Hippocampal structural and functional alterations in Alzheimer's disease (AD), detected by advanced imaging methods, have been linked to significant abnormalities in multiple internal and external networks in this critical brain region. Uncovering the temporal and anatomical pattern of these network alterations would provide important clues into understanding the pathophysiology of AD and suggest new therapeutic strategies for this multi­system and prevalent disorder. Over the last decade, we have focused on studying brain structures that provide major projections to the hippocampus (HC) and the pattern of de-afferentation of this area in mouse models of AD and a related neurodegenerative disorder, i.e. Down syndrome (DS). Our studies have revealed that major inputs into the hippocampal structure undergo significant age-dependent alterations. Studying locus coeruleus (LC), the sole source of noradrenergic terminals for the HC, it has been shown that these neurons show significant age-dependent degeneration in both mouse models of DS and AD. Furthermore, increasing noradrenergic signaling was able to restore cognitive function by improving synaptic plasticity, and possibly promoting microglia recruitment, and amyloid β (Aβ) clearance in transgenic (tg) mouse models of AD. Here, we re-examine the effects of alterations in major inputs to the hippocampal region and their structural and functional consequences in mouse models of neurodegenerative disorders. We will conclude that improving the function of major hippocampal inputs could lead to a significant improvement in cognitive function in both AD and DS.