Browsing by Author "Blauwendraat, Cornelis"
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Item A cross‐sectional study of α‐synuclein seed amplification assay in Alzheimer's disease neuroimaging initiative: Prevalence and associations with Alzheimer's disease biomarkers and cognitive function(Wiley, 2024) Tosun, Duygu; Hausle, Zachary; Iwaki, Hirotaka; Thropp, Pamela; Lamoureux, Jennifer; Lee, Edward B.; MacLeod, Karen; McEvoy, Sean; Nalls, Michael; Perrin, Richard J.; Saykin, Andrew J.; Shaw, Leslie M.; Singleton, Andrew B.; Lebovitz, Russ; Weiner, Michael W.; Blauwendraat, Cornelis; Alzheimer’s Disease Neuroimaging Initiative; Radiology and Imaging Sciences, School of MedicineIntroduction: Alzheimer's disease (AD) pathology is defined by β-amyloid (Aβ) plaques and neurofibrillary tau, but Lewy bodies (LBs; 𝛼-synuclein aggregates) are a common co-pathology for which effective biomarkers are needed. Methods: A validated α-synuclein Seed Amplification Assay (SAA) was used on recent cerebrospinal fluid (CSF) samples from 1638 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants, 78 with LB-pathology confirmation at autopsy. We compared SAA outcomes with neuropathology, Aβ and tau biomarkers, risk-factors, genetics, and cognitive trajectories. Results: SAA showed 79% sensitivity and 97% specificity for LB pathology, with superior performance in identifying neocortical (100%) compared to limbic (57%) and amygdala-predominant (60%) LB-pathology. SAA+ rate was 22%, increasing with disease stage and age. Higher Aβ burden but lower CSF p-tau181 associated with higher SAA+ rates, especially in dementia. SAA+ affected cognitive impairment in MCI and Early-AD who were already AD biomarker positive. Discussion: SAA is a sensitive, specific marker for LB-pathology. Its increase in prevalence with age and AD stages, and its association with AD biomarkers, highlights the clinical importance of α-synuclein co-pathology in understanding AD's nature and progression. Highlights: SAA shows 79% sensitivity, 97% specificity for LB-pathology detection in AD. SAA positivity prevalence increases with disease stage and age. Higher Aβ burden, lower CSF p-tau181 linked with higher SAA+ rates in dementia. SAA+ impacts cognitive impairment in early disease stages. Study underpins need for wider LB-pathology screening in AD treatment.Item Author Correction: Elucidating causative gene variants in hereditary Parkinson’s disease in the Global Parkinson’s Genetics Program (GP2)(Springer Nature, 2023-09-13) Lange, Lara M.; Avenali, Micol; Ellis, Melina; Illarionova, Anastasia; Keller Sarmiento, Ignacio J.; Tan, Ai-Huey; Madoev, Harutyun; Galandra, Caterina; Junker, Johanna; Roopnarain, Karisha; Solle, Justin; Wegel, Claire; Fang, Zih-Hua; Heutink, Peter; Kumar, Kishore R.; Lim, Shen-Yang; Valente, Enza Maria; Nalls, Mike; Blauwendraat, Cornelis; Singleton, Andrew; Mencacci, Niccolo; Lohmann, Katja; Klein, Christine; Global Parkinson’s Genetic Program (GP2); Medical and Molecular Genetics, School of MedicineItem Creating the Pick's disease International Consortium: Association study of MAPT H2 haplotype with risk of Pick's disease(medRxiv, 2023-04-24) Valentino, Rebecca R.; Scotton, William J.; Roemer, Shanu F.; Lashley, Tammaryn; Heckman, Michael G.; Shoai, Maryam; Martinez-Carrasco, Alejandro; Tamvaka, Nicole; Walton, Ronald L.; Baker, Matthew C.; Macpherson, Hannah L.; Real, Raquel; Soto-Beasley, Alexandra I.; Mok, Kin; Revesz, Tamas; Warner, Thomas T.; Jaunmuktane, Zane; Boeve, Bradley F.; Christopher, Elizabeth A.; DeTure, Michael; Duara, Ranjan; Graff-Radford, Neill R.; Josephs, Keith A.; Knopman, David S.; Koga, Shunsuke; Murray, Melissa E.; Lyons, Kelly E.; Pahwa, Rajesh; Parisi, Joseph E.; Petersen, Ronald C.; Whitwell, Jennifer; Grinberg, Lea T.; Miller, Bruce; Schlereth, Athena; Seeley, William W.; Spina, Salvatore; Grossman, Murray; Irwin, David