# Project-002

> **NIH NIH P01** · WASHINGTON UNIVERSITY · 2020 · $348,682

## Abstract

Elucidation of the decades’ long period of time during which Alzheimer disease (AD) pathologies begin
to develop prior to the appearance of cognitive symptoms (i.e., “preclinical” AD) has been largely driven by the
study of disease biomarkers. Such biomarkers are now being used to more precisely define various stages
within this preclinical period in order to better understand the pathologic processes taking place during this
early stage and to better inform the design and interpretation of prevention trials aimed at identifying diseasemodifying
therapies that have the best chance of preserving normal cognitive function.
Data from ACS Project 2 contributed to the finding that preclinical AD (defined by CSF biomarkers) in
older individuals (≥ 65 yrs) increases the risk for developing symptomatic AD in a stage-dependent manner. In
addition, changes in amyloid-related markers (Aß42) over time were observed in early middle-aged participants
(45-64 yrs), whereas changes in tau and ptau181 were observed in those in mid middle-age (55-64 yrs) and
coincided with initial declines in cognition. As the current ACS cohort is aging, we are now poised to evaluate
biomarker trajectories in individuals as they progress from being biomarker-negative to biomarker-positive
(preclinical AD) to cognitively impaired (symptomatic AD). The proposed experiments are designed to evaluate
the utility of CSF markers for identifying those individuals with preclinical AD who are in the transition period
from cognitive normality to impairment. Novel markers of synaptic dysfunction will be evaluated in addition to
the traditional markers of core AD pathologies. CSF tau and ptau181 will be compared with tau PET imaging to
validate their utility as presumed markers of neurofibrillary tangles. Finally, in an exploratory aim, we will utilize
the innovative method of Stable Isotope Labeling Kinetics (SILK) pioneered by Dr. Randall Bateman to
evaluate the potential of a plasma (and CSF) Aß kinetic measure as an indicator of brain amyloid pathology.
Aim 1. Continue to measure CSF concentrations of Aß40, Aß42, tau, ptau181, YKL-40, and VILIP-1, as well
as novel markers of synaptic dysfunction, Neurogranin and SNAP-25.
Aim 2. In longitudinal analyses, assess the annual rate of change in CSF biomarker concentrations as a
function of AD risk (age, family history, APOEϵ4 status) and their relationships with baseline and future rates
of change in other CSF markers.
Aim 3. Correlate fluid biomarker measures (and rate of change over time) with clinical and psychometric
performance (Clinical Core), novel tau imaging as assessed by T807 PET (Project 1), attentional control
measures (Project 3), and structural neuroimaging (via MRI) and amyloid PET (via florbetapir) (Project 4).
Aim 4. Evaluate the utility of Aß isotope kinetics (using stable isotope labeling kinetics methods [SILK]) in
CSF and plasma as indicators of the presence/absence of brain amyloid.

## Key facts

- **NIH application ID:** 9963099
- **Project number:** 5P01AG026276-15
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** JOHN MORRIS
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $348,682
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9963099

## Citation

> US National Institutes of Health, RePORTER application 9963099, Project-002 (5P01AG026276-15). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9963099. Licensed CC0.

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