**2. Chemotherapy,** *ApoE* **and memory**

Over the last 20 years it has become apparent that chemotherapy drugs not only attack cancer cells, but also cross the blood brain barrier (BBB) leading to negative effects on cognitive processing which is known as Chemo-brain or Chem-fog [11,12]. Methotrexate, 5- Flourouracil (5-FU) the most common chemotherapy drugs used to treat breast, colorectal, head and neck cancers been shown in both rodent models and clinical studies to lead to neurocognitive deficits in a variety of domains including visual memory and visuospatial functioning [11,13,14]. In clinical studies, there is considerable variability between studies as to the extent and frequency of such impairments heretofore mentioned. However, rodent studies are clearly show that the drugs in the CMF (cyclophosphamide, methotrexate, 5-FU) regiment lead to decreased hippocampus cell proliferation and induce MWM memory impairments [15,16]. In addition, cytarabine (cytosine arabinoside) and ifosfamide among other chemotherapy have been shown to lead to memory impairments, hemiparesis, aphasia and progressive dementia [17]. However, there is significant lack of pre-clinical testing of most chemotherapeutic agents and their long-term effects on memory.

Currently, only one study has examined if *ApoE4* carrier status as a potential genetic risk factor in breast or lymphoma survivors. They have found that even after 8 years, *ApoE4* carriers displayed impairments, specifically in visual memory and spatial ability [18]. This suggests that the *ApoE* genotype may be a confounding factor to consider when examining post-chemotherapy neurocognitive status. More studies are necessary to confirm this result.

Studies in women treated with CMF regiment for breast cancer found increased total cholesterol, LDL, HDL cholesterol and Apolipoprotein A-1 (ApoA-1) in those who developed permanent amenorrhea (loss of menstrual cycle, induced menopause) [19]. Studies report that around 30% of patients who have gone through chemotherapy develop permanent amenorrhea [20]. There is evidence that *ApoE4* carriers have an earlier onset of natural menopause [21]. Age of menopause and being an *ApoE4* carrier are both risk factors for age related diseases including AD and coronary artery disease (CAD). There is also a direct connection between ApoE mRNA levels and estrogen in various tissues, including the brain [22] leading to regulation of neurite outgrowth [7]. The data suggests that ApoE is a critical intermediary in the estrogen related neuroplasticity [7]. Lack of estrogen along with expression of ApoE4 protein which has reduced ApoE functioning is one potential cause of impaired cognitive performance in some women that have undergone chemotherapy. Studies do not take this factor into account or narrowly examine menopausal status at the time of testing.
