Chemotherapy for breast cancer can cause reduced cognitive functioning ("chemo brain" or "chemobrain"). Chemo brain is characterized by reduced verbal ability, impaired decision making, faulty short-term memory and other deficits. Chemo brain is the result of brain damage, much of which heals over time but some of which appears to persist for decades.
While there are no specific treatments for chemo brain, breast cancer survivors can adopt several strategies to address its symptoms.
Symptoms of chemo brain
At least one-third of women undergoing chemotherapy for breast cancer experience chemo brain during treatment and for some time afterwards. Studies using standard psychological testing have reported that chemotherapy reduces verbal ability, slows cognitive processing speed, impairs executive functioning, and reduces psychomotor processing speed. Cognitive processing speed refers to the ability to automatically and fluently perform relatively easy or routine cognitive tasks, especially when high mental efficiency (i.e., attention and focused concentration) is required. Executive functioning refers to the ability to organize thoughts and prioritize tasks, manage time well, make plans, and adapt to changing situations. Psychomotor processing speed refers to reaction time when a physical task is involved. It involves the coordination of a sensory or cognitive process and a motor activity.
The symptoms of chemo brain include slowed thinking and decision making, trouble remembering or spelling common words, problems with short-term memory and concentration, and reduced ability to multitask. There are glitches in the brain's operations. Unconscious mistakes can occur in tasks that are simple and routine. Typing and spelling errors may become common and all written work has to be checked for errors. Chemo brain can feel like moving through a fog, where the outlines of thoughts are indistinct and it's difficult for ideas to fully form. Conscious thinking itself can become more difficult, so that it takes effort to complete a thought or come to a conclusion.
Chemo brain is caused by brain injury
Researchers initially assumed that chemo brain did not involve actual physiological brain damage, in part because it was thought that chemotherapy did not cross the blood-brain barrier. Instead, the cognitive symptoms reported by women were studied as though they were primarily a consequence of depression or other emotional responses to breast cancer diagnosis and treatment. However, it has now been established that chemotherapy drugs can cause measurable brain damage in breast cancer patients. In fact, recent evidence suggests that cancer itself results in cognitive impairment, for reasons that have not been determined.
Breast cancer patients who have undergone chemotherapy have been shown to have reduced (1) activation in the left middle dorsolateral prefrontal cortex and premotor cortex; (2) left caudal lateral prefrontal cortex activation; (3) hippocampus size; and (4) white matter integrity compared to controls.
Studies that have compared women's brains before and after chemotherapy have reported (1) reduced left caudal lateral prefrontal cortex activation; (2) injury to white matter (likely reflecting a combination of axonal degeneration and demyelination); and (3) reduced gray matter density in bilateral frontal, temporal, and cerebellar regions and right thalamus.
A study of mice who were treated with CMF (methotrexate, cyclophosphamide, and 5-fluorouracil) chemotherapy demonstrated that methotrexate disrupted the formation of new nerve cells in the brain. Another study reported that rats treated with Adriamycin (doxorubicin) experienced significant declines in functional connectivity between the bilateral primary visual cortex and the right forelimb somatosensory cortex, and the right and left superior colliculus.
How long does chemo brain last?
Chemo brain normally starts to improve within one year of treatment and the improvement continues for an additional one to two years. However, some of the brain damage appears to be permanent. As mentioned above, chemotherapy can disrupt the formation of new nerve cells (neurogenesis) in the brain. Although there is some disagreement among researchers, neurogenesis appears to occur throughout adulthood and is controlled by cell cycle regulators. The hippocampus, a brain region important to memory and learning, is a primary site of neurogenesis. Chemotherapy drugs that act by inhibiting cell cycle progression appear to produce cognitive impairment by disrupting neurogenesis in the hippocampus. This means that neurogenesis can start to repair some of the damage caused by chemotherapy once treatment ends. The perception of being in a fog lifts and problems with short-term memory and executive functioning appear to resolve within one to five years of the end of treatment. However, problems with verbal fluency and psychomotor processing speed can persist long afterwards.
Long-term effects of chemotherapy on cognitive functioning
A 2012 Dutch study investigated whether cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy for breast cancer is associated with continued cognitive performance deficits more than two decades after treatment. CMF was the standard breast cancer chemotherapy from the 1970s to the 1990s. The study included 196 women with breast cancer who had been treated with CMF chemotherapy between 1976 and 1995 and a control sample of women never diagnosed with cancer. The average time since treatment was 21 years. Neuropsychological tests were used to compare the two groups. Women who had been treated with endocrine therapy (tamoxifen or aromatase inhibitor) or who had experienced a breast cancer recurrence were excluded from the study. Results were adjusted for age, level of education, and depression.
