# Skin biomarkers for diagnosing and characterizing AD and ADRD

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2024 · $751,076

## Abstract

ABSTRACT
Alzheimer's disease (AD) and AD-related dementias (ADRD) such as Lewy body dementia (LBD) are all
associated with deposition of misfolded protein aggregates in the brain including tau in AD and non-AD
tauopathies, and α-synuclein (αSyn) in LBD. Currently, a definite diagnosis of these disorders relies on the
histological and biochemical examination of the brain for the misfolded proteins. Development of reliable and
sensitive assays for these misfolded proteins in easily accessible peripheral specimens is critical for early or
differential diagnosis, determination of disease severity, and evaluation of therapeutic efficacy in clinical trials.
Interestingly, brain tau and αSyn aggregates exhibit prion-like aggregation seeding activity, which can be
specifically detected by two highly sensitive amplification assays including real-time quaking-induced conversion
(RT-QuIC) and protein misfolding cyclic amplification (PMCA). They have been proved to be highly sensitive for
detection of misfolded proteins in the brain and/or cerebrospinal fluid in prion disease (PrD), AD, or PD (Atarashi
et al., 2011; Peden et al., 2012; Foutz et al., 2017; Orrú et al., 2015; Saijo et al., 2017; Kraus et al., 2018). Using
RT-QuIC/PMCA, we were able to detect prion and αSyn aggregates in the skin of individuals with PrD or PD
(Orrú et al., 2017; Wang et al., 2019; 2020). Remarkably, our preliminary results have shown that prions-like tau-
seeding activity is detectable by RT-QuIC and PMCA in skin of AD patients but not in normal controls. Thus, we
hypothesize that skin tau-seeding activity detected by RT-QuIC and PMCA is a novel biomarker for
diagnosing, characterizing, and predicting outcomes of AD and non-AD tauopathies and for
differentiating AD from LBD. To test this hypothesis, the following four Aims will be pursued: (1) Establish the
tau-seeding activity in autopsied skin samples as a biomarker for POSTMORTEM diagnosis and characterization
of AD using RT-QuIC/PMCA assays; (2) Assess skin tau-seeding activity as a biomarker for PREMORTEM
diagnosis, characterization, and predicting clinical outcomes of AD; (3) Determine skin tau-seeding activity as a
biomarker for differentiating AD from non-AD tauopathies, and from LBD, a common ADRD; and (4) Determine
whether skin tau-seeding activity is detectable at an asymptomatic stage by RT-QuIC/PMCA in animal models
of AD tauopathies. We believe that the successful implementation of this project will develop RT-QuIC/PMCA
assays of skin tau-seeding activity as a biomarker for diagnostic testing and evaluating clinical trials across AD,
non-AD tauopathies, and LBD.

## Key facts

- **NIH application ID:** 10892803
- **Project number:** 5R01AG067607-04
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** SHU G. CHEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $751,076
- **Award type:** 5
- **Project period:** 2021-09-30 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10892803

## Citation

> US National Institutes of Health, RePORTER application 10892803, Skin biomarkers for diagnosing and characterizing AD and ADRD (5R01AG067607-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10892803. Licensed CC0.

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