Background

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and a major public health challenge, affecting more than 7 million Americans. It is characterized by cognitive decline, particularly in memory, attention, and executive function, and is associated with high morbidity and mortality. Hallmark features of AD include amyloid-beta plaque accumulation and neurofibrillary tangles, along with related pathological processes such as mitochondrial dysfunction, impaired autophagy, and degeneration of cholinergic pathways. Cholinergic projections are especially important for learning and memory, including projections from the medial septum to the hippocampus, a region critical for memory formation. This pathway is of particular interest because the hippocampus shows some of the earliest and most prominent pathological changes in AD. Degeneration of hippocampal cholinergic input may therefore contribute to early hippocampal dysfunction and memory impairment in the disease. Understanding how cholinergic circuit disruption interacts with other AD-related mechanisms may help identify targets for therapeutic intervention.

Hypothesis

 The granule cells of APOE4 mice receive increased glutamate inputs and decreased GABA inputs, resulting in neuronal hyperexcitability and amyloid β accumulation compared with APOE3 mice.