J.; Lee, Edward B.; Suh, EunRan; Trojanowski, John Q.; Van Deerlin, Vivianna M.; Wolk, David A.; Connors, Theresa R.; Dooley, Patrick M.; Frosch, Matthew P.; Oakley, Derek H.; Aldecoa, Iban; Balasa, Mircea; Gelpi, Ellen; Borrego-Écija, Sergi; de Eugenio Huélamo, Rosa Maria; Gascon-Bayarri, Jordi; Sánchez-Valle, Raquel; Sanz-Cartagena, Pilar; Piñol-Ripoll, Gerard; Molina-Porcel, Laura; Bigio, Eileen H.; Flanagan, Margaret E.; Gefen, Tamar; Rogalski, Emily J.; Weintraub, Sandra; Redding-Ochoa, Javier; Chang, Koping; Troncoso, Juan C.; Prokop, Stefan; Newell, Kathy L.; Ghetti, Bernardino; Jones, Matthew; Richardson, Anna; Robinson, Andrew C.; Roncaroli, Federico; Snowden, Julie; Allinson, Kieren; Green, Oliver; Rowe, James B.; Singh, Poonam; Beach, Thomas G.; Serrano, Geidy E.; Flowers, Xena E.; Goldman, James E.; Heaps, Allison C.; Leskinen, Sandra P.; Teich, Andrew F.; Black, Sandra E.; Keith, Julia L.; Masellis, Mario; Bodi, Istvan; King, Andrew; Sarraj, Safa-Al; Troakes, Claire; Halliday, Glenda M.; Hodges, John R.; Kril, Jillian J.; Kwok, John B.; Piguet, Olivier; Gearing, Marla; Arzberger, Thomas; Roeber, Sigrun; Attems, Johannes; Morris, Christopher M.; Thomas, Alan J.; Evers, Bret M.; White, Charles L.; Mechawar, Naguib; Sieben, Anne A.; Cras, Patrick P.; De Vil, Bart B.; De Deyn, Peter Paul P. P.; Duyckaerts, Charles; Le Ber, Isabelle; Seihean, Danielle; Turbant-Leclere, Sabrina; MacKenzie, Ian R.; McLean, Catriona; Cykowski, Matthew D.; Ervin, John F.; Wang, Shih-Hsiu J.; Graff, Caroline; Nennesmo, Inger; Nagra, Rashed M.; Riehl, James; Kovacs, Gabor G.; Giaccone, Giorgio; Nacmias, Benedetta; Neumann, Manuela; Ang, Lee-Cyn; Finger, Elizabeth C.; Blauwendraat, Cornelis; Nalls, Mike A.; Singleton, Andrew B.; Vitale, Dan; Cunha, Cristina; Carvalho, Agostinho; Wszolek, Zbigniew K.; Morris, Huw R.; Rademakers, Rosa; Hardy, John A.; Dickson, Dennis W.; Rohrer, Jonathan D.; Ross, Owen A.; Pathology and Laboratory Medicine, School of MedicineBackground: Pick's disease (PiD) is a rare and predominantly sporadic form of frontotemporal dementia that is classified as a primary tauopathy. PiD is pathologically defined by argyrophilic inclusion Pick bodies and ballooned neurons in the frontal and temporal brain lobes. PiD is characterised by the presence of Pick bodies which are formed from aggregated, hyperphosphorylated, 3-repeat tau proteins, encoded by the MAPT gene. The MAPT H2 haplotype has consistently been associated with a decreased disease risk of the 4-repeat tauopathies of progressive supranuclear palsy and corticobasal degeneration, however its role in susceptibility to PiD is unclear. The primary aim of this study was to evaluate the association between MAPT H2 and risk of PiD. Methods: We established the Pick's disease International Consortium (PIC) and collected 338 (60.7% male) pathologically confirmed PiD brains from 39 sites worldwide. 1,312 neurologically healthy clinical controls were recruited from Mayo Clinic Jacksonville, FL (N=881) or Rochester, MN (N=431). For the primary analysis, subjects were directly genotyped for MAPT H1-H2 haplotype-defining variant rs8070723. In secondary analysis, we genotyped and constructed the six-variant MAPT H1 subhaplotypes (rs1467967, rs242557, rs3785883, rs2471738, rs8070723, and rs7521). Findings: Our primary analysis found that the MAPT H2 haplotype was associated with increased risk of PiD (OR: 1.35, 95% CI: 1.12-1.64 P=0.002). In secondary analysis involving H1 subhaplotypes, a protective association with PiD was observed for the H1f haplotype (0.0% vs. 1.2%, P=0.049), with a similar trend noted for H1b (OR: 0.76, 95% CI: 0.58-1.00, P=0.051). The 4-repeat tauopathy risk haplotype MAPT H1c was not associated with PiD susceptibility (OR: 0.93, 95% CI: 0.70-1.25, P=0.65). Interpretation: The PIC represents the first opportunity to perform