Cholinergic Integrity in Down Syndrome in Association With Aging, Alzheimer’s Disease Pathology, and Cognition

Description

Down syndrome (DS) or Trisomy 21, is the most common genetic cause of intellectual disability. Among its consequences, by the age of 30, people with DS invariably develop amyloid plaques and neurofibrillary tangles such that up to 75% of people with DS will develop Alzheimer’s disease (AD). AD in DS is thought to be linked to the presence of three copies of the amyloid precursor protein (APP) gene, which resides on chromosome 21. This gene leads to higher levels of amyloid-β (Aβ) plaques. Preliminary data show that adults with DS exhibit significant changes in AD-related biomarkers between the ages of 35-55. It is also within this age range that AD-related cognitive decline and dementia typically manifest in DS. AD is the primary cause of death in adults with DS over the age of 35. Although it is currently suggested that the onset of dementia in DS is in part due to triplication of the amyloid precursor protein (APP) gene, other neurodegenerative features of sporadic AD may occur in DS and these can aggravate the onset of cognitive decline and dementia. Progressive cognitive deficits occurring in sporadic AD are associated with the degeneration of several neuronal populations. Throughout the progression of AD, the most consistent losses are seen in cholinergic neurons. While the loss of the cholinergic integrity has been established as a critical biological process in sporadic AD, the cholinergic system has not been evaluated in adults with DS to examine if age-related cholinergic decline can be detected in DS and whether it is associated with the progression of AD pathologies and cognitive decline as seen in sporadic AD.

The investigators propose to conduct a pilot study that aims to assess the integrity of the cholinergic neurotransmission system using in-vivo structural, functional, and molecular imaging biomarkers.

The examination of the cholinergic system in DS and its relationship to aging and known AD pathologies and cognitive decline would help validate whether the 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. The investigators anticipate using the data gathered here to inform future treatment studies where novel cholinergic treatments may offer opportunities for early intervention in DS and be complementary to disease-modifying approaches such as anti-amyloid treatments.

Objective: To examine the molecular, functional, and structural biomarkers of cholinergic integrity in Down syndrome (DS) in association with age, Alzheimer’s disease (AD) pathology, and cognitive/neurobehavioral performance.

Specific Aim: 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. The investigators will leverage this cohort’s well-characterized DS participants to initiate a new pathway for investigating our novel cholinergic biomarker in 10 TRC-DS participants (age:35-55) and enroll 110 additional adults with DS (age:18-55) outside of the TRC-DS study.

The investigators will use molecular, functional, and structural biomarkers to measure the cholinergic integrity of adults with DS. These methods will include resting and task-related electroencephalogram (EEG), basal forebrain volumetric measures on structural magnetic resonance imaging (MRI), and positron emission tomography (PET) with a vesicular cholinergic radiotracer known as fluoroethoxybenzovesamicol ([18F]FEOBV).