Online Exclusive Article

Apolipoprotein E Genotype and Cognitive Function in Postmenopausal Women With Early-Stage Breast Cancer

Theresa A. Koleck

Catherine Bender

Susan M. Sereika

Gretchen Ahrendt

Rachel C. Jankowitz

Kandace P. McGuire

Christopher M. Ryan

Yvette P. Conley

breast neoplasms, cognition, genes, biologic markers
ONF 2014, 41(6), E313-E325. DOI: 10.1188/14.ONF.E313-E325

Purpose/Objectives: To examine the role of apolipoprotein E (APOE) genotype in the cognitive function of postmenopausal women with early-stage breast cancer prior to initiation of adjuvant therapy and over time with treatment.

Design: Longitudinal, genetic association study.

Setting: Urban university cancer center.

Sample: Three cohorts of postmenopausal women: 37 women with breast cancer receiving chemotherapy and anastrozole, 41 women with breast cancer receiving anastrozole alone, and 50 healthy women.

Methods: Cognitive function was evaluated three times during a 12-month period using a comprehensive neuropsychological test battery. Participants were genotyped and classified based on the presence or absence of at least one APOE e4 allele. Multiple linear regression was used to determine if APOE genotype accounted for observed variability in cognitive function data.

Main Research Variables: APOE genotype, breast cancer treatment, and cognitive function.

Findings: Performance or changes in performance on tasks of executive function, attention, verbal learning and memory, and visual learning and memory were found to be influenced by APOE genotype and/or interactions between APOE genotype and study cohort.

Conclusions: The results indicate that cognitive function in postmenopausal women with breast cancer is modified by APOE genotype and the combination of APOE genotype and treatment.

Implications for Nursing: APOE genotype, along with other biomarkers, may be used in the future to assist nurses in identifying women with breast cancer most at risk for cognitive decline.

