# Dominantly Inherited Alzheimer Network: Project 1

> **NIH NIH U19** · WASHINGTON UNIVERSITY · 2020 · $324,222

## Abstract

Project 1: Amyloid Beta SUMMARY/ABSTRACT
Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ) and neurofibrillary tangles
composed of the tau protein in the brain. More than 200 mutations have been identified in amyloid-β precursor
protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) that cause autosomal dominant forms of AD
(ADAD). PSEN1 and PSEN2 form the catalytic domain of the γ-secretase enzyme, which cleaves APP to
generate many Aβ proteoforms which can be modified into variants including posttranslational modifications,
truncations and sequence variations. Changes in the relative ratios of Aβ42/40 isoforms have been used to
predict pathogenicity of ADAD variants. However, we know less about the contribution of other Aβ proteoforms
to AD pathogenesis and the utility of the Aβ proteoform signature as a biomarker of mutation status and/or
disease course. For example, what are the Aβ pathogenic cause(s) of ADAD? Several Aβ proteoforms support
a causal role for AD, including Aβ42, Aβ43, Aβ37, Aβ39 and modifications including pyroglutamate, oxidation,
isomerization, and N- and C-terminal truncation. The objective of this study is to define the effects of ADAD
mutations and amyloidosis on Aβ proteoform and disease pathogenesis. To meet this objective, we will define
mutation and gene-specific effects on Aβ proteoform signatures using novel mass spectrometry approaches in
human plasma, CSF, stem cell derived neurons, and brain tissue. We will then determine how Aβ proteoform
signatures relate to histologic amyloid plaque structure in human brains. We hypothesize that ADAD mutations
produce a common pathogenic Aβ proteoform signature. The rationale for this proposal is that defining the
effects of ADAD mutations and amyloidosis on Aβ proteoforms will be critical to define the common pathogenic
Aβ signatures which cause AD. This target validation will guide clinical studies, therapeutic strategies and
classify future novel ADAD mutations. This work will be performed in collaboration with the Genetics,
Biomarker, Clinical, Neuropathology, Imaging, and Biostatistics Cores.

## Key facts

- **NIH application ID:** 10017841
- **Project number:** 5U19AG032438-09
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Celeste Marie Karch
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $324,222
- **Award type:** 5
- **Project period:** 2008-09-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10017841

## Citation

> US National Institutes of Health, RePORTER application 10017841, Dominantly Inherited Alzheimer Network: Project 1 (5U19AG032438-09). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10017841. Licensed CC0.

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