relatively large-scale studies to enhance our understanding of the pathobiology of PiD. This study demonstrates that in contrast to its protective role in 4R tauopathies, the MAPT H2 haplotype is associated with an increased risk of PiD. This finding is critical in directing isoform-related therapeutics for tauopathies.Item Defining the causes of sporadic Parkinson's disease in the global Parkinson's genetics program (GP2)(Springer Nature, 2023-09-12) Towns, Clodagh; Richer, Madeleine; Jasaityte, Simona; Stafford, Eleanor J.; Joubert, Julie; Antar, Tarek; Martinez-Carrasco, Alejandro; Makarious, Mary B.; Casey, Bradford; Vitale, Dan; Levine, Kristin; Leonard, Hampton; Pantazis, Caroline B.; Screven, Laurel A.; Hernandez, Dena G.; Wegel, Claire E.; Solle, Justin; Nalls, Mike A.; Blauwendraat, Cornelis; Singleton, Andrew B.; Tan, Manuela M. X.; Iwaki, Hirotaka; Morris, Huw R.; Global Parkinson’s Genetics Program (GP2); Medical and Molecular Genetics, School of MedicineThe Global Parkinson’s Genetics Program (GP2) will genotype over 150,000 participants from around the world, and integrate genetic and clinical data for use in large-scale analyses to dramatically expand our understanding of the genetic architecture of PD. This report details the workflow for cohort integration into the complex arm of GP2, and together with our outline of the monogenic hub in a companion paper, provides a generalizable blueprint for establishing large scale collaborative research consortia.Item Differences in the Presentation and Progression of Parkinson's Disease by Sex(Wiley, 2021) Iwaki, Hirotaka; Blauwendraat, Cornelis; Leonard, Hampton L.; Makarious, Mary B.; Kim, Jonggeol J.; Liu, Ganqiang; Maple-Grødem, Jodie; Corvol, Jean-Christophe; Pihlstrøm, Lasse; van Nimwegen, Marlies; Smolensky, Luba; Amondikar, Ninad; Hutten, Samantha J.; Frasier, Mark; Nguyen, Khanh-Dung H.; Rick, Jacqueline; Eberly, Shirley; Faghri, Faraz; Auinger, Peggy; Scott, Kirsten M.; Wijeyekoon, Ruwani; Van Deerlin, Vivianna M.; Hernandez, Dena G.; Gibbs, Raphael J.; Day-Williams, Aaron G.; Brice, Alexis; Alves, Guido; Noyce, Alastair J.; Tysnes, Ole-Bjørn; Evans, Jonathan R.; Breen, David P.; Estrada, Karol; Wegel, Claire E.; Danjou, Fabrice; Simon, David K.; Andreassen, Ole A.; Ravina, Bernard; Toft, Mathias; Heutink, Peter; Bloem, Bastiaan R.; Weintraub, Daniel; Barker, Roger A.; Williams-Gray, Caroline H.; van de Warrenburg, Bart P.; Van Hilten, Jacobus J.; Scherzer, Clemens R.; Singleton, Andrew B.; Nalls, Mike A.; Medical and Molecular Genetics, School of MedicineBackground: Previous studies reported various symptoms of Parkinson's disease (PD) associated with sex. Some were conflicting or confirmed in only one study. Objectives: We examined sex associations to PD phenotypes cross-sectionally and longitudinally in large-scale data. Methods: We tested 40 clinical phenotypes, using longitudinal, clinic-based patient cohorts, consisting of 5946 patients, with a median follow-up of 3.1 years. For continuous outcomes, we used linear regressions at baseline to test sex-associated differences in presentation, and linear mixed-effects models to test sex-associated differences in progression. For binomial outcomes, we used logistic regression models at baseline and Cox regression models for survival analyses. We adjusted for age, disease duration, and medication use. In the secondary analyses, data from 17 719 PD patients and 7588 non-PD participants from an online-only, self-assessment PD cohort were cross-sectionally evaluated to determine whether the sex-associated differences identified in the primary analyses were consistent and unique to PD. Results: Female PD patients had a higher risk of developing dyskinesia early during the follow-up period, with a slower progression in activities of daily living difficulties, and a lower risk of developing cognitive impairments