# "What is N?" Towards operationalizing neurodegeneration in Alzheimer's and related dementias

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2024 · $793,724

## Abstract

PROJECT SUMMARY / ABSTRACT
Neurodegeneration markers (N markers) are associated with cognitive impairment in Alzheimer's disease (AD)
and related dementias. Since they are more proximally related to cognitive decline than AD-specific biomarkers
(amyloid and tau measures), they have been proposed as surrogate endpoints in clinical trials and even for
prognosis in the clinical setting. Despite the promise of N markers, several barriers to their implementation
exist. The major limitations include i) only validation in convenience samples that exclude those with significant
cerebrovascular disease rather than the general population, ii) lack of systematic comparison of the frequently
used N markers across modalities (i.e., imaging, CSF, blood) to predict cognitive outcomes at varying levels of
AD and cerebrovascular disease pathology, and iii) lack of understanding of the pathological profile associated
with each N marker. In the current application, our overall goal is to understand the unique information each N
marker (imaging, CSF, blood) provides with regards to cognitive decline and underlying pathology to optimize
their use in clinical practice and clinical trials. We will utilize the Mayo Clinic Study of Aging (MCSA) a
longitudinal population-based study where participants undergo psychometric, neurologic, and neuroimaging
investigations (MRI, amyloid and tau PET, FDG PET), and blood draws; a subset also have CSF and/or post-
mortem data as the primary dataset for this grant. In Aim 1, we will compare N markers from neuroimaging,
CSF, and blood in MCSA in relation to demographics (including socioeconomic status), in vivo AD (amyloid
and tau PET) and cerebrovascular disease biomarkers, and cognition. We will validate some of these
relationships in a biracial Mayo Clinic Jacksonville sample and in ADNI. In Aim 2, we will conduct an ante-
mortem N marker – post-mortem validation study to determine the pathological profiles associated with (each
and combination of) N markers. The findings of the grant will lead to better understanding of N markers
associated with longitudinal cognitive decline and the pathologies associated these N markers. This knowledge
will inform clinical trial design and guidance of which N marker(s) to choose for future clinical use for AD and
ADRD.

## Key facts

- **NIH application ID:** 10883934
- **Project number:** 4R01AG069052-02
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Jonathan Graff-Radford
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $793,724
- **Award type:** 4N
- **Project period:** 2021-04-15 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10883934

## Citation

> US National Institutes of Health, RePORTER application 10883934, "What is N?" Towards operationalizing neurodegeneration in Alzheimer's and related dementias (4R01AG069052-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10883934. Licensed CC0.

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