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

> **NIH NIH R21** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2022 · $475,750

## Abstract

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 ea...

## Key facts

- **NIH application ID:** 10353561
- **Project number:** 1R21AG075643-01
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** PAUL A. NEWHOUSE
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $475,750
- **Award type:** 1
- **Project period:** 2022-03-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10353561

## Citation

> US National Institutes of Health, RePORTER application 10353561, The cholinergic integrity in Down syndrome in association with aging, Alzheimer's disease pathology, and cognition (1R21AG075643-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10353561. Licensed CC0.

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