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    Ahles, T. A., & Saykin, A. J. (2007). Candidate mechanisms for chemotherapy-induced cognitive changes. Nature Reviews. Cancer, 7, 192-201. doi:10.1038/nrc2073
    Ahles, T. A., Saykin, A. J., Noll, W. W., Furstenberg, C. T., Guerin, S., Cole, B., & Mott, L. A. (2003). The relationship of APOE genotype to neuropsychological performance in long-term cancer survivors treated with standard dose chemotherapy. Psycho-Oncology, 12, 612-619. doi:10.1002/pon.742
    American Cancer Society. (2013). Breast cancer: What are the key statistics about breast cancer? Retrieved from
    Amin, K. A., Mohamed, B. M., El-Wakil, M. A. M., & Ibrahem, S. O. (2012). Impact of breast cancer and combination chemotherapy on oxidative stress, hepatic and cardiac markers. Journal of Breast Cancer, 15, 306-312. doi:10.4048/jbc.2012.15.3.306
    Azzi, A. (2007). Oxidative stress: A dead end or a laboratory hypothesis? Biochemical and Biophysical Research Communications, 362, 230-232. doi:10.1016/j.bbrc.2007.07.124
    Beck, A. T., Steer, R. A., & Brown, G. K. (1996). Beck Depression Inventory-II. San Antonio, TX: The Psychological Corporation.
    Bender, C. M., Sereika, S. M., Berga, S. L., Vogel, V. G., Brufsky, A. M., Paraska, K. K., & Ryan, C. M. (2006). Cognitive impairment associated with adjuvant therapy in breast cancer. Psycho-Oncology, 15, 422-430. doi:10.1002/pon.964
    Bender, C. M., Sereika, S. M., Houze, M. P., Brufsky, A. M., Berga, S. L., Richey, S. M., … Ryan, C. M. (2010). Deterioration in cognitive function with anastrozole therapy in women with breast cancer. Presented at the International Cognition in Cancer Task Force Meeting, New York, NY.
    Bender, C. M., Sereika, S. M., Ryan, C. M., Brufsky, A. M., Puhalla, S., & Berga, S. L. (2013). Does lifetime exposure to hormones predict pretreatment cognitive function in women before adjuvant therapy for breast cancer? Menopause, 20(9), 1-8. doi:10.1097/gme.0b013e3182843eff
    Blasiak, J., Arabski, M., Krupa, R., Wozniak, K., Rykala, J., Kolacinska, A., … Zadrozny, M. (2004). Basal, oxidative and alkylative DNA damage, DNA repair efficacy and mutagen sensitivity in breast cancer. Mutation Research, 554(1-2), 139-148. doi:10.1016/j.mrfmmm.2004.04.001
    Bonda, D. J., Wang, X., Perry, G., Nunomura, A., Tabaton, M., Zhu, X., & Smith, M. A. (2010). Oxidative stress in Alzheimer disease: A possibility for prevention. Neuropharmacology, 59(4-5), 290-294. doi:10.1016/j.neuropharm.2010.04.005
    Bondi, M. W., Houston, W. S., Eyler, L. T., & Brown, G. G. (2005). fMRI evidence of compensatory mechanisms in older adults at genetic risk for Alzheimer disease. Neurology, 64, 501-508. doi:10.1212/01.WNL.0000150885.00929.7E
    Boykoff, N., Moieni, M., & Subramanian, S. K. (2009). Confronting chemobrain: An in-depth look at survivors' reports of impact on work, social networks, and health care response. Journal of Cancer Survivorship: Research and Practice, 3, 223-232. doi:10.1007/s11764-009-0098-x
    Caselli, R. J., Dueck, A. C., Locke, D. E. C., Sabbagh, M. N., Ahern, G. L., Rapcsak, S. Z., … Reiman, E. M. (2011). Cerebrovascular risk factors and preclinical memory decline in healthy APOE e4 homozygotes. Neurology, 76, 1078-1084. doi:10.1212/WNL.0b013e318211c3ae
    Cleeland, C. S. (1989). Measurement of pain by subjective report. In C. R. Chapman & J. D. Loeser (Eds.), Advances in pain research and therapy (vol. 12., pp. 391-403). New York, NY: Raven Press.
    Conroy, S. K., McDonald, B. C., Smith, D. J., Moser, L. R., West, J. D., Kamendulis, L. M., … Saykin, A. J. (2012). Alterations in brain structure and function in breast cancer survivors: Effect of post-chemotherapy interval and relation to oxidative DNA damage. Breast Cancer Research and Treatment, 137, 493-502. doi:10.1007/s10549-012-2385-x
