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Journal of Cancer Survivorship
Published in: Journal of Cancer Survivorship 2/2024

24-10-2022 | Breast Cancer

The impact of APOE and smoking history on cognitive function in older, long-term breast cancer survivors

Authors: Tim A. Ahles, Irene Orlow, Elizabeth Schofield, Yuelin Li, Elizabeth Ryan, James C. Root, Sunita K. Patel, Katrazyna McNeal, Alexandra Gaynor, Heidi Tan, Vani Katheria, Jessica Vazquez, Sergio Corrales–Guerrero, Keimya Sadeghi, Tiffany Traina, Arti Hurria

Published in: Journal of Cancer Survivorship | Issue 2/2024

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Abstract

Purpose

This study aims to determine whether older breast cancer survivors score lower on neuropsychological tests compared to matched non-cancer controls and to test the hypotheses that survivors who were APOE ε4 carriers would have the lowest cognitive performance but that smoking history would decrease the negative effect of ε4 on cognition.

Methods

Female breast cancer survivors who had been diagnosed and treated at age 60 or older and were 5–15-year survivors (N = 328) and age and education matched non-cancer controls (N = 162) were assessed at enrollment and at 8-, 16-, and 24-month follow-ups with standard neuropsychological and psychological assessments. Blood for APOE genotyping was collected, and smoking history was assessed at enrollment. Participants were purposely recruited so that approximately 50% had a history of treatment with chemotherapy or no chemotherapy and approximately 50% had a smoking history.

Results

After adjusting for age, cognitive reserve, depression, and fatigue, breast cancer survivors scored significantly lower on all domains of cognitive function. A significant two-way interaction demonstrated that the negative effect of ε4 on cognitive performance was stronger among survivors. A significant three-way interaction supported the hypothesis that smoking history had a protective effect on cognitive function in ε4 carriers that was more pronounced in the controls than the survivors.

Conclusions

The results support the long-term cognitive impact of breast cancer diagnosis and treatments on older, disease-free survivors, particularly for ε4 carriers. The results also emphasize the importance of assessing smoking history when examining APOE and cognition and are an example of the complex interactions of age, genetics, health behaviors, and disease history in determining cognitive function.

