Objective: We aim to advance precision medicine strategies for Parkinson’s disease (PD) through data-driven research led by the Critical Path for Parkinson’s (CPP) global public-private partnership. Here, we examined whether sex modifies the association between apolipoprotein E (APOE) ε4 carrier status and longitudinal cognitive decline in PD

Background: The risk of developing PD is approximately twice as high in men as in women, yet women have a higher mortality rate and faster disease progression. Sex and APOE ε4 have each been implicated in cognitive outcomes in neurodegenerative diseases, including PD

Method: This retrospective longitudinal cohort study (2010–2024) pooled PPMI and CPP integrated data from 2,123 patients with PD, including 1,833 with sporadic PD (sPD), 124 with GBA1-PD, and 166 with LRRK2-PD. Linear and curvilinear mixed-effects models were used to evaluate cognitive trajectories measured by Montreal Cognitive Assessment (MoCA) scores, adjusting for age, education, and disease duration. Main effects and interactions involving sex, APOE ε4 status, and time were examined to assess overall cognitive performance and rate of decline, with subgroup analyses performed separately in sPD, GBA1-PD, and LRRK2-PD

Results: At baseline, females were slightly younger, had lower educational attainment, similar APOE ε4 frequency and disease duration, and higher MoCA scores than males. Across follow-up, female sex was independently associated with better overall cognitive performance (0.69-point higher MoCA; 95% CI 0.41-0.97; F=30.47, p<0.001), but not with a different decline. APOE ε4 was associated with greater cognitive worsening over time, whereas the APOE ε4 × sex × time interaction was not significant in the overall PD cohort or within PD subtypes

Conclusion: Sex was associated with overall cognitive performance, whereas APOE ε4 genotype was associated with longitudinal cognitive decline. These results support growing evidence for biological sex differences in PD and underscore the value of integrated data and multistakeholder initiatives to translate such findings into therapies. The Critical Path Institute’s Global Evidence in Medicine for Parkinson’s disease (GEM-PD) initiative is poised to leverage these insights to advance therapeutic strategies targeting women with PD and related disorders

References: Botta, R., Locascio, J. J., Ye, R., Goodheart, A. E. & Gomperts, S. N. APOE, Aβ42, and tau differentially impact cognitive decline in Sporadic, GBA1 and LRRK2 Parkinson’s disease. npj Parkinson’s Disease 2026 https://doi.org/10.1038/s41531-026-01290-2 (2026) doi:10.1038/s41531-026-01290-2.
2. Reekes, T. H. et al. Sex specific cognitive differences in Parkinson disease. npj Parkinson’s Disease 2020 6:1 6, 1–6 (2020).
3. Umeh, C. C., Mahajan, A., Mihailovic, A. & Pontone, G. M. APOE4 Allele, Sex, and Dementia Risk in Parkinson’s Disease: Lessons From a Longitudinal Cohort. J. Geriatr. Psychiatry Neurol. 35, 810–815 (2022).
4. MacAulay, R. K. et al. Predictors of Heterogeneity in Cognitive Function: APOE-e4, Sex, Education, Depression, and Vascular Risk. Archives of Clinical Neuropsychology 35, 660–670 (2020).
5. Tipton, P. W. et al. Effects of sex and APOE on Parkinson’s Disease-related cognitive decline. Neurol. Neurochir. Pol. 55, 559–566 (2021).

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MDS Abstracts - https://www.mdsabstracts.org/abstract/sex-specific-associations-of-apoe-%ce%b54-with-cognitive-decline-in-parkinsons-disease-insights-from-the-critical-path-institute-gem-pd-initiative/