    Delis, D. C., Kaplan, E., & Kramer, J. H. (2001). Delis-Kaplan (D-KEFS) executive function system, examiners manual. San Antonio, TX: Psychological Corporation.
    DNA Genotek. (2012). Laboratory protocol for manual purification of DNA from whole sample. Retrieved from
    Downie, F. P., Mar Fan, H. G., Houédé-Tchen, N., Yi, Q., & Tannock, I. F. (2006). Cognitive function, fatigue, and menopausal symptoms in breast cancer patients receiving adjuvant chemotherapy: Evaluation with patient interview after formal assessment. Psycho-Oncology, 15, 921-930. doi:10.1002/pon.1035
    Edge, S. B., Byrd, D. R., Compton, C. C., Fritz, A. G., Greene, F. L., & Trotti, A. (Eds.). (2010). AJCC cancer staging manual (7th ed.). New York, NY: Springer.
    Falleti, M. G., Sanfilippo, A., Maruff, P., Weih, L., & Phillips, K. A. (2005). The nature and severity of cognitive impairment associated with adjuvant chemotherapy in women with breast cancer: A meta-analysis of the current literature. Brain and Cognition, 59, 60-70. doi:10.1016/j.bandc.2005.05.001
    Farrer, L., Cupples, L., Haines, J., Hyman, B., Kukull, W., Mayeux, R., … Van Duijn, C. (1997). Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. JAMA, 278, 1349-1356. doi:10.1001/jama.1997.03550160069041
    Finkel, T., & Holbrook, N. J. (2000). Oxidants, oxidative stress and the biology of ageing. Nature, 408, 239-247. doi:10.1038/35041687
    Flory, J. D., Manuck, S. B., Ferrell, R. E., Ryan, C. M., & Muldoon, M. F. (2000). Memory performance and the apolipoprotein E polymorphism in a community sample of middle-aged adults. American Journal of Medical Genetics, 96, 707-711. doi:10.1002/1096-8628(20001204)96:6<707
    Hamed, E. A., Zakhary, M. M., & Maximous, D. W. (2012). Apoptosis, angiogenesis, inflammation, and oxidative stress: Basic interactions in patients with early and metastatic breast cancer. Journal of Cancer Research and Clinical Oncology, 138, 999-1009. doi:10.1007/s00432-012-1176-4
    Han, S. D., & Bondi, M. W. (2008). Revision of the apolipoprotein E compensatory mechanism recruitment hypothesis. Alzheimer's and Dementia, 4, 251-254. doi:10.1016/j.jalz.2008.02.006
    Hayek, T., Oiknine, J., Brook, J. G., & Aviram, M. (1994). Increased plasma and lipoprotein lipid peroxidation in Apo E-deficient mice. Biochemical and Biophysical Research Communications, 201, 1567-1574. doi:10.1006/bbrc.1994.1883
    Hermelink, K., Untch, M., Lux, M. P., Kreienberg, R., Beck, T., Bauerfeind, I., & Münzel, K. (2007). Cognitive function during neoadjuvant chemotherapy for breast cancer: Results of a prospective, multicenter, longitudinal study. Cancer, 109, 1905-1913. doi:10.1002/cncr.22610
    Hofer, S. M., Christensen, H., Mackinnon, A. J., Alisa, E., Jorm, A. F., Henderson, A. S., & Easteal, S. (2002). Change in cognitive functioning associated with ApoE genotype in a community sample of older adults. Psychology and Aging, 17, 194-208. doi:10.1037/0882-7974.17.2.194
    Howlader, N., Noone, A. M., Krapcho, M., Neyman, N., Aminou, R., Altekruse, S. F., … Cronin, K. A. (2011). SEER cancer statistics review, 1975-2008 (Vintage 2009 Populations). Retrieved from
    Hubacek, J. A., Pitha, J., Skodova, Z., Adamkova, V., Lanska, V., & Poledne, R. (2001). A possible role of apolipoprotein E polymorphism in predisposition to higher education. Neuropsychobiology, 43, 200-203. doi:10.1159/000054890
    Hurria, A., Goldfarb, S., Rosen, C., Holland, J., Zuckerman, E., Lachs, M. S., … Hudis, C. (2006). Effect of adjuvant breast cancer chemotherapy on cognitive function from the older patient's perspective. Breast Cancer Research and Treatment, 98, 343-348. doi:10.1007/s10549-006-9171-6
