Objective: To evaluate whether association between apolipoprotein E ε4 (APOE ε4) and cognition differ for men and women with pathologically-confirmed Lewy body dementia (LBD).

Background: APOE ε4 is a genetic risk factor for LBD [1–3]. In Parkinson’s disease, APOE ε4 is associated with different rates of cognitive decline for men and women [4], suggesting sex-specific effects of APOE in Lewy body diseases, although it has not been investigated in LBD.

Method: We obtained data from the Uniform Data Set [5] and Neuropathology Data Set [6] from the National Alzheimer’s Coordinating Center. Only participants with a clinical dementia diagnosis, a clinical LBD diagnosis as the primary etiology for cognitive decline at the last visit, and Lewy body pathology were included (Parkinson’s disease dementia, n = 16 women and 60 men; dementia with Lewy bodies, n = 31 women and 120 men). The analysis included data from 28 past and present Alzheimer’s Disease Research Centers for visits conducted between September 2005 and August 2019. APOE ε4 allele count associations with CDR® Dementia Staging Instrument scores, adjusting for age at last visit and education, were analyzed separately for men and women. p values were corrected for multiple comparisons.

Results: Ratio of those without, with one allele and with two APOE ε4 alleles were similar for men and women (p=.90).
[figure1]
Women and men with APOE ε4 were significantly younger at the last visit and death compared to women and men without APOE ε4.
[table1]
Men with APOE ε4 had significantly more years of education than men without APOE ε4. For women, APOE ε4 count was not associated with any of the CDR scores (p>.98 for all). For men, CDR-Sum of Boxes scores increased with each APOE ε4 allele (B=1.42, p=.042). In particular, scores on CDR-Memory, Orientation, and Community affairs increased significantly with each APOE ε4 count for men (B=0.33, p=.013; B=0.34, p=.013; B=0.25, p=.033; respectively).

Conclusion: For pathologically-confirmed LBD patients, APOE ε4 was associated with worse decline in memory, orientation and social skills, and overall more severe dementia specifically for men. The lack of APOE ε4 and cognition association for women, despite significant associations for men, supports the need for sex-specific genetic risk factors in LBD. Men and women may be impacted differently by Lewy body pathology [7] and genetic mechanisms can play a role in this sex difference.

References: 1. Tsuang D, Leverenz JB, Lopez OL, Hamilton RL, Bennett DA, Schneider JA, et al. APOE ϵ4 Increases Risk for Dementia in Pure Synucleinopathies. JAMA Neurol. 2013 Feb 1;70(2):223. 2. Pang S, Li J, Zhang Y, Chen J. Meta-Analysis of the relationship between the APOE gene and the onset of Parkinson’s disease dementia. Parkinson’s Disease. 2018; 2018: 1–12. 3. Chia R, Sabir MS, Bandres-Ciga S, Saez-Atienzar S, Reynolds RH, Gustavsson E, et al. Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture. Nat Genet. 2021 Feb 15. 4. Kim R, Park S, Yoo D, Ju Suh Y, Jun J-S, Jeon B. Potential Sex-Specific Effects of Apolipoprotein E ɛ4 on Cognitive Decline in Early Parkinson’s Disease. J Parkinsons Dis. 2020 Dec 3;1–9. 5. Besser L, Kukull W, Knopman DS, Chui H, Galasko D, Weintraub S, et al. Version 3 of the National Alzheimer’s Coordinating Center’s Uniform Data Set. Alzheimer Dis Assoc Disord. 2018 Oct;32(4):1. 6. Besser LM, Kukull WA, Teylan MA, Bigio EH, Cairns NJ, Kofler JK, et al. The Revised National Alzheimer’s Coordinating Center’s Neuropathology Form—Available Data and New Analyses. J Neuropathol Exp Neurol. 2018 Aug 1;77(8):717–26. 7. Bayram E, Coughlin DG, Banks SJ, Litvan I. Sex differences for phenotype in pathologically defined dementia with Lewy bodies. J Neurol Neurosurg Psychiatry. 2021 Feb 9;jnnp-2020-325668.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/sex-specific-apoe-%ce%b54-association-with-cognition-in-lewy-body-dementia/