. 2021 Jan 27;5(2):pkab013.

doi: 10.1093/jncics/pkab013. eCollection 2021 Apr.

Protective Effects of APOE ε2 Genotype on Cognition in Older Breast Cancer Survivors: The Thinking and Living With Cancer Study

Kathleen Van Dyk¹, Xingtao Zhou², Brent J Small³, Jaeil Ahn⁴, Wanting Zhai⁴, Tim Ahles⁵, Deena Graham⁶, Paul B Jacobsen⁷, Heather Jim⁸, Brenna C McDonald⁹, Kelly Nudelman Holohan¹⁰, Sunita K Patel¹¹, G William Rebeck¹², James C Root^{5

13}, Andrew J Saykin¹⁴, Harvey Jay Cohen¹⁵, Jeanne S Mandelblatt¹⁶, Judith E Carroll^{1

17}

Affiliations

¹ UCLA Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, David Geffen School of Medicine, Jane and Terry Semel Institute for Neuroscience and Human Behavior, Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA.
² Department of Biostatistics, Bioinformatics and Biomathematics, Georgetown-Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
³ School of Aging Studies, University of South Florida, and Senior Member, Health Outcome and Behavior Program and Biostatistics Resource Core, H. Lee Moffitt Cancer Center and Research Institute at the University of South Florida, Tampa, FL, USA.
⁴ Department of Biostatistics, Bioinformatics, and Biomathematics, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
⁵ Department of Psychiatry and Behavioral Sciences, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
⁶ John Theurer Cancer Center, Hackensack, NJ, USA.
⁷ Division of Cancer Control and Population Sciences, Healthcare Delivery Research Program, National Cancer Institute, Bethesda, MD, USA.
⁸ Department of Health Outcomes and Behavior, Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, FL, USA.
⁹ Department of Radiology and Imaging Sciences, Center for Neuroimaging, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA.
¹⁰ Department of Medical and Molecular Genetics, Indiana Alzheimer's Disease Research Center, Indiana University School of Medicine, Indianapolis, IN, USA.
¹¹ Departments of Population Sciences and Supportive Care Medicine, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
¹² Department of Neurosciences, Georgetown University School of Medicine, Georgetown University, Washington, DC, USA.
¹³ Departments of Psychiatry and Anesthesiology, Weill Medical College of Cornell University, New York, NY, USA.
¹⁴ Department of Radiology and Imaging Sciences, Center for Neuroimaging, Indiana Alzheimer's Disease Research Center, and the Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA.
¹⁵ Center for the Study of Aging and Human Development, Duke Cancer Institute, Duke University School of Medicine, Durham, NC, USA.
¹⁶ Department of Oncology, Cancer Prevention and Control Program, Georgetown-Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
¹⁷ Cousins Center for Psychoneuroimmunology, University of California, Los Angeles, Los Angeles, CA, USA.

PMID: 33748669
PMCID: PMC7962698
DOI: 10.1093/jncics/pkab013

Protective Effects of APOE ε2 Genotype on Cognition in Older Breast Cancer Survivors: The Thinking and Living With Cancer Study

Kathleen Van Dyk et al. JNCI Cancer Spectr. 2021.

. 2021 Jan 27;5(2):pkab013.

doi: 10.1093/jncics/pkab013. eCollection 2021 Apr.