    Izaks, G. J., Gansevoort, R. T., Van der Knaap, A. M., Navis, G., Dullaart, R. P. F., & Slaets, J. P. J. (2011). The association of APOE genotype with cognitive function in persons aged 35 years or older. PLOS One, 6, e27415. doi:10.1371/journal.pone.0027415
    Janelsins, M. C., Kohil, S., Mohile, S. G., Usuki, K., Ahles, T., & Morrow, G. R. (2012). An update on cancer- and chemotherapy-related cognitive dysfunction. Seminars in Oncology, 38, 431-438. doi:10.1053/j.seminoncol.2011.03.014.AN
    Jenkins, V., Shilling, V., Deutsch, G., Bloomfield, D., Morris, R., Allan, S., … Winstanley, J. (2006). A 3-year prospective study of the effects of adjuvant treatments on cognition in women with early stage breast cancer. British Journal of Cancer, 94, 828-834. doi:10.1038/sj.bjc.6603029
    Jofre-Monseny, L., Minihane, A. M., & Rimbach, G. (2008). Impact of apoE genotype on oxidative stress, inflammation and disease risk. Molecular Nutrition and Food Research, 52, 131-145. doi:10.1002/mnfr.200700322
    Jolivalt, C., Leininger-Muller, B., Bertrand, P., Herber, R., Christen, Y., & Siest, G. (2000). Differential oxidation of apolipoprotein E isofroms and interaction with phospholipids. Free Radical Biology and Medicine, 28, 129-140. doi:10.1016/S0891-5849(99)00232-4
    Jorm, A. F., Mather, K. A., Butterwork, P., Anstey, K. J., Christensen, H., & Easteal, S. (2007). APOE genotype and cognitive functioning in a large age-stratified population sample. Neuropsychology, 21, 1-8. doi:10.1037/0894-4105.21.1.1
    Joshi, G., Sultana, R., Tangpong, J., Cole, M. P., St. Clair, D. K., Vore, M., … Butterfield, D. A. (2005). Free radical mediated oxidative stress and toxic side effects in brain induced by the anti cancer drug adriamycin: Insight into chemobrain. Free Radical Research, 39, 1147-1154. doi:10.1080/10715760500143478
    Kasapovic, J., Pejic, S., Stojiljkovic, V., Todorovic, A., Radoševic-Jelic, L., Saicic, Z. S., & Pajovic, S. B. (2010). Antioxidant status and lipid peroxidation in the blood of breast cancer patients of different ages after chemotherapy with 5-fluorouracil, doxorubicin and cyclophosphamide. Clinical Biochemistry, 43(16-17), 1287-1293. doi:10.1016/j.clinbiochem.2010.08.009
    Lezak, M. D., Howieson, D. B., & Loring, D. W. (2004). Neuropsychological assessment (4th ed.). New York, NY: Oxford University Press.
    Mahley, R. W., Innerarity, T. L., Rall, S. C., & Weisgraber, K. H. (1984). Plasma lipoproteins: Apolipoprotein structure and function. Journal of Lipid Research, 25, 1277-1294. Retrieved from
    Mariani, E., Polidori, M. C., Cherubini, A., & Mecocci, P. (2005). Oxidative stress in brain aging, neurodegenerative and vascular diseases: An overview. Journal of Chromatography, 827, 65-75. doi:10.1016/j.jchromb.2005.04.023
    Matthews, C. G. (1964). Adult neuropsychological test battery. Madison, WI: University of Wisconsin Medical Center.
    McNair, D., Lorr, M., & Droppleman, L. F. (1992). EdITS manual for the Profile of Mood States. San Diego, CA: Educational and Industrial Testing Service.
    Mehnert, A., Scherwath, A., Schirmer, L., Schleimer, B., Petersen, C., Schulz-Kindermann, F., … Koch, U. (2007). The association between neuropsychological impairment, self-perceived cognitive deficits, fatigue and health related quality of life in breast cancer survivors following standard adjuvant versus high-dose chemotherapy. Patient Education and Counseling, 66, 108-118. doi:10.1016/j.pec.2006.11.005
    Miller, S. A., Dykes, D. D., & Polesky, H. F. (1988). A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Research, 16, 1215. Retrieved from
