Objective: Assess whether Alzheimer’s (AD) or Lewy body (LB) pathologies mediate the association between APOEe4 and clinical profile differently for females and males with LB pathology
Background: APOEe4 impacts phenotype of LB disease (LBD) through both direct and indirect AD pathology-related mechanisms. In AD, APOEe4 is associated with worse cognition for females than males. As clinical correlations of AD and LB pathologies differ by sex, APOEe4 effect on clinical profile may differ by sex in LBD in relation to these pathologies.
Method: We included 178 females, 293 males with LB pathology, available AD pathology staging data, and no other neurodegenerative diagnoses from National Alzheimer’s Coordinating Center dataset. Clinical outcomes were clinical diagnosis (AD, LBD), clinician report of cognitive (memory, orientation, judgment, language, visuospatial, attention, cognitive fluctuation), behavioral (hallucination, delusion, disinhibition, irritability, agitation, personality change, REM sleep behavior disorder, anxiety, apathy, depression), motor (gait, falls, tremor, bradykinesia, parkinsonism) changes at last visit. Parallel mediation models with nonparametric bootstrapping (1000 iterations) and false discovery rate correction assessed whether APOEe4 effect on outcomes was mediated by LB or AD pathology controlling for age.
Results: For females, APOEe4 was associated with lower likelihood of parkinsonism; higher likelihood of memory decline, delusions, clinical AD diagnosis. Association with clinical AD diagnosis was partially mediated by AD pathology. For males, APOEe4 was associated with lower likelihood of gait changes, bradykinesia, clinical LBD diagnosis; higher likelihood of orientation, language decline, clinical AD diagnosis. Associations with bradykinesia, language, clinical diagnoses were mediated by AD pathology. Although total, direct, or indirect effects of APOEe4 on likelihood of REM sleep behavior disorder were not significant for either sex, indirect effect differed by sex (diff=-0.06, 95% CI=-0.11, -0.02). There were no significant indirect effects by LB pathology.
Conclusion: For people with LB pathology, APOEe4 can have sex-specific effects on clinical profile mediated by AD pathology. Sex differences should be considered to improve the determination of genetic and pathology targets for risk assessment and treatments in LBD.
To cite this abstract in AMA style:
E. Bayram, B. Bettcher, S. Holden. Sex differences for clinical impact of APOEe4 mediated by Alzheimer’s pathology in people with Lewy body pathology [abstract]. Mov Disord. 2026; 41 (suppl 1). https://www.mdsabstracts.org/abstract/sex-differences-for-clinical-impact-of-apoee4-mediated-by-alzheimers-pathology-in-people-with-lewy-body-pathology/. Accessed October 1, 2026.« Back to 2026 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/sex-differences-for-clinical-impact-of-apoee4-mediated-by-alzheimers-pathology-in-people-with-lewy-body-pathology/