# Elucidating the molecular drivers of impaired mobility within and outside the CNS in Alzheimer’s disease and related disorders

> **NIH NIH R01** · RUSH UNIVERSITY MEDICAL CENTER · 2020 · $711,340

## Abstract

ABSTRACT
Responding to PAR 17-029: Dynamic Interactions between systemic or non-neuronal systems and the brain in
aging and in AD, this study will identify the molecular mechanisms driving impaired mobility, an understudied
aging and AD phenotype, as highlighted by NIA workshops, Aging, the CNS, and Mobility. AD and other brain
pathologies are related to impaired mobility in older adults with and without dementia, but do not fully explain
impaired mobility. These pathologies extend beyond the brain to spinal cord, but even accounting for these
pathologies does not fully explain mobility and the molecular drivers of these pathologies are unknown. This
suggests that there are also drivers without a pathologic footprint that remain unidentified in these tissues.
Mobility derives from interacting subsystems that extend beyond the brain to spinal cord and muscle.
Therefore, this postmortem study in older adults will identify molecular drivers (genes and their
proteins) of impaired mobility in key mobility tissues controlling for the presence of AD and other CNS
pathologies. This study will leverage clinical and postmortem resources from older participants of the Rush
Memory and Aging Project (R01AG17917). Our systems biology approach will be applied to new gene
expression data obtained from key mobility tissues in brain, spinal cord and muscle (Aim1). Tissues will come
from the same persons, all of whom had instrumented gait testing with a wearable sensor proximate to death.
In each tissue, we will identify mobility-related molecular systems controlling for CNS pathologies (Aim2).
Causal network inference will be used to nominate influential genes controlling these systems (Aim3).
Validating protein levels of influential genes within and across these tissues will yield a high-confidence list of
genes driving impaired mobility (Aim4). Compelling pilot studies support this proposal. 1) Combinations of
wearable sensor mobility metrics are more specific for AD dementia than conventional gait speed. 2) AD and
other pathologies extend to spinal cord and are related to mobility, emphasizing the need to identify drivers of
these pathologies in motor tissues outside the brain. 3) Also, the limited explanatory power of CNS pathologies
for mobility highlights the need to identify molecular drivers of impaired mobility in key motor tissues that may
not have a known pathologic footprint. 4) High quality genome-wide transcriptomic data extracted from key
motor tissues show differentially expressed genes are related to gait, cognition and AD pathology. 5) Applying
the system biology methods to a cortical cognitive gene network, followed by validation with protein, we
identified cortical proteins driving cognition. Leveraging broad expertise, this study will provide an in-depth
description of the molecular drivers within interconnected subsystems underlying mobility within and outside
the CNS. Validating influential genes provides a means to move beyond a descriptive...

## Key facts

- **NIH application ID:** 9920077
- **Project number:** 5R01AG059732-02
- **Recipient organization:** RUSH UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** ARON S BUCHMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $711,340
- **Award type:** 5
- **Project period:** 2019-05-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9920077

## Citation

> US National Institutes of Health, RePORTER application 9920077, Elucidating the molecular drivers of impaired mobility within and outside the CNS in Alzheimer’s disease and related disorders (5R01AG059732-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9920077. Licensed CC0.

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