The women who received CMF chemotherapy were found to perform worse on cognitive tests than matched controls. The differences in performance were subtle and occurred primarily in word learning, memory and information processing speed. The breast cancer survivors also had lower scores on psychomotor speed (coordination of thinking and hand movement). The magnitude of the effects was comparable to approximately six years of age-related decline in cognitive function, according to the authors.
Risk factors for chemo brain
Not all women experience chemo brain, however predicting which women would be most susceptible is not possible. There is some evidence that old age, low cognitive reserve and depression each are associated with increased magnitude of the cognitive deficits associated with chemotherapy. Cognitive reserve refers to the difference between the cognitive performance predicted by an individual's level of brain pathology or injury and that individual's actual performance. In other words, those whose measured cognitive performance is better than predicted have high reserve, whereas those who perform worse than predicted have low reserve. This information does not appear to be particularly useful for determining who would be most susceptible to chemo brain.
Breast cancer patients can also adopt coping strategies designed to address specific chemo brain symptoms. First, it might be helpful to know that while chemo brain is unpleasant, it does not affect all areas of intelligence and it is to a great degree temporary. To address specific chemo brain symptoms, women can make lists and keep detailed calendars to organize their lives, become more systematic in their daily routines, check all their work or other written output, and prepare more thoroughly for business meetings or travel. In other words, women can take advantage of the more lucid times to organize and set up for the times when thinking is more difficult and less reliable.
Getting enough sleep (to facilitate the brain's memory storage and housekeeping functions) could be important. Turmeric has been shown to protect the brain from various types of injury and could possibly reduce the magnitude of chemo brain. It might also be helpful to avoid the factors listed in section below that are known to contribute to cognitive impairment in old age.
Preserving brain health in old age
Generally speaking, rates of cognitive impairment increase with age. However, individuals vary considerably and genetic heritage is only part of the reason. The following factors increase the likelihood of cognitive impairment in old age: depression; lack of exercise; diet high in saturated fat, trans fats and/or sugar; high levels of systemic inflammation; diabetes; high blood pressure; and high cholesterol. Maintaining satisfying social connections and a healthy lifestyle might protect against cognitive decline in some women.
Endocrine treatments can also impair cognitive functioning
Tamoxifen and aromatase inhibitors can also cause some of the symptoms of chemo brain in some women. However, this appears to be the result of brain estrogen deprivation, not outright brain damage. The symptoms caused by estrogen deprivation appear to improve within a year after endocrine treatment ends. Women who undergo radiotherapy can also experience chemo brain-like symptoms. While the reasons for this have not been explained, these symptoms also appear to be temporary. One major 2021 study found no links between use of endocrine treatments in non-metastatic breast cancer and risk of subsequent dementia.
Does chemo brain lead to Alzheimer's disease?
Although the evidence is mixed, chemo brain does not appear to lead directly to Alzheimer's disease in old age. Several studies have examined the question as to whether breast cancer patients who undergo chemotherapy have a higher risk of developing dementia in old age:
- A large prospective study that included 62,565 U.S. breast cancer patients who were at least 65 and free of cognitive impairments at diagnosis reported that the risk of developing Alzheimer disease, vascular dementia, or other dementias was lower in patients who received chemotherapy for breast cancer.
- Another study of older U.S. breast cancer survivors (2,913 of whom received chemotherapy and 18,449 who did not) reported that chemotherapy was not associated with a greater risk of the development of dementia over time for any of three age groups: 66 to 70, 71 to 75, or 76 to 80.
- A study that included 18,360 older women diagnosed with Stage II, III, or IV breast cancer found that there were significant differences at baseline between individuals who received and did not receive chemotherapy. In the first few years after breast cancer diagnosis, dementia was more common in women who had not had chemotherapy, probably reflecting group differences at baseline.
Strategies for coping with chemo brain
One small 2022 study reported that a probiotic supplement taken during treatment significantly reduced chemotherapy-related cognitive impairment. There are no proven drug treatments for chemo brain once it occurs. Regular exercise and other physical activity have been shown to improve executive function, information processing speed and concentration in women with chemo brain. Cognitive and memory training have been shown to improve cognitive function, memory, verbal functioning and orientation/attention, although studies are inconsistent.
Foods that help protect the brain
A wide variety of foods have been shown to have neuroprotective properties, in part by reducing oxidative stress in the brain. Generally speaking, high fruit and vegetable intake has been shown to be associated with better cognitive functioning in cancer survivors. Below are foods that have been demonstrated to have neuroprotective effects while at the same time protecting against breast cancer.
