INCLUDE Grants​

The role of immune deregulation and NGF dysmetabolism in the development of Alzheimer disease in individuals with Down syndrome

Busciglio, Jorge ACuello, A ClaudioFortea, JuanWisniewski, Thomas M

Down syndrome (DS) is a developmental genetic condition caused by trisomy of human chromosome 21. DS occurs in approximately 1 in 600-1000 live births and is estimated to affect more than 300,000 individuals in the USA. Neuropathological and clinical features of Alzheimer’s disease (AD) present early in life through the sixth decade, and include amyloid plaques, neurofibrillary tangles, NGF dysmetabolism and cholinergic basal forebrain degeneration, CNS inflammation, and cognitive decline leading to AD dementia. Despite the molecular and genetic similarities between AD and DS, there exists a paucity of information on the biological mechanisms underlying the onset of cognitive decline in adults with DS. Responding to the INCLUDE initiative, the overall goal of this proposal is to investigate pathophysiological mechanisms and novel biomarkers in different stages of AD in DS. The proposed studies use a multidisciplinary and complementary approach, which includes biochemical analysis of plasma, CSF, and extracellular vesicles (EVs), neuropathological assessments, trancriptomics, proteomics, in vitro cellular/molecular analyses, and a well-characterized cohort of DS individuals to uncover the molecular pathobiological progression of AD in DS. This powerful combination of neuropathological, cellular, and clinical studies using the same biomarkers will lead to a detailed characterization of AD stages that will enable a precision medicine approach that will inform future preventive trials and assist in the prediction of the onset and evolution of AD dementia and in the identification of novel therapeutic targets in this vulnerable population.