Abstract

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.

Aims

About the Consortium

The Consortium is a large, multidisciplinary team of clinicians, human geneticists, developmental psychologists, mouse geneticists, psychiatrists and cellular scientists, funded by the Wellcome Trust.

Aim of the Project
We are investigating the link between Down syndrome and Alzheimer’s disease from the different perspectives of our fields. People with Down syndrome are predisposed to developing Alzheimer’s disease and we are working together towards finding out why. We hope that working together, across disciplines, will be mutually beneficial and enrich our findings leading to a better and deeper understanding of why people with Down syndrome are predisposed to develop dementia and what the differences are between people with Down syndrome who do and do not develop dementia in later life.

The project aims to explore the cognitive, genetic and cellular factors underlying individual differences in susceptibility to Alzheimer’s disease in both our participants and through the use of mouse models. We are also interested in individual differences in cognitive abilities and brain activity and have designed our assessment battery to encompass all of these objectives.