- Arctic char, wild
- Beans, black
- Bell peppers
- Black cumin
- Brussels sprouts
- Currants, black
- Grapes, red and muscadine
- Green tea
- Honey, min. processed
- Hot peppers
- Lake trout
- Lettuce, romaine
- Olives and olive oil
- Pistachio nuts
Alcohol can increase neural damage, as can exposure to bisphenol A (BPA), phthalates, and heavy metals such as cadmium, mercury and lead. Diets high in saturated fat, trans fats and/or sugar have been found to be associated with cognitive decline. The soy isoflavones genistein and daidzein have been shown to induce neurotoxicity at high concentrations and should not be taken as supplements. One study reported that mice fed a diet supplemented with canola oil showed signs of memory impairment compared to mice on a regular mouse chow diet. A 2021 study reported that high habitual caffeinated coffee intake (greater than 6 cups per day) was associated with lower brain volume and increased odds of dementia. High blood pressure, high cholesterol and high blood sugar also can harm the brain.
Below are links to recent studies concerning chemo brain. For a more complete list of studies, please click on chemo brain.
Selected breast cancer studies
An Examination of the Longitudinal Relationship Between Cognitive Function and Physical Activity Among Older Breast Cancer Survivors in the Thinking and Living With Cancer Study
Tometich DB, Mosher CE, Cyders M, McDonald BC, Saykin AJ, Small BJ, et al. An Examination of the Longitudinal Relationship Between Cognitive Function and Physical Activity Among Older Breast Cancer Survivors in the Thinking and Living With Cancer Study. Annals of Behavioral Medicine. Oxford University Press (OUP); 2022; 10.1093/abm/kaac048
1438P Effects of tamoxifen on cognitive functions in premenopausal patients with breast cancer: A cross-sectional study
Ferencz V, Tóth-Fáber E, Németh D, Landherr L, Tóth M. 1438P Effects of tamoxifen on cognitive functions in premenopausal patients with breast cancer: A cross-sectional study. Annals of Oncology. Elsevier BV; 2022; 33:S1201 10.1016/j.annonc.2022.07.1541
Elevated C-Reactive Protein and Subsequent Patient-Reported Cognitive Problems in Older Breast Cancer Survivors: The Thinking and Living With Cancer Study
Carroll JE, Nakamura ZM, Small BJ, Zhou X, Cohen HJ, Ahles TA, et al. Elevated C-Reactive Protein and Subsequent Patient-Reported Cognitive Problems in Older Breast Cancer Survivors: The Thinking and Living With Cancer Study. Journal of Clinical Oncology. American Society of Clinical Oncology (ASCO); 2022; 10.1200/jco.22.00406
Association of raloxifene and tamoxifen therapy with cognitive performance, odds of mild cognitive impairment, and brain MRI markers of neurodegeneration
Kara F, Lohse CM, Castillo AM, Tosakulwong N, Lesnick TG, Jack CR, et al. Association of raloxifene and tamoxifen therapy with cognitive performance, odds of mild cognitive impairment, and brain MRI markers of neurodegeneration. Cancer Medicine. Wiley; 2022; 10.1002/cam4.5175
Neural correlates in functional brain mapping among breast cancer survivors receiving different chemotherapy regimens: a qEEG/HEG-based investigation
Vasaghi Gharamaleki M, Mousavi SZ, Owrangi M, Gholamzadeh MJ, Kamali A, Dehghani M, et al. Neural correlates in functional brain mapping among breast cancer survivors receiving different chemotherapy regimens: a qEEG/HEG-based investigation. Japanese Journal of Clinical Oncology. Oxford University Press (OUP); 2022; 10.1093/jjco/hyac121
Cognitive function is well preserved in a cohort of breast cancer survivors: Roles of cognitive reserve, resilience, and general health
Liesto S, Sipilä R, Hietanen M, Kalso E. Cognitive function is well preserved in a cohort of breast cancer survivors: Roles of cognitive reserve, resilience, and general health. The Breast. Elsevier BV; 2022; 10.1016/j.breast.2022.07.013
The Effects of Chemotherapy on Circulating Plasma Omega-9, Omega-3 Fatty Acids and Plasmalogen in Breast Cancer Patients
Bennouna D, Orchard T, Lustberg M, Kopec R. The Effects of Chemotherapy on Circulating Plasma Omega-9, Omega-3 Fatty Acids and Plasmalogen in Breast Cancer Patients. Current Developments in Nutrition. Oxford University Press (OUP); 2022; 6:237-237 10.1093/cdn/nzac052.004
The Association of Serum Inflammatory Markers and Self-Reported Cognitive Outcomes in Women With Breast Cancer Undergoing Chemotherapy