Authors

Affiliations

¹ UCLA Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, David Geffen School of Medicine, Jane and Terry Semel Institute for Neuroscience and Human Behavior, Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA.
² Department of Biostatistics, Bioinformatics and Biomathematics, Georgetown-Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
³ School of Aging Studies, University of South Florida, and Senior Member, Health Outcome and Behavior Program and Biostatistics Resource Core, H. Lee Moffitt Cancer Center and Research Institute at the University of South Florida, Tampa, FL, USA.
⁴ Department of Biostatistics, Bioinformatics, and Biomathematics, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
⁵ Department of Psychiatry and Behavioral Sciences, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
⁶ John Theurer Cancer Center, Hackensack, NJ, USA.
⁷ Division of Cancer Control and Population Sciences, Healthcare Delivery Research Program, National Cancer Institute, Bethesda, MD, USA.
⁸ Department of Health Outcomes and Behavior, Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, FL, USA.
⁹ Department of Radiology and Imaging Sciences, Center for Neuroimaging, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA.
¹⁰ Department of Medical and Molecular Genetics, Indiana Alzheimer's Disease Research Center, Indiana University School of Medicine, Indianapolis, IN, USA.
¹¹ Departments of Population Sciences and Supportive Care Medicine, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
¹² Department of Neurosciences, Georgetown University School of Medicine, Georgetown University, Washington, DC, USA.
¹³ Departments of Psychiatry and Anesthesiology, Weill Medical College of Cornell University, New York, NY, USA.
¹⁴ Department of Radiology and Imaging Sciences, Center for Neuroimaging, Indiana Alzheimer's Disease Research Center, and the Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA.
¹⁵ Center for the Study of Aging and Human Development, Duke Cancer Institute, Duke University School of Medicine, Durham, NC, USA.
¹⁶ Department of Oncology, Cancer Prevention and Control Program, Georgetown-Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
¹⁷ Cousins Center for Psychoneuroimmunology, University of California, Los Angeles, Los Angeles, CA, USA.

PMID: 33748669
PMCID: PMC7962698
DOI: 10.1093/jncics/pkab013

Abstract

Background: Cancer-related cognitive decline (CRCD) has been linked to apolipoprotein E (APOE) gene ε4 polymorphisms. APOE ε4 polymorphisms are also the strongest genetic risk for late-onset Alzheimer disease (AD), whereas ε2 polymorphisms protect against AD. However, the effects of ε2 polymorphisms on CRCD have not been evaluated.

Methods: We evaluated nonmetastatic breast cancer survivors (n = 427) and matched noncancer controls (n = 407) ages 60-98 years assessed presystemic therapy from August 2010 to December 2017 with annual follow-up to 24 months. Neuropsychological assessment measured attention, processing speed, executive function, and learning and memory. Linear mixed-effects models tested the effects of having an ε2 allele (vs none) on longitudinal cognitive domain z scores by treatment group (chemotherapy with or without hormonal therapy, hormonal therapy, and control) controlling for covariates; participants with ε2/ε4 genotype were excluded. Sensitivity analyses examined effects of other covariates and any ε4 positivity.

Results: There was an interaction with genotype for attention, processing speed, and executive functioning domain scores (Beta = 0.32, 95% confidence interval = 0.00 to 0.65); the chemotherapy group with an ε2 allele had higher scores at baseline and maintained higher scores over time compared with those without an ε2 allele, and this protective effect was not seen for other groups. There was no effect of ε2 on learning and memory domain scores.

Conclusions: APOE ε2 polymorphisms may protect against CRCD in older breast cancer survivors receiving chemotherapy. With replication, this information could be useful for survivorship care and informing future studies of possible links to AD and defining mechanisms of protection.

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Figures

**Figure 1.**
Analytic sample of older breast cancer survivors and matched noncancer controls. *APOE* = apolipoprotein E.

**Figure 2.**
Impact of *APOE* ε2 genotype on adjusted longitudinal scores on attention, processing speed, and executive functioning z scores among older breast cancer survivors (n = 378) and noncancer controls (n = 388) excluding ε2/4 genotype 1. Results for **(A)** chemotherapy with and without hormonal therapy, **(B)** hormonal therapy only, and **(C)** controls are shown. Supplementary Tables 11 and 12 (available online) provide adjusted mean attention, processing speed, and executive functioning z scores over time and post hoc group comparisons.

**Figure 3.**
Impact of *APOE* ε2 genotype on adjusted longitudinal scores on learning and memory z scores among older breast cancer survivors (n = 378) and noncancer controls (n = 388) excluding ε2/4 genotype. Results for **(A)** chemotherapy with and without hormonal therapy, **(B)** hormonal therapy only, and **(C)** controls are shown. Supplementary Tables 12 and 13 (available online) provide adjusted mean learning and memory z scores over time and post hoc group comparisons.

See this image and copyright information in PMC

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Protective Effects of APOE ε2 Genotype on Cognition in Older Breast Cancer Survivors: The Thinking and Living With Cancer Study

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Protective Effects of APOE ε2 Genotype on Cognition in Older Breast Cancer Survivors: The Thinking and Living With Cancer Study

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