The cholinergic integrity in Down syndrome in association with aging, Alzheimer's disease pathology, and cognition

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PROJECT SUMMARY Down Syndrome (DS) is the leading cause of a genetically-defined intellectual disability, affecting all racial and socioeconomic groups. In addition to intellectual disability, most individuals with DS show characteristics of premature aging and early presentation of Alzheimer’s disease (AD)-like neuropathology and dementia. AD in DS may be driven by triplication of the amyloid precursor protein gene, but other neurodegenerative features of sporadic AD may occur in DS. Understanding these neurodegenerative processes is critical to assessing how similar or different AD in DS is to sporadic AD and how these factors influence the onset of cognitive decline and dementia in DS. In sporadic AD, progressive cognitive deficits are associated with the degeneration of specific neuronal populations, most notably the cholinergic neurons. The loss of cholinergic integrity negatively affects the cognitive performance, particularly in attention, learning, and memory formation. However, the brain cholinergic system has not been evaluated in adult with DS. Current cholinergic markers do not directly measure the cholinergic integrity/function, thereby showing modest translatability for monitoring disease progression or treatment evaluation. We propose to use a novel positron emission tomography (PET) radiotracer, known as [18F]FEOBV, as a direct/specific method for assessing the brain cholinergic integrity in non-demented adults with DS in relationship to age, cognitive/neurobehavioral alterations, and biomarkers of AD pathologies to establish whether the proposed cholinergic biomarker can serve as a novel endpoint for AD clinical trials in DS that best reflect disease progression. The Center for Cognitive Medicine is a site for the Trial- Ready Cohort-Down Syndrome (TRC-DS) study, to enable a systematic biomarker characterization of middle aged and older individuals with DS by using neuroimaging, cognitive, and clinical measures, in preparation for an AD-like prevention trial (likely using anti-amyloid agents). Facilitated by the TRC-DS (as a parent study), which provides well-characterized DS subjects, we propose to initiate a new pathway for investigating our novel cholinergic biomarker. The examination of cholinergic system in DS and its relationship to aging and known AD pathologies and cognitive decline would help validate whether cholinergic decline is an early marker of dementia risk in DS and proceeds or follows changes in standard AD imaging and fluid biomarkers, thus helping establish how similar AD in DS is to that of sporadic AD. Also, our cholinergic biomarker may identify whether individuals with DS are likely to respond to future pro-cholinergic interventions, including the novel cholinergic modulators that are being developed to enhance cholinergic-sensitive cognitive functioning. We anticipate using the data gathered here to inform future treatment studies in TRC-DS where novel cholinergic treatments may offer opportunities for early intervention in DS and be complementary to disease-modifying approaches such as anti- amyloid treatments.