Septhohippocamal connectome dysfunction in Down syndrome associated with Alzheimer’s disease pathophysiology

Down syndrome (DS) is the most common genetic cause of intellectual disability, and individuals with DS transition to Alzheimer’s disease (AD) by early midlife, developing premature dementia and pathological hallmarks of AD including amyloid-beta and tau pathology, synaptic deficits, and neurodegeneration of key circuits underlying memory, attention, and executive function including the septohippocampal and basocortical connectomes. We propose to define underlying mechanisms how DS-driven gene-level alterations in key neuronal networks regulating cognitive abilities impact function, and link DS to AD onset and/or progression through a multidisciplinary approach including single population RNA sequencing (RNA-seq) and electrophysiological studies using an established trisomic mouse model of DS and AD, human induced neurons (HiN) derived from DS, AD, and control fibroblasts, along with analogous profiling of septohippocampal and basocortical neurons from postmortem DS, AD, and age-matched nondemented control brains. Leveraging rigorous preliminary data, we hypothesize neuronal signaling dysfunction and mitochondrial/oxidative phosphorylation deficits, driven by gene and pathway level changes, underlie cognitive decline associated with memory, attention, and executive function failure in DS preceding the transition to AD.