Implications for Cancer Survivors

These results help explain why only a subset of breast cancer survivors appear to be vulnerable to cognitive problems.
Appendix
Available only for authorised users
Literature
1.
Ahles TA, Root JC. Cognitive effects of cancer and cancer treatments. Annu Rev Clin Psychol. 2018;14:435–51.CrossRef
2.
Lange M, Joly F, Vardy J, Ahles T, et al. Cancer-related cognitive impairment: an update on state of the art, detection, and management strategies in cancer survivors. Ann Oncol. 2019;30:1925–40.PubMedCrossRef
3.
Pergolotti M, Luca Battisti NM, Padgett L, Sleight AG, et al. Embracing the complexity: older adults with cancer-related cognitive decline: a Young International Society of Geriatric Oncology position paper. Journal of Geriatric Oncology. 2020;11:237–43.PubMedCrossRef
4.
Magnuson A, Ahles TA, Chen BT, Mandelblatt J, Janelsins M. Cognitive function in older adults with cancer: assessment, management and research opportunities. J Clin Oncol. 2021;39:2138–49.PubMedPubMedCentralCrossRef
5.
Yamada TH, Denburg NL, Beglinger LJ, Schultz SK. Neuropsychological outcomes of older breast cancer survivors: cognitive features ten or more years after chemotherapy. J Neuropsychiatry Clin Neurosci. 2010;22:48–54.PubMedPubMedCentralCrossRef
6.
Hurria A, Rosen C, Hudis C, et al. Cognitive function of older patients receiving adjuvant chemotherapy for breast cancer: a pilot study in breast cancer. Journal of the American Geriatric Society. 2006;98:1742–5.
7.
Hurria A, Goldfarb S, Rosen C, et al. Effect of adjuvant breast cancer chemotherapy on cognitive function from the older patient’s perspective. Breast Cancer Res Treat. 2006;98:343–8.PubMedCrossRef
8.
Nguyen CM, Yamada TH, Beglinger L, Cavanaugh JE, Denburg N, Schultz SK. Cognitive features ten or more years after successful breast cancer survival: comparisons across types of cancer interventions. Psychooncology. 2013;22:862–8.PubMedCrossRef
9.
Mandelblatt JS, Small BJ, Luta G, Hurria A, Jim H, McDonald BC, et al. Cancer-related cognitive outcomes among older breast cancer survivors in the thinking and living with cancer study. J Clin Oncol. 2018;36:3211–22.PubMedCentralCrossRef
10.
11.
Chang L, Weiner LS, Hartman SJ, Horvath S, et al. Breast cancer treatment and its effects on aging. J Geriatric Oncol. 2019;10:346–55.CrossRef
12.
Salas-Ramiriz KY, Bagnall C, Abdali FCSA, Ahles TA, et al. Doxorubicin and cyclophosphamide induce cognitive dysfunction and activate ERK and AKT signaling pathways. Behavioural Brain Research. 2015;292:133–41.CrossRef
13.
Bagnall-Moreau C, Chaudhry S, Salas-Ramirez K, Ahles TA, et al. Chemotherapy-induced cognitive impairment is associated with increased inflammation and oxidative damage in the hippocampus. Mol Neurobiol. 2019;56:7159–72.PubMedPubMedCentralCrossRef
14.
Ahles TA, Root JC, Ryan EL. Cancer- and cancer-treatment-associated cognitive change: an update of the state of the science. J Clin Oncol. 2012;30:3675–86.PubMedPubMedCentralCrossRef
15.
Mandelblatt JS, Jacobsen PB, Ahles TA. Cognitive effects of cancer systemic therapy: implications for the care of older patients and survivors. J Clin Oncol. 2014;32:2617–26.PubMedPubMedCentralCrossRef
16.
17.
Fernandez HR, Varma A, Flowers SA, Rebeck GW. Cancer chemotherapy related cognitive impairment and the impact of the Alzheimer’s disease risk factor apoe. Cancers. 2020;12:3842.PubMedPubMedCentralCrossRef
18.
Tai LM, Thomas R, Marottoli FM, Koster KP, et al. The role of APOE in cerebrovascular dysfunction. Acta Neuropathol. 2016;13:709–23.CrossRef
19.
Piers RJ. Structural brain volume differences between cognitively intact ApoE4 carriers and non-carriers across the lifespan. Neural Regen Res. 2018;13:1309–12.PubMedPubMedCentralCrossRef
20.
