Fortea, Juan MD

Down syndrome (DS), the most frequent cause of intellectual disability and the most frequent form of Alzheimer´s disease (AD) of genetic origin, involves an ultra-high risk for developing AD (>95% in the seventh decade). While the age of AD onset in people with DS is on average ~20–30 years younger than in sporadic AD, there is considerable heterogeneity, with some individuals developing AD later in life. This project focuses on sleep disturbance and impaired circadian thermoregulation as potentially modifiable risk factors for AD, which may lead to interventions to delay AD onset in people with DS.

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.

Down syndrome (DS) is an outstanding natural genetic model for the study of neuropathological mechanisms of Alzheimer´s disease (AD) and for identifying potential AD biomarkers. The study of the Alzheimer's preclinical phase is crucial for the development of new future treatments that could eventually slow down or stop the progression of the disease before any cognitive decline. This competing revision application will provide additional biochemical biomarkers of neurodegeneration and oxidative stress, as well as neuroimaging studies in our well-characterized cohort which will significantly expand the relevance and impact of the original parent RO1.!