The e4 variant of the APOE gene is the strongest risk factor for late onset Alzheimer’s disease (AD). There are 3 versions of the gene e2, e3 and e4. The e4 version is carried by 65% of AD patients and increases susceptibility to AD up to 15-fold. The 3 versions of the APOE gene encode corresponding versions of the APOE protein, which is produced by brain cells called astrocytes. AD was traditionally considered to result exclusively from dysfunctional nerve cells but recent findings challenge this view, implicating astrocytes in nerve cell death. Astrocytes are the most abundant cell type in the brain and provide critical support for nerve cells, which are, in turn, responsible for all thought processes. In AD nerve cells stop working properly, which is why cognitive ability declines. APOE keeps nerve cells healthy by enabling them to repair themselves, build connections and get rid of Beta-Amyloid, a toxic protein that builds up in the brain in AD. However, APOΕ4 is less effective than APOΕ2 or APOΕ3 at doing so. Elucidating why APOE4 is associated with AD has been limited by a lack of live human brain cells to study in AD. However, we can now produce astrocytes from skin cells to produce cells carrying either APOΕ3 or APOΕ4. We will use these cells to find out why APOE4 is such a strong risk factor for AD, and to what extent the risk depends on how the different form of APOE affect the properties of astrocytes.
