2023 Alzheimer's Association Clinician Scientist Fellowship (AACSF)
Chemotherapy as a risk factor for dementia: the role of senescence and APOE
How does cognitive impairment following cancer treatment relate to genetic risk factors for developing Alzheimer’s?
Matthew Torre, M.D.
Brigham and Women's Hospital
Boston, MA - United States
Background
ApoE is a protein produced by the apolipoprotein E (APOE) gene, and it is thought to help carry lipids (fats) throughout the body. There are several APOE gene variations and, in some populations, the APOE-e4 version is thought to be the largest genetic risk factor for developing Alzheimer’s. APOE-e4 also leads to a greater susceptibility to chemotherapy-related cognitive impairment (CRCI), a decline in memory following cancer treatment.
Dr. Matthew Torre proposes that APOE-e4 may contribute to the development of senescence (aging cells during which the cells become unable to divide) in brain cells after chemotherapy. Senescent cells have been shown to increase levels of inflammation, and previous studies demonstrate that “senolytics” (chemical compounds that clear away senescent cells) can improve cognition in genetically engineered Alzheimer's-like mice.
Research Plan
To determine whether clearance of senescent cells may be a beneficial treatment for CRCI, the researchers will examine genetically engineered CRCI-like mice that contain either APOE-e4 or APOE-e3 (a version not associated with increased or decreased risk for development of Alzheimer’s). Following chemotherapy treatment, the scientists will observe whether different APOE versions lead to increases in the number of senescent cells or impairments in cognition. They will then treat mice with senolytic compounds to determine if removal of senescent cells improves cognition.
Impact
This study will help researchers understand how APOE-e4 affects the occurrence of CRCI. This work may also determine whether senolytics are a beneficial treatment for CRCI and Alzheimer’s.