# Protein variants as blood based biomarkers for diagnosing and staging AD

> **NIH NIH R01** · ARIZONA STATE UNIVERSITY-TEMPE CAMPUS · 2020 · $349,601

## Abstract

ABSTRACT
 There are over 5 million cases of Alzheimer's Disease (AD) in the US, the number of cases is expected to
nearly double over the next 15 years, and the total annual economic costs are over $225 billion. Despite these
tremendous costs, there is still no effective treatment for AD. The protein amyloid-beta (Aß) has been linked to
AD for many years, but despite thousands of publications on the connection between Aß and AD, there is still
much confusion over the role of Aß in AD, and therapeutics targeting Aß have met with very limited success.
The protein tau has also been linked to AD. Similar to Aß, tau also exists in a wide variety of different forms in
the human brain, so the role of tau in the onset and progression of AD is also not clear. Two other neuronal
proteins, alpha-synuclein (a-syn) and Tar-DNA binding protein (TDP-43), have also been implicated in
neurodegenerative diseases and play major roles in Parkinson's disease and Amyotrophic lateral sclerosis
(ALS), respectively. All four of these key neuronal proteins, Aß, tau, a-syn and TDP-43, are prone to misfolding
and aggregation and small toxic aggregates of each of these proteins are thought to play a role in the onset,
progression and spread of a number of different neurodegenerative diseases. Cellular stress caused by toxic
aggregates of one protein can induce formation of toxic aggregates of other proteins ultimately resulting in a
spectrum of neurodegenerative diseases. Clearly generation and accumulation of toxic protein variants of tau,
Aß, TDP-43 and a-syn AD play an important role in the onset and progression of neurodegenerative diseases
including AD. Because of the important role of these protein variants in different neurodegenerative
disease, we hypothesize that there are distinct toxic protein variant profiles that distinguish AD, and
that levels of key protein variants in these profiles will change during progression of AD and also from
patient to patient. We hypothesize that by determining each individual's toxic protein variant
fingerprint using biomarkers present in sera or plasma samples, we can facilitate pre-symptomatic
diagnosis and staging of AD, identify appropriate therapeutic strategies for each individual patient, and
also monitor effectiveness of different therapeutics in real time. The goal of this proposal is to identify
blood based biomarker fingerprints that distinguish different stages AD, including presymptomatic AD,
and that identify the most appropriate therapeutic strategy for each individual patient. We developed
novel technology that enables us to generate antibody fragments (nanobodies) that selectively bind disease
related protein variants. We have a panel of 15 nanobodies to different toxic variants of Aß, tau, a-syn and
TDP-43 and have shown that we can detect these variants in blood samples of patients suffering from AD, PD
and other neurodegenerative diseases, but not in age-matched cognitively normal cases.
 The aims of this proposa...

## Key facts

- **NIH application ID:** 9977069
- **Project number:** 5R01AG054048-05
- **Recipient organization:** ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
- **Principal Investigator:** MICHAEL R SIERKS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $349,601
- **Award type:** 5
- **Project period:** 2016-09-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9977069

## Citation

> US National Institutes of Health, RePORTER application 9977069, Protein variants as blood based biomarkers for diagnosing and staging AD (5R01AG054048-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9977069. Licensed CC0.

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