Zhang Z, Schnell P, Ormiston K, Weinhold K, Kopec R, Lustberg M, et al. The Association of Serum Inflammatory Markers and Self-Reported Cognitive Outcomes in Women With Breast Cancer Undergoing Chemotherapy. Current Developments in Nutrition. Oxford University Press (OUP); 2022; 6:258-258 10.1093/cdn/nzac052.025
Effects of physical exercise on cognitive function of breast cancer survivors receiving chemotherapy: A systematic review of randomized controlled trials
Ren X, Wang X, Sun J, Hui Z, Lei S, Wang C, et al. Effects of physical exercise on cognitive function of breast cancer survivors receiving chemotherapy: A systematic review of randomized controlled trials. The Breast. Elsevier BV; 2022; 63:113-122 10.1016/j.breast.2022.03.014
Long-term changes of cognitive impairment among older breast cancer survivors
Luo J, Schousboe JT, Ensrud KE, Hendryx M. Long-term changes of cognitive impairment among older breast cancer survivors. Journal of Cancer Survivorship. Springer Science and Business Media LLC; 2022; 10.1007/s11764-022-01220-0
Abstract P4-11-09: Cancer-related cognitive impairment (CRCI) in early breast cancer (BC) survivors
Presti D, Joly F, Soldato D, Christodoulidis S, Noce AD, Havas J, et al. Abstract P4-11-09: Cancer-related cognitive impairment (CRCI) in early breast cancer (BC) survivors. Cancer Research. American Association for Cancer Research (AACR); 2022; 82:P4-11-09-P4-11-09 10.1158/1538-7445.sabcs21-p4-11-09
Inflammation, Attention, and Processing Speed in Patients with Breast Cancer before and after Chemotherapy
Belcher EK, Culakova E, Gilmore NJ, Hardy SJ, Kleckner AS, Kleckner IR, et al. Inflammation, Attention, and Processing Speed in Patients with Breast Cancer before and after Chemotherapy. JNCI: Journal of the National Cancer Institute. Oxford University Press (OUP); 2022; 10.1093/jnci/djac022
Cancer diagnosis is associated with a lower burden of dementia and less Alzheimer’s-type neuropathology
Karanth SD, Katsumata Y, Nelson PT, Fardo DW, McDowell JK, Schmitt FA, et al. Cancer diagnosis is associated with a lower burden of dementia and less Alzheimer’s-type neuropathology. Brain. Oxford University Press (OUP); 2022; 10.1093/brain/awac035
Probiotic supplement attenuates chemotherapy-related cognitive impairment in patients with breast cancer: a randomised, double-blind, and placebo-controlled trial
Juan Z, Chen J, Ding B, Yongping L, Liu K, Wang L, et al. Probiotic supplement attenuates chemotherapy-related cognitive impairment in patients with breast cancer: a randomised, double-blind, and placebo-controlled trial. European Journal of Cancer. Elsevier BV; 2022; 161:10-22 10.1016/j.ejca.2021.11.006
Impact of taxane-based chemotherapy among older women with breast cancer on cognition and quality of life: a longitudinal pooled analysis
Small BJ, Lange M, Zhai W, Ahn J, Ahles TA, Carroll JE, et al. Impact of taxane-based chemotherapy among older women with breast cancer on cognition and quality of life: a longitudinal pooled analysis. Breast Cancer Research and Treatment. Springer Science and Business Media LLC; 2021; 10.1007/s10549-021-06455-6
Paclitaxel Chemotherapy Induces Long-Term Memory Impairment and Neuroinflammation in a Mouse Model of Breast Cancer Survivorship
Chung N, Chang A, Gillis R, Sloan E, Walker AK. Paclitaxel Chemotherapy Induces Long-Term Memory Impairment and Neuroinflammation in a Mouse Model of Breast Cancer Survivorship. Research Square Platform LLC; 2021; 10.21203/rs.3.rs-783452/v1
Association of Endocrine Therapy and Dementia in Women with Breast Cancer
Thompson MR, Niu J, Lei X, Nowakowska M, Wehner MR, Giordano SH, et al. Association of Endocrine Therapy and Dementia in Women with Breast Cancer. Breast Cancer: Targets and Therapy. Informa UK Limited; 2021; Volume 13:219-224 10.2147/bctt.s300455
Protective Effects of APOE ε2 Genotype on Cognition in Older Breast Cancer Survivors: The Thinking and Living With Cancer Study
Van Dyk K, Zhou X, Small BJ, Ahn J, Zhai W, Ahles T, et al. Protective Effects of APOE ε2 Genotype on Cognition in Older Breast Cancer Survivors: The Thinking and Living With Cancer Study. JNCI Cancer Spectrum. Oxford University Press (OUP); 2021; 5 10.1093/jncics/pkab013
Cancer Chemotherapy Related Cognitive Impairment and the Impact of the Alzheimer’s Disease Risk Factor APOE
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. MDPI AG; 2020; 12:3842 10.3390/cancers12123842