PROJECT SUMMARY/ABSTRACT
Down syndrome (DS) is a developmental genetic condition caused by trisomy of human chromosome 211-6. DS occurs
in approximately 1 in 600-1000 live births and affects more than 300,000 individuals in the USA. Neuropathological
and clinical features of Alzheimer’s disease (AD) present early in life through the seventh decade in a predictable
sequence of events, and include amyloid plaques, neurofibrillary tangles, nerve growth factor (NGF) dysmetabolism
and cholinergic basal forebrain degeneration, CNS inflammation, and cognitive decline1-10. DS is an outstanding
natural genetic model for the study of AD pathophysiology, AD biomarkers research and to conduct
preventive clinical trials. 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. For this
INCLUDE application, our overall goal is to investigate DS-specific pathophysiological mechanisms of AD
and identify novel biomarkers within and outside of the AT(N) framework, with a special focus on immune
and NGF dysregulation at different stages of AD pathology in DS by capitalizing on the ongoing highly successful
collaboration between our teams: Jorge Busciglio (University of California, Irvine, USA), Claudio Cuello (McGill
University, Montreal, Canada), Thomas Wisniewski (New York University, NY, USA) and Juan Fortea (Hospital of
Sant Pau, Barcelona, Spain)7-9, 11, 12.
We propose to test the central hypothesis that CNS inflammation and NGF metabolic dysfunction are early and key
pathophysiological mechanisms leading to neurodegeneration, accelerated aging and cognitive decline in DS. As
detailed below, we will utilize a novel approach combining unbiased discovery (transcriptomics and proteomics)
(Aim 1) and targeted biomarker analyses (Aim 2), using multiple complementary model systems, to establish a
model of the temporal relationship between immune and NGF dysregulation and AD-related
neurodegenerative changes in persons with DS (Aim 3). This will be achieved by correlating our findings with AD
pathology, related biofluidic and imaging biomarker data from among the largest well characterized, DS patient
population found globally. We propose the following 3 aims:
Aim 1: To elucidate the relationships between immune deregulation and NGF dysmetabolism with AT(N)
hallmarks in the DS brain and in human trisomy 21 cortical cultures.
Aim 2: To investigate the presence of immune dysregulation and NGF dysmetabolism markers in plasma and
CSF and in extracellular vesicles derived from brain tissue, primary cultures and body fluids across the AD
continuum in DS.
Aim 3: To establish the temporal ordering of immune dysregulation and NGF dysmetabolism with respect to
the AT(N) framework within a cohort of adults with DS assessed longitudinally with multimodal biomarkers.
The comprehensive combination of neuropathological, cellular, and clinical studies using the same biomarkers will
lead to a detailed characterization of the role of immune and trophic factor alterations in the development of AD
pathology and associated cognitive decline in DS. Guided by the INCLUDE initiative goals, the results will inform
future preventive trials and assist in the prediction of the onset and evolution of AD dementia and in the identification
of potential novel biomarkers and therapeutic targets in this vulnerable population.
