Request for enhancement funding LonDowns (360G-Wellcome-098330_Z_12_A)

Most studies treat Down syndrome (DS) as a single entity. Our novel aim is to focus on individual differences and subgroups at the cellular, genetic and cognitive levels to explain why the DS phenotype varies so much. For example, despite all DS individuals presenting with Alzheimer's Disease pathology, only a subgroup develops dementia. Is this due to cellular, molecular, genetic and/or cognitive differences? Can we identify these differences not only in adulthood, but also in infancy? If so, early diagnosis and intervention can be targeted. To study DS cognition longitudinally, we will develop comparable assessments for DS infants, adults and mouse models, to characterise deficits associated with hippocampal, cerebellar and frontal regions. Uniquely, we will correlate cognitive/genetic profiles with defects in neurogenesis, neurite/synapse plasticity, mitochondrial dysfunction, A-beta accumulation within participants neurons, differentiated from iPSC. We will create a Biobank and genotype/phenotype database as platforms for add-on pharmacologic/metabolomic/imaging projects, and clinical trials. This project aligns methods with other DS studies globally, but is unique in encompassing different age cohorts, integrating human cognitive development, ageing, neurobiology, genetics, cellular and mouse modelling. It is strategic for improved health, and timely, as therapies for DS cognitive deficits and decline are now realistic.