# Role of age, dopamine, and tau related network disruption in setting a context for progression toward Alzheimer's disease

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $846,975

## Abstract

PROJECT SUMMARY
The heterogeneous, multifactorial nature of Alzheimer's disease and the overlap of its temporal course with
changes attributable to typical aging has been a critical barrier to the development of diagnostic tools and
interventions targeting the direct effects of the disease on brain function and cognition. A major challenge is to
understand how multiple age-related cascades combine in an individual to create vulnerabilities to cognitive
decline during the progression of Alzheimer's disease. One prominent age-related cascade involves disruption
of the dopaminergic system. While the dopamine system is not generally understood to be a direct contributor
to Alzheimer's disease, patients with Alzheimer's disease exhibit impairments in the mesolimbic dopamine
pathway and dopamine may play a role in the severity of neuropsychiatric and cognitive symptoms of
Alzheimer's disease. This application proposes a disconnection model in which parallel pathways lead from
neuropathological alterations to impaired brain network integrity and cognition. These parallel pathways are
proposed to have direct and indirect points of interaction by which age-linked dopaminergic changes induce
vulnerabilities to tauopathy and amyloidosis. That is, this is a “dual hit” model where individuals with pre-
existing age-related dopaminergic disruption are proposed to be more likely to exhibit declines in network
integrity and cognition in the presence of tauopathy and amyloidosis. The overall goal is to test whether the
pathways proposed by this model induce vulnerabilities during the progression of Alzheimer's disease. Each
aim tests a different set of pathways in the model.
 First, the project tests an Alzheimer's disease cascade whereby tauopathy and amyloidosis impact
integrity of a network known as the default network, leading to change in memory performance. Second, the
project tests an age-related cascade whereby dopaminergic function impacts integrity of a frontoparietal control
network, leading to change in executive function. Third, the project tests whether increased vulnerability to the
Alzheimer's disease cascade is a function of network alterations from the age-related dopaminergic cascade.
To test these aims, the project applies simultaneous magnetic resonance imaging and positron emission
tomography data to acquire multiple measures of brain function and pathology. A sample of cognitively normal
older adults and patients with mild cognitive impairment is tested and followed over time to cover the early
spectrum of progression toward Alzheimer's disease. Successful completion will aid differential diagnosis,
provide a model for vulnerability to Alzheimer's disease that could be extended to other age-related cascades,
and provide alternative targets for bolstering neural integrity to delay or prevent vulnerability during the
progression of early Alzheimer's disease.

## Key facts

- **NIH application ID:** 10159809
- **Project number:** 5R01AG054110-05
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Julius C Hedden
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $846,975
- **Award type:** 5
- **Project period:** 2017-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10159809

## Citation

> US National Institutes of Health, RePORTER application 10159809, Role of age, dopamine, and tau related network disruption in setting a context for progression toward Alzheimer's disease (5R01AG054110-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10159809. Licensed CC0.

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