# Dominantly Inherited Alzheimer Network: Project 2

> **NIH NIH U19** · WASHINGTON UNIVERSITY · 2021 · $993,696

## Abstract

Project 2: Tau SUMMARY
Alzheimer's disease (AD) is a growing worldwide health crisis. It is critical to develop biomarkers to identify
individuals at high risk for AD, better understand the biological underpinnings of the disease, and to develop
new therapeutic agents. Autosomal dominant AD (ADAD) is a rare form of the disease (<1%) that is caused
by mutations in one of three genes. Individuals with these mutations develop dementia at a relatively young
age that is heritable within families. This provides a unique cohort of individuals where it is possible to
predict the disease stage of individuals relative to their estimated years to symptom onset (EYO) even
decades before they show cognitive decline. During the initial funding periods DIAN investigators have
mapped out a sequential progression of biomarkers; first, measures of beta-amyloid become abnormal,
followed by metabolism, measures of tau pathology, loss of grey matter, and eventually cognitive decline.
Work by DIAN investigators and others suggests that the abnormal accumulation of tau pathology may be a
key factor in this cascade that impacts the transition from cognitive normality to impairment. However, prior
work examining tau has previously been limited only to one biomarker measured in the cerebrospinal fluid
(CSF). While informative, this solitary measure may not adequately convey the role tau pathology plays in
AD.
This project seeks to understand new measures of tau pathology in the DIAN cohort to further elucidate the
role this protein plays in ADAD. Aim 1 explores tau pathology measured using three different positron
emission tomography (PET) compounds to map the spread of tau pathology in the brain. This will quantify
the amount as well as location of pathological burden in the brain. Aim 2 uses post mortem brain tissue to
validate these tracers and learn more about the sensitivity and specific of these three compounds. This is
critical before these PET tracers can be used broadly for research and clinical purposes. Aim 3 uses mass
spectrometry to quantify novel forms of tau which have distinct structural properties (e.g. different
phosphorylation or cleavage sites). These novel forms of tau will be measured in the CSF, brain tissue, and
human cell models of AD and is a strong compliment to the tau PET imaging. The rationale for this proposal
is that better understanding the temporal and spatial evolution of tau pathology is critical to understanding
the pathobiology of AD and for formulating successful therapeutic trials. These three Aims are highly
collaborative with the other Projects and Cores, and will provide new insights in the role tau pathology plays
in AD.

## Key facts

- **NIH application ID:** 10225489
- **Project number:** 5U19AG032438-10
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** BRIAN Andrew GORDON
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $993,696
- **Award type:** 5
- **Project period:** 2008-09-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10225489

## Citation

> US National Institutes of Health, RePORTER application 10225489, Dominantly Inherited Alzheimer Network: Project 2 (5U19AG032438-10). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10225489. Licensed CC0.

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