    Miyata, M., & Smith, J. D. (1996). Apolipoprotein E allele-specific antioxidant activity and effects on cytotoxicity by oxidation insults and β-amyloid peptides. Nature Genetics, 14, 55-61. doi:10.1038/ng0996-55
    Mondadori, C. R. A., De Quervain, D. J. F., Buchmann, A., Mustovic, H., Wollmer, M. A., Schmidt, C. F., … Henke, K. (2007). Better memory and neural efficiency in young apolipoprotein E epsilon4 carriers. Cerebral Cortex, 17, 1934-1947. doi:10.1093/cercor/bhl103
    Munir, F., Burrows, J., Yarker, J., Kalawsky, K., & Bains, M. (2010). Women's perceptions of chemotherapy-induced cognitive side affects on work ability: A focus group study. Journal of Clinical Nursing, 19(9-10), 1362-1370. doi:10.1111/j.1365-2702.2009.03006.x
    Myers, J. S. (2012). Chemotherapy-related cognitive impairment: The breast cancer experience [Online exclusive]. Oncology Nursing Forum, 39, E31-E40. doi:10.1188/12.ONF.E31-E40
    Nelson, H. (1981). Nelson Adult Reading Test (NART) manual. Windsor, Ontario: NFER-Nelson.
    Nilsson, L. G., Nyberg, L., & Bäckman, L. (2002). Genetic variation in memory functioning. Neuroscience and Biobehavioral Reviews, 26, 841-848. doi:10.1016/S0149-7634(02)00070-2
    Osterrieth, P. A. (1944). Le test de copie d'une figure complexe. Archives de Psychologie, 30, 206-356.
    Owen, A. M., Sahakian, B. J., Semple, J., Polkey, C. E., & Robbins, T. W. (1995). Visuo-spatial short-term recognition memory and learning after temporal lobe excisions or amygdalo-hippocampectomy in man. Neuropsychologia, 33, 1-24. doi:10.1016/0028-3932(94)00098-A
    Pedersen, W. A., Chan, S. L., & Mattson, M. P. (2000). A mechanism for the neuroprotective effect of apolipoprotein E: Isoform-specific modification by the lipid peroxidation product 4-hydroxynonenal. Journal of Neurochemistry, 74, 1426-1433. doi:10.1046/j.1471-4159.2000.0741426.x
    Reitan, R., & Wolfson, D. (1985). The Halstead-Reitan neuropsychological test battery. Tucson, AZ: Neuropsychology Press.
    Rey, A. (1964). L'examen psychologique dans les cas d'encephalopathie traumatique. Archives in Psychology, 1252, 340-382.
    Richard, F., & Amouyel, P. (2001). Genetic susceptibility factors for Alzheimer's disease. European Journal of Pharmacology, 412(1), 1-12. doi:10.1016/S0014-2999(00)00903-1
    Sadigh-Eteghad, S., Talebi, M., & Farhoudi, M. (2012). Association of apolipoprotein E epsilon 4 allele with sporadic late onset Alzheimer's disease. A meta-analysis. Neurosciences, 17, 321-326.
    Schagen, S. B., Van Dam, F. S., Muller, M. J., Boogerd, W., Lindeboom, J., & Bruning, P. F. (1999). Cognitive deficits after postoperative adjuvant chemotherapy for breast carcinoma. Cancer, 85, 640-650. doi: 10.1002/(SICI)1097-0142(19990201)85:3<640::AID-CNCR14>3.0.CO;2-G
    Schilder, C. M., Eggens, P. C., Seynaeve, C., Linn, S. C., Boogerd, W., Gundy, C. M., … Schagen, S. B. (2009). Neuropsychological functioning in postmenopausal breast cancer patients treated with tamoxifen or exemestane after AC-chemotherapy: Cross-sectional findings from the neuropsychological TEAM-side study. Acta Oncologica, 48, 76-85. doi:10.1080/02841860802314738
    Schilder, C. M., Seynaeve, C., Beex, L. V., Boogerd, W., Linn, S. C., Gundy, C. M., … Schagen, S. B. (2010). Effects of tamoxifen and exemestane on cognitive functioning of postmenopausal patients with breast cancer: Results from the neuropsychological side study of the tamoxifen and exemestane adjuvant multinational trial. Journal of Clinical Oncology, 28, 1294-1300. doi:10.1200/JCO .2008.21.3553
    Shilling, V., & Jenkins, V. (2007). Self-reported cognitive problems in women receiving adjuvant therapy for breast cancer. European Journal of Oncology Nursing, 11, 6-15. doi:10.1016/j.ejon.2006.02.005