compared with male patients. The findings in the longitudinal, clinic-based cohorts were mostly consistent with the results of the online-only cohort. Conclusions: We observed sex-associated contributions to PD heterogeneity. These results highlight the necessity of future research to determine the underlying mechanisms and importance of personalized clinical management.Item Elucidating causative gene variants in hereditary Parkinson's disease in the Global Parkinson's Genetics Program (GP2)(Springer Nature, 2023-06-27) Lange, Lara M.; Avenali, Micol; Ellis, Melina; Illarionova, Anastasia; Keller Sarmiento, Ignacio J.; Tan, Ai-Huey; Madoev, Harutyun; Galandra, Caterina; Junker, Johanna; Roopnarain, Karisha; Solle, Justin; Wegel, Claire; Fang, Zih-Hua; Heutink, Peter; Kumar, Kishore R.; Lim, Shen-Yang; Valente, Enza Maria; Nalls, Mike; Blauwendraat, Cornelis; Singleton, Andrew; Mencacci, Niccolo; Lohmann, Katja; Klein, Christine; Global Parkinson’s Genetic Program (GP2); Medical and Molecular Genetics, School of MedicineThe Monogenic Network of the Global Parkinson’s Genetics Program (GP2) aims to create an efficient infrastructure to accelerate the identification of novel genetic causes of Parkinson’s disease (PD) and to improve our understanding of already identified genetic causes, such as reduced penetrance and variable clinical expressivity of known disease-causing variants. We aim to perform short- and long-read whole-genome sequencing for up to 10,000 patients with parkinsonism. Important features of this project are global involvement and focusing on historically underrepresented populations.Item Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture(Springer Nature, 2021-03) Chia, Ruth; Sabir, Marya S.; Bandres-Ciga, Sara; Saez-Atienzar, Sara; Reynolds, Regina H.; Gustavsson, Emil; Walton, Ronald L.; Ahmed, Sarah; Viollet, Coralie; Ding, Jinhui; Makarious, Mary B.; Diez-Fairen, Monica; Portley, Makayla K.; Shah, Zalak; Abramzon, Yevgeniya; Hernandez, Dena G.; Blauwendraat, Cornelis; Stone, David J.; Eicher, John; Parkkinen, Laura; Ansorge, Olaf; Clark, Lorraine; Honig, Lawrence S.; Marder, Karen; Lemstra, Afina; St. George-Hyslop, Peter; Londos, Elisabet; Morgan, Kevin; Lashley, Tammaryn; Warner, Thomas T.; Jaunmuktane, Zane; Galasko, Douglas; Santana, Isabel; Tienari, Pentti J.; Myllykangas, Liisa; Oinas, Minna; Cairns, Nigel J.; Morris, John C.; Halliday, Glenda M.; Van Deerlin, Vivianna M.; Trojanowski, John Q.; Grassano, Maurizio; Calvo, Andrea; Mora, Gabriele; Canosa, Antonio; Floris, Gianluca; Bohannan, Ryan C.; Brett, Francesca; Gan-Or, Ziv; Geiger, Joshua T.; Moore, Anni; May, Patrick; Krüger, Rejko; Goldstein, David S.; Lopez, Grisel; Tayebi, Nahid; Sidransky, Ellen; Norcliffe-Kaufmann, Lucy; Palma, Jose-Alberto; Kaufmann, Horacio; Shakkottai, Vikram G.; Perkins, Matthew; Newell, Kathy L.; Gasser, Thomas; Schulte, Claudia; Landi, Francesco; Salvi, Erika; Cusi, Daniele; Masliah, Eliezer; Kim, Ronald C.; Caraway, Chad A.; Monuki, Edwin S.; Brunetti, Maura; Dawson, Ted M.; Rosenthal, Liana S.; Albert, Marilyn S.; Pletnikova, Olga; Troncoso, Juan C.; Flanagan, Margaret E.; Mao, Qinwen; Bigio, Eileen H.; Rodríguez-Rodríguez, Eloy; Infante, Jon; Lage, Carmen; González-Aramburu, Isabel; Sanchez-Juan, Pascual; Ghetti, Bernardino; Keith, Julia; Black, Sandra E.; Masellis, Mario; Rogaeva, Ekaterina; Duyckaerts, Charles; Brice, Alexis; Lesage, Suzanne; Xiromerisiou, Georgia; Barrett, Matthew J.; Tilley, Bension S.; Gentleman, Steve; Logroscino, Giancarlo; Serrano, Geidy E.; Beach, Thomas G.; McKeith, Ian G.; Thomas, Alan J.; Attems, Johannes; Morris, Christopher M.; Palmer, Laura; Love, Seth; Troakes, Claire; Al-Sarraj, Safa; Hodges, Angela K.; Aarsland, Dag; Klein, Gregory; Kaiser, Scott M.; Woltjer, Randy; Pastor, Pau; Bekris, Lynn M.; Leverenz, James B.; Besser, Lilah M.; Kuzma, Amanda; Renton, Alan