Ahles TA, Saykin AJ, Noll WW, et al. The relationship of APOE genotype to neuropsychological performance in long-term cancer survivors treated with standard dose chemotherapy. Psychooncology. 2003;12:612–9.PubMedCrossRef
21.
Ahles TA, Li Y, McDonald BC, et al. Longitudinal assessment of cognitive changes associated with adjuvant treatment for breast cancer: the impact of APOE and smoking. Psychooncology. 2014;23:1382–90.PubMedPubMedCentralCrossRef
22.
Amidi A, Agerbaek M, Wu LM, et al. Changes in cognitive functions and cerebral grey matter and their associations with inflammatory markers, endocrine markers, and APOE genotypes in testicular cancer patients undergoing treatment. Brain Imaging Behav. 2017;11:769–83.PubMedCrossRef
23.
Correa DD, Satagopan J, Baser RE, et al. APOE polymorphisms and cognitive functions in patients with brain tumors. Neurology. 2014;83:1–8.CrossRef
24.
Reitz C, Luchsinger J, Tang MX, Mayeuz R. Effect of smoking and time on cognitive function in the elderly without dementia. Neurology. 2005;65:870–5.PubMedCrossRef
25.
Sabina S, Kiyimaki M, Kumari M, et al. Effect of apolipoprotein E4 on the association between health behaviors and cognitive function in late midlife. Mol Neurodegener. 2010;5:1–7.
26.
Dufouil C, Tzourio C, Brayne C, et al. Influence of apolipoprotein E genotype on the risk of cognitive deterioration in moderate drinkers and smokers. Epidemiology. 2000;11:280–4.PubMedCrossRef
27.
Carmelli D, Swan GE, Reed T, et al. The effect of apolipoprotein E4 in the relationships of smoking and drinking to cognition. Neuroepidemiology. 1999;18:125–33.PubMedCrossRef
28.
Slotkin TA. Nicotine and the adolescent brain: insights from an animal model. Neurotoxicol Teratol. 2002;24:369–84.PubMedCrossRef
29.
Katzman R, Brown T, Fuld P, et al. Validation of a short orientation-memory-concentration test of cognitive impairment. Am J Psychiatry. 1983;140:734–9.PubMedCrossRef
30.
Box GEP, Cox DR. An analysis of transformations. J Roy Stat Soc B. 1964;26:211–52.
31.
Wilkinson G, Robertson G. Wide Range Achievement Test 4 (WRAT4). Lutz, FL: Psychological Assessment Resources, 2006.
32.
33.
Weintraub S, Salmon D, Mercaldo N, Ferris S, et al. The Alzheimer’s disease centers’ uniform data set (UDS): the neuropsychological test battery. Alzheimer Dis Assoc Disord. 2009;23:91–101.PubMedPubMedCentralCrossRef
34.
Benton A. Differential behavioral effects in frontal lobe disease. Neuropsychologia. 2006;6:53–60.CrossRef
35.
Reitan R, Wolfson D. The Halstead-Reitan neuropsychological test battery. Tucson: AZ, Neuropsychological Press; 1985.
36.
Delis DC, Kaplan E, Kramer JH. Delis-Kaplan executive function system. San Antonio, TX: The Psychological Corporation; 2001.
37.
Stern RA, White T. Neuropsychological assessment battery (NAB). Psychological Assessment Resources (PAR), Lutz, Fl. 2003.
38.
Stern RA, White T. NAB psychometric and technical manual. Lutz, FL: Psychological Assessment Resources, 2003.
39.
WMS-R - Wechsler D. WMS-R: Wechsler Memory Scale–Revised. San Antonio, TX: Psychological Corporation; 1987.
40.
Radloff LS. The CES-D scale: a self-report depression scale for research in the general population. Appl Pscyhol Measurement. 1977;1:385–401.CrossRef
41.
Spielberger CD. Manual for the State-Trait Anxiety Inventory (STAI: Form Y). Palo Alto: Consulting Psychologists Press; 1983.
42.
Hann DM, Jacobsen PB, Martin SC, et al. Fatigue in women treated with bone marrow transplantation for breast cancer: a comparison with women with no history of cancer. Support Care Cancer. 1997;5:44–52.PubMedCrossRef
43.
44.
Orlow I, Reiner AS, Thomas NE, Roy P, et al. Vitamin D receptor polymorphisms and survival in patients with cutaneous melanoma: a population-based study. Carcinogenesis. 2016;37:30–8.PubMedCrossRef
45.