    Small, B. J., Rawson, K. S., Walsh, E., Jim, H. S. L., Hughes, T. F., Iser, L., … Jacobsen, P. B. (2011). Catechol-O-methyltransferase genotype modulates cancer treatment-related cognitive deficits in breast cancer survivors. Cancer, 117, 1369-1376. doi:10.1002/cncr.25685
    Stilley, C. S., Bender, C. M., Dunbar-Jacob, J., Sereika, S., & Ryan, C. M. (2011). The impact of cognitive function on medication management: Three studies. Health Psychology, 29, 50-55. doi:10.1037/a0016940
    Strehlow, K., Rotter, S., Wassmann, S., Adam, O., Grohé, C., Laufs, K., … Nickenig, G. (2003). Modulation of antioxidant enzyme expression and function by estrogen. Circulation Research, 93, 170-177. doi:10.1161/01.RES.0000082334.17947.11
    Tchen, N., Juffs, H. G., Downie, F. P., Yi, Q. L., Hu, H., Chemerynsky, I., … Tannock, I. F. (2003). Cognitive function, fatigue, and menopausal symptoms in women receiving adjuvant chemotherapy for breast cancer. Journal of Clinical Oncology, 21, 4175-4183. doi:10.1200/JCO.2003.01.119
    Unfer, T. C., Conterato, G. M., Da Silva, J. C., Duarte, M. M., & Emanuelli, T. (2006). Influence of hormone replacement therapy on blood antioxidant enzymes in menopausal women. Clinica Chimica Acta, 369, 73-77. doi:10.1016/j.cca.2006.01.006
    Vardy, J., Wefel, J. S., Ahles, T., Tannock, I. F., & Schagen, S. B. (2008). Cancer and cancer-therapy related cognitive dysfunction: An international perspective from the Venice cognitive workshop. Annals of Oncology, 19, 623-629. doi:10.1093/annonc/mdm500
    Von Ah, D., Habermann, B., Carpenter, J. S., & Schneider, B. L. (2013). Impact of perceived cognitive impairment in breast cancer survivors. European Journal of Oncology Nursing, 17, 236-241. doi:10.1016/j.ejon.2012.06.002
    Walker, C. H., Drew, B. A., Antoon, J. W., Kalueff, A. V., & Beckman, B. S. (2012). Neurocognitive effects of chemotherapy and endocrine therapies in the treatment of breast cancer: Recent perspectives. Cancer Investigation, 30, 135-148. doi:10.3109/07357907.2011.636116
    Wechsler, D. (1981). Manual for the Wechsler Adult Intelligence Scale-Revised. New York, NY: The Psychological Corporation.
    Wefel, J. S., Lenzi, R., Theriault, R., Buzdar, A. U., Cruickshank, S., & Meyers, C. A. (2004). "Chemobrain" in breast carcinoma?: A prologue. Cancer, 101, 466-475. doi:10.1002/cncr.20393
    Wefel, J. S., Saleeba, A. K., Buzdar, A. U., & Meyers, C. A. (2010). Acute and late onset cognitive dysfunction associated with chemotherapy in women with breast cancer. Cancer, 116, 3348-3356. doi:10.1002/cncr.25098
    Wehling, E., Lundervold, A. J., Standnes, B., Gjerstad, L., & Reinvang, I. (2007). APOE status and its association to learning and memory performance in middle aged and older Norwegians seeking assessment for memory deficits. Behavioral and Brain Functions, 3, 57. doi:10.1186/1744-9081-3-57
    Wilson, B., Cockburn, J., Baddeley, A., & Hiorns, R. (1989). The development and validation of a test battery for detecting and monitoring everyday memory problems. Journal of Clinical and Experimental Neuropsychology, 11, 855-870. doi:10.1080/01688638908400940
    Wishart, H. A., Saykin, A. J., Rabin, L. A., Santulli, R. B., Flashman, L. A., Guerin, S. J., … Mcallister, T. W. (2006). Increased brain activation during working memory in cognitively intact adults with the APOE ε4 allele. American Journal of Psychiatry, 163, 1603-1610. doi:10.1176/appi.ajp.163.9.1603
    Yu, Y. W., Lin, C. H., Chen, S. P., Hong, C. J., & Tsai, S. J. (2000). Intelligence and event-related potentials for young female human volunteer apolipoprotein E epsilon4 and non-epsilon4 carriers. Neuroscience Letters, 294, 179-181.