E.; Goate, Alison; Bennett, David A.; Scherzer, Clemens R.; Morris, Huw R.; Ferrari, Raffaele; Albani, Diego; Pickering-Brown, Stuart; Faber, Kelley; Kukull, Walter A.; Morenas-Rodriguez, Estrella; Lleó, Alberto; Fortea, Juan; Alcolea, Daniel; Clarimon, Jordi; Nalls, Mike A.; Ferrucci, Luigi; Resnick, Susan M.; Tanaka, Toshiko; Foroud, Tatiana M.; Graff-Radford, Neill R.; Wszolek, Zbigniew K.; Ferman, Tanis; Boeve, Bradley F.; Hardy, John A.; Topol, Eric J.; Torkamani, Ali; Singleton, Andrew B.; Ryten, Mina; Dickson, Dennis W.; Chiò, Adriano; Ross, Owen A.; Gibbs, J. Raphael; Dalgard, Clifton L.; Traynor, Bryan J.; Scholz, Sonja W.; Pathology and Laboratory Medicine, School of MedicineThe genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.Item Genome-wide case-only analysis of gene-gene interactions with known Parkinson's disease risk variants reveals link between LRRK2 and SYT10(Springer Nature, 2023-06-29) Aleknonytė-Resch, Milda; Trinh, Joanne; Leonard, Hampton; Delcambre, Sylvie; Leitão, Elsa; Lai, Dongbing; Smajić, Semra; Orr-Urtreger, Avi; Thaler, Avner; Blauwendraat, Cornelis; Sharma, Arunabh; Makarious, Mary B.; Kim, Jonggeol Jeff; Lake, Julie; Rahmati, Pegah; Freitag-Wolf, Sandra; Seibler, Philip; Foroud, Tatiana; Singleton, Andrew B.; The International Parkinson Disease Genomics Consortium; Grünewald, Anne; Kaiser, Frank; Klein, Christine; Krawczak, Michael; Dempfle, Astrid; Medical and Molecular Genetics, School of MedicineThe effects of one genetic factor upon Parkinson’s disease (PD) risk may be modified by other genetic factors. Such gene-gene interaction (G×G) could explain some of the ‘missing heritability’ of PD and the reduced penetrance of known PD risk variants. Using the largest single nucleotide polymorphism (SNP) genotype data set currently available for PD (18,688 patients), provided by the International Parkinson’s Disease Genomics Consortium, we studied G×G with a case-only (CO) design. To this end, we paired each of 90 SNPs previously reported to be associated with PD with one of 7.8 million quality-controlled SNPs from a genome-wide panel. Support of any putative G×G interactions found was sought by the analysis of independent genotype-phenotype and experimental data. A total of 116 significant pairwise SNP genotype associations were identified in PD cases, pointing towards G×G. The most prominent associations involved a region on chromosome 12q containing SNP rs76904798, which is a non-coding variant of the LRRK2 gene. It yielded the lowest interaction p-value overall with SNP rs1007709 in the promoter region of the SYT10 gene (interaction OR = 1.80, 95% CI: 1.65–1.95, p = 2.7 × 10−43). SNPs around SYT10 were also associated with the age-at-onset of PD in an independent cohort of carriers of LRRK2 mutation p.G2019S. Moreover, SYT10 gene expression during neuronal development was found to differ between cells from affected and non-affected p.G2019S carriers. G×G interaction on PD risk, involving the LRRK2 and SYT10 gene regions, is biologically plausible owing to the known link between PD and LRRK2, its involvement in neural plasticity, and the contribution of SYT10 to the exocytosis of secretory vesicles in neurons.Item Harnessing diversity to study Alzheimer's disease: A new iPSC resource from the NIH CARD and ADNI(Elsevier, 2024) Screven, Laurel A.; Pantazis, Caroline B.; Andersh, Katherine M.; Hong, Samantha; Vitale, Dan; Lara, Erika; Ku, Ray Yueh; Heutink, Peter; Meyer, Jason; Faber, Kelley; Nho, Kwangsik; Saykin, Andrew J.; Foroud, Tatiana M.; Nalls, Mike A.; Blauwendraat, Cornelis; Singleton, Andrew; Narayan, Priyanka S.; Medical and Molecular Genetics, School of MedicineThe iDA Project (iPSCs to Study Diversity in Alzheimer's and Alzheimer's Disease-related Dementias) is generating 200 induced pluripotent stem cell lines from Alzheimer's Disease Neuroimaging Initiative