Amy Chung

Introduction. Alzheimer’s Disease (AD) is a progressive neurodegenerative disease that is responsible for 50-75% of dementia cases and is one of the leading causes of death in the world¹. It affects individuals over the age of 65 and clinical presentation includes worsening progressive impairment of cognition and function. Due to confounding variables of comorbidities, the diagnosis and cause of AD has been difficult to establish¹. However, it has been recognized that apolipoprotein E4 (ApoE4) is considered to be one of the strongest genetic risk factors for developing AD. This may be in part due to ApoE4 induced neuronal hyperactivity, which may influence faster neurodegeneration².  Methods. To evaluate neuronal hyperactivity, the entorhinal cortex (EC) of mice with ApoE3 and ApoE4 isoforms was observed using fMRI to generate cerebral blood volume (CBV) maps. In vitro and in vivo electrophysiology were performed by placing tetrodes in the brains of the mice and LFP recordings were performed twice a day. Brain tissue samples were obtained for LTP induction and the signals were used to compare neuronal firing. Additional brain tissue samples from the EC were obtained for metabolite profiling using chromatography and mass analysis². Results. CBV maps showed increased cerebral blood flow during resting state in the bilateral hippocampal formations with centralization around the lateral region of the EC and CA1 region of the hippocampus in ApoE4 carriers. There was also an increased firing rate of excitatory neurons in the EC of ApoE4 carriers compared to ApoE3, which suggests that there may be decreased response to GABAergic inhibitory inputs in EC pyramidal neurons². The ApoE4 mice were also found to have higher basal brain metabolism at the hippocampal formations and lateral regions of EC compared to ApoE3 mice. They had upregulation of ATP and other mitochondrial metabolites, which supported that ApoE4 mice had neuronal hyperactivity². Conclusion.  ApoE4 carriers have been found to have anomalies in regions of the brain that are highly associated with AD. It is proposed that the neuronal hyperactivity seen in ApoE4 carriers may accelerate the accumulation of tau and Aβ, which would hasten neurodegeneration and cause earlier onset of AD². Based on the influence of ApoE4 on AD onset, it may be beneficial to perform future studies on genetic targeting of the ApoE4 polymorphic allele.

1.  Masters CL, Bateman R, Blennow K, Rowe C1C, Sperling RA, Cummings JL. Alzheimer’s disease. Nature Review Disease Primers. 2015;1:15-56. doi: 10.1038/nrdp.2015.56.
2. Nuriel T, Angulo SL, Khan U, et al. Neuronal hyperactivity due to loss of inhibitory tone in APOE4 mice lacking Alzheimer’s disease-like pathology. Nat Commun. 2017;8(1):1464. doi:10.1038/s41467-017-01444-0