# Dominantly Inherited Alzheimer Network: Project 3

> **NIH NIH U19** · WASHINGTON UNIVERSITY · 2022 · $468,629

## Abstract

Project 3: Novel Mechanisms PROJECT SUMMARY/ABSTRACT
Recently, significant progress has been made in understanding the trajectory of amyloid and tau changes in
both late-onset (LOAD) and autosomal-dominant AD (ADAD), clearly establishing a long preclinical stage
during which pathologies develop prior to symptoms. While these two forms of AD share many fundamental
pathological and clinical features, ADAD is mechanistically distinct, with mutations resulting in overproduction
of β-amyloid in addition to impaired clearance as is found in LOAD. Since both forms of AD are complex and
heterogeneous, a more complete understanding of AD is necessary to accelerate progress towards a cure.
Challenges now remain to unravel the processes that initiate and promulgate disease and to assess their
potential as novel therapeutic targets and biomarkers. In particular, there is an urgent need to better
understand other molecular processes tracking early triggers of neurodegeneration, such as neuro-
inflammation and synaptic injury and their associated biomarkers that herald disease progression. The
Accelerating Medicines Partnership for Alzheimer’s disease (AMP-AD) consortium has identified molecular
networks and novel target biomarkers (including those involved in neurinflammation and synaptic injury) in
post-mortem LOAD brain tissue. However, the understanding of the role of APP, PSEN1 and PSEN2 in ADAD
pathogenesis and downstream mechanisms remains limited. The goal of Project 3 is to use systems-based
approaches to define the impact of ADAD mutations and neuroinflammatory and synaptic networks on disease
progression in participants in the Dominantly Inherited Alzheimer network (DIAN), which will, in turn, identify
novel disease biomarkers. We hypothesize that neuroinflammatory processes in ADAD, as defined by direct
molecular analysis of ADAD brain and detected in living individuals by their associated fluid biomarkers, are
altered early in the natural course of disease and impact progressive neuronal injury and cognitive decline.
In Aim 1, we will use “-omics” and systems biology approaches (with molecular profiling via transcriptomics and
mass spectrometry [MS]-based proteomics) to define the inflammatory and synaptic networks that are
dysregulated in ADAD brains. Paired with network data derived from mutation carriers and isogenic control
induced pluripotent stem cell (iPSC)-derived neurons, astrocytes, and microglia, we will create a systematic
molecular interaction map to elucidate connections between ADAD mutations, inflammation, synaptic function,
and associated therapeutic targets. In order to translate AD brain network information into applications that
have potential clinical relevance and utility, in Aim 2, CSF obtained longitudinally from DIAN participants will be
interrogated by MS and immunoassays for proteins revealed in Aim 1, along with several “emerging”
biomarkers of neuroinflammation (YKL-40, sTREM2, and progranulin) and synaptic injury (VIL...

## Key facts

- **NIH application ID:** 10462567
- **Project number:** 5U19AG032438-11
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Anne Fagan
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $468,629
- **Award type:** 5
- **Project period:** 2008-09-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10462567

## Citation

> US National Institutes of Health, RePORTER application 10462567, Dominantly Inherited Alzheimer Network: Project 3 (5U19AG032438-11). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10462567. Licensed CC0.

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