# Toward a neuroscientific understanding of the interaction between Down syndrome and Alzheimer's disease pathology

> **NIH NIH K01** · STANFORD UNIVERSITY · 2024 · $125,847

## Abstract

This application will combine the neuroimaging expertise of the investigator with new knowledge of biomarkers
for aging pathology, advanced computational methods and Down syndrome clinical translational research. The
goal is to produce a unique skill set which will be used to advance the candidate’s career as an independent
lifespan developmental cognitive neuroscientist focusing on Down syndrome. Neurodegenerative changes
associated with Alzheimer's disease (AD) are present in almost all individuals with Down syndrome by age 40
years, and the lifetime risk of developing dementia is more than 90% in this population. Understanding patterns
of neuropsychiatric and pathological brain changes before AD diagnosis is critical in order to facilitate
interventions prior to onset of irreversible neuropsychiatric and pathological brain changes. Yet charting of
pathological brain changes and diagnosis of dementia is extremely challenging in individuals with DS who have
brain and neuropsychological differences present through the lifespan. Here we propose a computational
neuroscientific framework in which we will utilize conventional resting state functional MRI, advanced
quantitative MRI and multimodal biomarker data to disentangle brain and neuropsychological changes specific
to DS and AD (within the context of DS). Specifically, we will test the overarching hypothesis that whole brain
connectivity (i.e. connectomes based on resting state functional MRI) and brain microstructure (quantitative
MRI) represent intermediate phenotypes between primary brain pathologies and neuropsychological outcomes
in DS and AD. First, we will leverage data from the Alzheimer's Biomarkers Consortium — Down Syndrome
(ABC-DS) to identify connectome-wide signatures specific to DS, and a separate set of signatures specific to
AD in the context of DS. Then, we will examine relationships between connectome-wide signatures and AD
pathology within the amyloid, tau and neurodegeneration (ATN) framework. Next, we will examine relationships
between connectome-wide signatures and critical neuropsychological functions including memory, social
cognition, and executive function dimensionally. Finally, we will enroll a novel cohort of adults with DS and
collect complementary advanced MRI studies (not available in ABC-DS) and fluid biomarkers, to examine brain
microstructural properties which may be more a) sensitive to neurodegenerative changes when compared to
traditional MRI and b) complementary to PET imaging. Together, the results of this proposal will advance a
mechanistic understanding of DS- and AD-specific pathological brain changes and how reorganization of
functional networks relate to neuropsychological changes. Further, these data form the basis for a follow-up
R01 combining ABC-DS emerging longitudinal data with advanced complementary MRI and multimodal
biomarkers.

## Key facts

- **NIH application ID:** 10909365
- **Project number:** 5K01AG083224-02
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** JENNIFER L BRUNO
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $125,847
- **Award type:** 5
- **Project period:** 2023-09-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10909365

## Citation

> US National Institutes of Health, RePORTER application 10909365, Toward a neuroscientific understanding of the interaction between Down syndrome and Alzheimer's disease pathology (5K01AG083224-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10909365. Licensed CC0.

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