Mahley RW, Rall SC. Apolipoprotein E: far more than a lipid transport protein. Annu Rev Genomics hum Genet. 2000;1:507–37.PubMedCrossRef
46.
47.
Gelman A, Rubin DB. Inference from iterative simulation using multiple sequences. Stat Sci. 1992;7:457–72.CrossRef
48.
49.
Gelman A, Jakulin A, Grazia Pittau M, Su Y-S. A weakly informative default prior distribution for logistic and other regression models Annals of. Appl Stat. 2008;2008(2):1360–83.
50.
51.
Horton NJ, Brown ER, Qian LJ. Use of R as a toolbox for mathematical statistics exploration. Am Stat. 2004;58:343–57.CrossRef
52.
Ahles TA, Schofield E, Li Y, Ryan E, Root JC, Patel SK, McNeal K, Gaynor A, Tan H, Katheria V, Vazquez J, Traina T, Hurria A. Relationship between cognitive functioning and frailty in older breast cancer survivors. J Geriatr Oncol. 2022;13:27–32.PubMedCrossRef
53.
Small BJ, Raswon KS, Walsh E, et al. Catechol-O-methyltransferase genotype modulates cancer treatment-related cognitive deficits in breast cancer survivors. Cancer. 2011;117:1369–76.PubMedCrossRef
54.
Cheng H, Wen L, Gan C, et al. The COMT (re165599) gene polymorphism contributes to chemotherapy-induced cognitive impairment in breast cancer patients. Am J TSransl Res. 2016;8:5087–97.
55.
Li W, Shao J, Ding K, et al. Catechol-O-methyltransferase gene polymorphisms and the risk of chemotherapy-induced prospective memory impairment in breast cancer patients with varying tumor hormonal receptor expression. Med Sci Monit. 2020;26:e923567.PubMedPubMedCentral
56.
Vega JN, Albert KM, Mayer IA, Taylor WD, Newhouse PA. Nicotinic treatment of post-chemotherapy subjective cognitive impairment: a pilot study. J Cancer Surviv. 2019;13:673–86.PubMedPubMedCentralCrossRef
57.
Majdi A, Sadigh-Eteghad S, Gjedde A. Effects of transdermal nicotine delivery on cognitive outcomes: a meta-analysis. Acta Neurol Scand. 2021;144:179–91.PubMedCrossRef
58.
Durazzo TC, Mattsson N, Weiner WW. Interaction of cigarette smoking history with APOE genotype and age on amyloid level, glucose metabolism, and neurocognition in cognitively normal elders. Nicotine Tob Res. 2016;18:204–11.PubMedCrossRef
59.
Amini R, Sahli M, Ganai S. Cigarette smoking and cognitive function among older adults living in the community Neuropsychology, Development, and Cognition. Sect B, Aging, Neuropsychol Cognition. 2021;28:616–31.CrossRef
60.
Mortensen EL, Hogh P. Gender differences in the association between APOE genotype and age-related cognitive decline. Neurology. 2001;57:89–95.PubMedCrossRef
61.
Damoiseaux JS, Seeley WW, Zhou J, Shirer WR, et al. Gender modulates the APOE epsilon4 effect in healthy older adults: convergent evidence from functional brain connectivity and spinal fluid tau levels. J Neurosci. 2012;32:8254–62.PubMedPubMedCentralCrossRef
62.
Zhang Q, Wu L, Du C, Xu K, et al. Effects of an APOE promoter polymorphism on fronto-parietal functional connectivity during nondemented aging. Front Aging Neurosci. 2020;12:183.PubMedPubMedCentralCrossRef
63.
Laws SM, Clarnette RM, Taddei K, Martins G, et al. APOE- ε4 and APOE-491A polymorphisms in individuals with subjective memory loss. Mol Psychiatry. 2002;7:768–75.PubMedCrossRef
Metadata
Title
The impact of APOE and smoking history on cognitive function in older, long-term breast cancer survivors
Authors
Tim A. Ahles
Irene Orlow
Elizabeth Schofield
Yuelin Li
Elizabeth Ryan
James C. Root
Sunita K. Patel
Katrazyna McNeal
Alexandra Gaynor
Heidi Tan
Vani Katheria
Jessica Vazquez
Sergio Corrales–Guerrero
Keimya Sadeghi
Tiffany Traina
Arti Hurria
Publication date
24-10-2022
Publisher
Springer US
Published in
Journal of Cancer Survivorship / Issue 2/2024
Print ISSN: 1932-2259
Electronic ISSN: 1932-2267
DOI
https://doi.org/10.1007/s11764-022-01267-z

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