participants. These lines are sex balanced, include common APOE genotypes, span disease stages, and are ancestrally diverse. Cell lines and characterization data will be shared openly.Item LRRK2-associated parkinsonism with and without in vivo evidence of alpha-synuclein aggregates: longitudinal clinical and biomarker characterization(Oxford University Press, 2025-03-06) Chahine, Lana M.; Lafontant, David-Erick; Choi, Seung Ho; Iwaki, Hirotaka; Blauwendraat, Cornelis; Singleton, Andrew B.; Brumm, Michael C.; Alcalay, Roy N.; Merchant, Kalpana; Holohan Nudelman, Kelly Nicole; Dagher, Alain; Vo, Andrew; Tao, Qin; Venuto, Charles S.; Kieburtz, Karl; Poston, Kathleen L.; Bressman, Susan; Gonzalez-Latapi, Paulina; Avants, Brian; Coffey, Christopher; Jennings, Danna; Tolosa, Eduardo; Siderowf, Andrew; Marek, Ken; Simuni, Tatyana; Parkinson’s Progression Markers Initiative; Medical and Molecular Genetics, School of MedicineAmong LRRK2-associated parkinsonism cases with nigral degeneration, over two-thirds demonstrate evidence of pathologic alpha-synuclein, but many do not. Understanding the clinical phenotype and underlying biology in such individuals is critical for therapeutic development. Our objective was to compare clinical and biomarker features, and rate of progression over 4 years of follow-up, among LRRK2-associated parkinsonism cases with and without in vivo evidence of alpha-synuclein aggregates. Data were from the Parkinson's Progression Markers Initiative, a multicentre prospective cohort study. The sample included individuals diagnosed with Parkinson disease with pathogenic variants in LRRK2. Presence of CSF alpha-synuclein aggregation was assessed with seed amplification assay. A range of clinician- and patient-reported outcome assessments were administered. Biomarkers included dopamine transporter scan, CSF amyloid-beta1-42, total tau, phospho-tau181, urine bis(monoacylglycerol)phosphate levels and serum neurofilament light chain. Linear mixed-effects (LMMs) models examined differences in trajectory in CSF-negative and CSF-positive groups. A total of 148 LRRK2 parkinsonism cases (86% with G2019S variant), 46 negative and 102 positive for CSF alpha-synuclein seed amplification assay, were included. At baseline, the negative group was older than the positive group [median (inter-quartile range) 69.1 (65.2-72.3) versus 61.5 (55.6-66.9) years, P < 0.001] and a greater proportion were female [28 (61%) versus 43 (42%), P = 0.035]. Despite being older, the negative group had similar duration since diagnosis and similar motor rating scale [16 (11-23) versus 16 (10-22), P = 0.480] though lower levodopa equivalents. Only 13 (29%) of the negative group were hyposmic, compared with 75 (77%) of the positive group. The negative group, compared with the positive group, had higher per cent-expected putamenal dopamine transporter binding for their age and sex [0.36 (0.29-0.45) versus 0.26 (0.22-0.37), P < 0.001]. Serum neurofilament light chain was higher in the negative group compared with the positive group [17.10 (13.60-22.10) versus 10.50 (8.43-14.70) pg/mL; age-adjusted P-value = 0.013]. In terms of longitudinal change, the negative group remained stable in functional rating scale score in contrast to the positive group who had a significant increase (worsening) of 0.729 per year (P = 0.037), but no other differences in trajectory were found. Among individuals diagnosed with Parkinson disease with pathogenic variants in the LRRK2 gene, we found clinical and biomarker differences in cases without versus with in vivo evidence of CSF alpha-synuclein aggregates. LRRK2 parkinsonism cases without evidence of alpha-synuclein aggregates as a group exhibit less severe motor manifestations and decline. The underlying biology in LRRK2 parkinsonism cases without evidence of alpha-synuclein aggregates requires further investigation.