Objective: Determine if there are sex-based differences in associations of baseline (BL) immunoglobulin G (IgG) index with development of cognitive impairment (CI) among cognitively normal Parkinson’s Disease (PD) participants up to 9 years later.

Background: Neuroinflammation has been associated with both PD and CI[1,2]. Prior sex-based investigations of CI in PD suggest that men are more affected in severity and rate of progression[3,4]. Cross-sectionally, elevated IgG index has been associated with lower MoCA scores in either sex for PD [5]. We hypothesize that higher BL IgG index will be associated with higher degree of CI severity in men, but not women.

Method: BL IgG index (CSF:serum IgG ratio normalized to albumin ratio) and cognitive characterization data (up to 9 years later) were collected from the Parkinson’s Progression Markers Initiative (PPMI) database[6]. Participants with normal cognition at baseline were separated by sex and grouped according to CI severity at their most recently reported visit: normal cognition (PD-N), subjective cognitive complaint (PD-CC), mild cognitive impairment (PD-MCI), and dementia (PD-D). BL IgG index was averaged within groups and associations with CI severity were compared via linear regression models. Multinomial logistic regression models were fit for each cohort to estimate risk associated with BL IgG and placement in each CI group.

Results: For both sexes, there were lower mean IgG index for PD-CC, PD-MCI, and PD-D compared to PD-N (Table 2). Increased BL IgG index was associated with lower probability of PD-CC characterization for males (OR=0.360) and females (OR=0.278); however, there was no significant association with characterization as PD-MCI (p=0.145, 0.823) or PD-D (p=0.241, 0.619) (Table 1). IgG index for both sexes increased between BL and 4-year follow up for all categories, with the greatest change among female PD-MCI (40% for female vs 7% for male).

Conclusion: Contrary to our hypothesis, lower BL IgG index up to 9 years prior was associated with development of CI severity of any type in PD participants of either sex. The association of lower BL IgG index with PD-CI is interesting, as prior work associating higher IgG index with CI was cross-sectional[5], raising the possibility of a time-dependent difference underpinning a potential pathogenic mechanism, which is supported by our observations at 4-year follow up.

Table 1

Table 2

References: 1. Scott, K. M., Spindler, L. R. B., Peattie, A. R. D., Kouli, A., Fryer, T. D., Hong, Y. T., Camacho, M., Solim, I., Kahanawita, L., & Williams-Gray, C. H. (2025). Multimodal markers of immune activation predict cognitive outcomes in Parkinson’s disease. Brain, behavior, and immunity, 129, 165–178. https://doi.org/10.1016/j.bbi.2025.05.020

2. Kouli A, Spindler LRB, Fryer TD, Hong YT, Malpetti M, Aigbirhio FI, White SR, Camacho M, O’Brien JT, Williams-Gray CH. Neuroinflammation is linked to dementia risk in Parkinson’s disease. Brain. 2024 Mar 1;147(3):923-935. doi: 10.1093/brain/awad322. PMID: 37757857; PMCID: PMC10907093.

3. Reekes, T.H., Higginson, C.I., Ledbetter, C.R. et al. Sex specific cognitive differences in Parkinson disease. npj Parkinsons Dis. 6, 7 (2020). https://doi.org/10.1038/s41531-020-0109-1

4. Cholerton, B., Johnson, C. O., Fish, B., Quinn, J. F., Chung, K. A., Peterson-Hiller, A. L., … & Edwards, K. L. (2018). Sex differences in progression to mild cognitive impairment and dementia in Parkinson’s disease. Parkinsonism & related disorders, 50, 29-36. https://doi.org/10.1016/j.parkreldis.2018.02.007

5. Marian Shahid, Patricia Linortner, Li Zhu, Cyrus P. Zabetian, Joseph Quinn, Brenna Cholerton, Thomas Montine, Lu Tian, Marion S. Buckwalter, and Kathleen L. Poston.
Antibody Synthesis in the CNS is Associated with Cognition in Parkinson’s disease (1586). Parkinson’s Disease Biomarkers and Pathophysiology.April 14, 2020. https://www.neurology.org/doi/10.1212/WNL.94.15_supplement.1586

6. Poston, K., Zhu L., Shahid M., Buckwalter M. Adaptive Immune Markers for Predicting Cognitive Decline in PD [database online]. Parkinson’s Progression Markers Initiative (PPMI). Accessed January 8, 2026.

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