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. Down Syndrome (DS) is the most common condition involving learning disability, and arises because people have an extra copy of chromosome number 21. This proposal is for cutting-edge inter-disciplinary research by leading geneticists, psychiatrists and neuroscientists to understand how learning disabilities develop in people with DS and to identify the processes involved in the decline that often occurs as people with DS age. We will link with US and European colleagues to develop similar asses sments for babies and adults with DS. We will particularly focus on individual differences and sub-groups in DS to understand for example why some go on to develop dementia. Participants will be asked for sputum or blood tests and hair samples for genetic analyses to identify the genes involved in DS learning and ageing. We will also study cultured cells from DS people to examine related processes. We will link this work with studying similar functions in specially created mice to help us unders tand the biology of DS. This research will reveal how genes influence brain functions throughout life in people with DS and will lead, we hope, to treatments to prevent decline and improve brain function, which can be tested in clinical trials.