# Project 1: Identification of Early Life molecular determinants of Alzheimer's Disease pathogenesis

> **NIH NIH U19** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $229,992

## Abstract

PROJECT SUMMARY PROJECT 1
The overarching aims of this proposal are to identify the initial cascade of events that drive the inception and
progression of Alzheimer’s Disease (AD). There is an urgent need to prevent, and treat AD. We hypothesize
that genetic risk for AD confers disease pathogenesis in early life that will be detected by studying molecular and
cellular events before the age of adolescence which will inform prevention. By employing a model system that
more faithfully recapitulates the genetic, molecular, cellular, physiological, anatomical and structural organization
of the primate brain, we will be able to identify underlying drivers of AD and better model disease pathogenesis
and progression in order to prevent disease. In support of these goals, this project (Project 1) aims to identify
the early life primate-specific molecular determinants of Alzheimer’s disease emergence and progression using
marmosets genetically engineered with the presenilin 1 (PSEN1) risk variant, an early onset AD mutation. The
PSEN1 marmoset models provide the ability to evaluate divergent changes at the molecular, cellular, and
systems level from birth through infancy, adolescence, and aging. The Specific Aims of this project are: 1) to
evaluate the disease trajectory of PSEN1 mutant marmosets relative to healthy age-matched and normal aged
controls using established and emerging AD biomarkers; 2) to conduct comprehensive behavioral
characterization of the PSEN1 marmoset models relative to healthy controls via longitudinal multimodal
phenotypic characterization from neurodevelopment through lifespan; and 3) investigate the molecular
signatures of neuronal cells derived from fibroblasts as a surrogate to brain. Through these specific aims, we
expect to have comprehensively characterized the first genetically engineered marmoset models of AD that
recapitulates the spectrum of AD-related phenotypes observed in AD patients for behavioral, cognitive,
biomarker, and neuropathological hallmarks using translational approaches; identified early molecular changes
at the cellular level using multi-omics approaches prior to the emergence of frank AD neuropathology and
cognitive decline; and created the foundation of knowledge for the utility of genetically engineered marmosets
with AD risk variants as validated models.

## Key facts

- **NIH application ID:** 10899741
- **Project number:** 5U19AG074866-03
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Stacey J Rizzo
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $229,992
- **Award type:** 5
- **Project period:** 2022-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10899741

## Citation

> US National Institutes of Health, RePORTER application 10899741, Project 1: Identification of Early Life molecular determinants of Alzheimer's Disease pathogenesis (5U19AG074866-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10899741. Licensed CC0.

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