnership—is funded by the Michael J. Fox Foundation for Parkinson’s Research and funding partners, including 4D Pharma, Abbvie, AcureX, Allergan, Amathus Therapeutics, Aligning Science Across Parkinson’s, AskBio, Avid Radiopharmaceuticals, BIAL, BioArctic, Biogen, Biohaven, BioLegend, BlueRock Therapeutics, Bristol-Myers Squibb, Calico Labs, Capsida Biotherapeutics, Celgene, Cerevel Therapeutics, Coave Therapeutics, DaCapo Brainscience, Denali, Edmond J. Safra Foundation, Eli Lilly, Gain Therapeutics, GE HealthCare, Genentech, GSK, Golub Capital, Handl Therapeutics, Insitro, Jazz Pharmaceuticals, Johnson & Johnson Innovative Medicine, Lundbeck, Merck, Meso Scale Discovery, Mission Therapeutics, Neurocrine Biosciences, Neuron23, Neuropore, Pfizer, Piramal, Prevail Therapeutics, Roche, Sanofi, Servier, Sun Pharma Advanced Research Company, Takeda, Teva, UCB, Vanqua Bio, Verily, Voyager. D.B. was supported by the Brain Canada Foundation, through the Canada Brain Research Fund, with the financial support of Health Canada, National Institutes of Health (NIH R01 AG068563A, NIH R01 DA053301-01A1, NIH R01 MH129858-01A1), the Canadian Institute of Health Research (CIHR 438531, CIHR 470425), the Healthy Brains Healthy Lives initiative (Canada First Research Excellence fund), the IVADO R3AI initiative (Canada First Research Excellence fund), and by the CIFAR Artificial Intelligence Chairs program (Canada Institute for Advanced Research). The funders had no role in study design, data collection and analysis, the decision to publish, or the preparation of the manuscript.
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J.K. performed the analyses and drafted the manuscript. A.D. conceived the project and provided neurological expertise. D.B. led the analytical pipeline design and supervised the methodological framework. AV curated the dataset. Q.T. assisted with data preparation and quality control. S.T. and L.M.C. contributed to interpretation of the results in clinical context. All authors reviewed and approved the final manuscript.
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D.B. is a shareholder and advisory board member at MindState Design Labs, USA. All other authors declare no competing interests.
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Kopal, J., Vo, A., Tao, Q. et al. Carriers of LRRK2 pathogenic variants show a milder, anatomically distinct brain signature of Parkinson’s disease. Commun Med (2026). https://doi.org/10.1038/s43856-025-01330-7
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DOI: https://doi.org/10.1038/s43856-025-01330-7
