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, but 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
There are no proven drug treatments for chemo brain. 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
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
Focal white matter microstructural alteration after anthracycline-based systemic treatment in long-term breast cancer survivors: a structural magnetic resonance imaging study
Zhang H, Li P, Liu T, Wang X, Feng W, Chen R, et al. Focal white matter microstructural alteration after anthracycline-based systemic treatment in long-term breast cancer survivors: a structural magnetic resonance imaging study. Brain Imaging and Behavior. Springer Science and Business Media LLC; 2021; 10.1007/s11682-021-00551-3
125P Cognitive impairment in breast cancer patients up to 18 months after cancer treatments: The French multicentric longitudinal CANTO-Cog cohort substudy
Lobbedez FJ, Hardy-Léger I, Arbogast SL, Rigal O, Le Fel J, Pistilli B, et al. 125P Cognitive impairment in breast cancer patients up to 18 months after cancer treatments: The French multicentric longitudinal CANTO-Cog cohort substudy. Annals of Oncology. Elsevier BV; 2021; 32:S412-S413 10.1016/j.annonc.2021.08.406
Inverse Correlation Between Alzheimer’s Disease and Cancer: Short Overview
Zabłocka A, Kazana W, Sochocka M, Stańczykiewicz B, Janusz M, Leszek J, et al. Inverse Correlation Between Alzheimer’s Disease and Cancer: Short Overview. Molecular Neurobiology. Springer Science and Business Media LLC; 2021; 10.1007/s12035-021-02544-1
Cancer-related cognitive impairment is associated with perturbations in inflammatory pathways
Oppegaard K, Harris CS, Shin J, Paul SM, Cooper BA, Chan A, et al. Cancer-related cognitive impairment is associated with perturbations in inflammatory pathways. Cytokine. Elsevier BV; 2021; 148:155653 10.1016/j.cyto.2021.155653
Behavioral and morphological effects of resveratrol and curcumin in rats submitted to doxorubicin-induced cognitive impairment
Moretti R, Dias E, Kiel S, Augusto M, Rodrigues P, Sampaio A, et al. Behavioral and morphological effects of resveratrol and curcumin in rats submitted to doxorubicin-induced cognitive impairment. Research in Veterinary Science. Elsevier BV; 2021; 10.1016/j.rvsc.2021.09.009
Luteolin mitigates tamoxifen-associated fatty liver and cognitive impairment in rats by modulating beta-catenin
El-Asfar RK, El-Derany MO, Sallam AM, Wahdan SA, El-Demerdash E, Sayed SA, et al. Luteolin mitigates tamoxifen-associated fatty liver and cognitive impairment in rats by modulating beta-catenin. European Journal of Pharmacology. Elsevier BV; 2021; 908:174337 10.1016/j.ejphar.2021.174337
Chemo-Brain: An Activation Likelihood Estimation Meta-Analysis of Functional Magnetic Resonance Imaging Studies
Bernstein LJ, Edelstein K, Sharma A, Alain C. Chemo-Brain: An Activation Likelihood Estimation Meta-Analysis of Functional Magnetic Resonance Imaging Studies. Neuroscience & Biobehavioral Reviews. Elsevier BV; 2021; 10.1016/j.neubiorev.2021.08.024
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
Physical Activity Patterns and Relationships With Cognitive Function in Patients With Breast Cancer Before, During, and After Chemotherapy in a Prospective, Nationwide Study
Salerno EA, Culakova E, Kleckner AS, Heckler CE, Lin P, Matthews CE, et al. Physical Activity Patterns and Relationships With Cognitive Function in Patients With Breast Cancer Before, During, and After Chemotherapy in a Prospective, Nationwide Study. Journal of Clinical Oncology. American Society of Clinical Oncology (ASCO); 2021;:JCO.20.03514 10.1200/jco.20.03514
Endocrine therapy with or without CDK4/6 inhibitors in women with hormone-receptor positive breast cancer: What do we know about the effects on cognition?
Kjoe PRLM, van der Wall E, Schagen SB. Endocrine therapy with or without CDK4/6 inhibitors in women with hormone-receptor positive breast cancer: What do we know about the effects on cognition?. Clinical Breast Cancer. Elsevier BV; 2021; 10.1016/j.clbc.2021.08.002
Long-term Dietary Flavonoid Intake and Subjective Cognitive Decline in US Men and Women
Yeh T, Yuan C, Ascherio A, Rosner B, Willett W, Blacker D. Long-term Dietary Flavonoid Intake and Subjective Cognitive Decline in US Men and Women. Neurology. Ovid Technologies (Wolters Kluwer Health); 2021;:10.1212/WNL.0000000000012454 10.1212/wnl.0000000000012454
Cognitive dysfunction prevalence and associated factors in older breast cancer survivors
Crouch A, Champion VL, Unverzagt FW, Pressler SJ, Huber L, Moser LR, et al. Cognitive dysfunction prevalence and associated factors in older breast cancer survivors. Journal of Geriatric Oncology. Elsevier BV; 2021; 10.1016/j.jgo.2021.07.001
High coffee consumption, brain volume and risk of dementia and stroke
Pham K, Mulugeta A, Zhou A, O’Brien JT, Llewellyn DJ, Hyppönen E. High coffee consumption, brain volume and risk of dementia and stroke. Nutritional Neuroscience. Informa UK Limited; 2021;:1-12 10.1080/1028415x.2021.1945858
Impact of chemotherapy on cognitive functioning in older patients with HER2-positive breast cancer: a sub-study in the RESPECT trial
Hagiwara Y, Sawaki M, Uemura Y, Kawahara T, Shimozuma K, Ohashi Y, et al. Impact of chemotherapy on cognitive functioning in older patients with HER2-positive breast cancer: a sub-study in the RESPECT trial. Breast Cancer Research and Treatment. Springer Science and Business Media LLC; 2021; 10.1007/s10549-021-06253-0
Trajectories of cognitive performance over five years in a prospective cohort of patients with breast cancer (NEON-BC)
Araújo N, Severo M, Lopes-Conceição L, Fontes F, Dias T, Branco M, et al. Trajectories of cognitive performance over five years in a prospective cohort of patients with breast cancer (NEON-BC). The Breast. Elsevier BV; 2021; 10.1016/j.breast.2021.05.006
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
Effects of tamoxifen on cognition and language in women with breast cancer: A systematic search and a scoping review
Jebahi F, Sharma S, Bloss JE, Wright HH. Effects of tamoxifen on cognition and language in women with breast cancer: A systematic search and a scoping review. Psycho-Oncology. Wiley; 2021; 30:1262-1277 10.1002/pon.5696
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
Cognitive Reserve, Incident Cancer, and Rate of Memory Decline in Later Life
Romero MO, Brenowitz W, Hayes-Larson E, Ackley SF, Mayeda ER, Glymour MM, et al. Cognitive Reserve, Incident Cancer, and Rate of Memory Decline in Later Life. Innovation in Aging. Oxford University Press (OUP); 2020; 4:146-146 10.1093/geroni/igaa057.477