# Neuropathology of synapses in AD and ADRD

> **NIH NIH RF1** · STANFORD UNIVERSITY · 2023 · $2,155,924

## Abstract

PROJECT SUMMARY / ABSTRACT
Although its molecular mechanisms remain to be clarified, the anatomic basis of cognitive impairment in
Alzheimer's disease (AD) is injury and degeneration of synapses. Subpopulations of neurons in different brain
areas may be more or less susceptible to specific types such insults Yet, molecular characterization of
synapses in AD and AD–related dementias (ADRD) is limited, leaving the factors underlying this selectivity and
the fidelity of widely-used mouse models to the human condition unclear. Here, we propose to fill these
important gaps in selective cell vulnerability in aging and AD by identifying molecular signatures to suggest or
confirm cellular pathways that may mediate vulnerability. The proposed project will accomplish this using a
unique tissue resource and novel technology developed by us, and couple them with cutting-edge machine
learning (ML) techniques to enhance differential signals and achieve deeper insights into the factors underlying
selective neuron vulnerability or resilience. The novel technology that we have developed is called
Synaptometry by Time-of-Flight, or SynTOF, and it provides an unparalleled opportunity for multiplex molecular
analysis of millions of single synaptic events. We will build on our preliminary data, which coupled this new
technology with ML approaches to gain novel insights into synaptic injury in AD, including in a transgenic
mouse model that regionally overexpresses amyloid (A) β peptides in neurons, and which highlight the value of
SynTOF in discovering the molecular patterns of injury in human synaptic subtypes, as well as assessing the
fidelity of mouse models at the single synaptic level. Drawing on our unique tissue resource of cryopreserved
synaptic preparations from participants with extensive clinical, genetic, and neuropathologic annotation, novel
and powerful technology, and robust computational approaches, we propose to test the hypothesis that
synapse injury in AD and ADRD is disease-, brain region-, and synapse subtype-specific, thereby highlighting
new targets for therapeutic intervention and determining the extent to which three commonly used transgenic
mouse lines model the synaptic injury of humans. When successfully completed, our novel resources and
approach will provide unique insights into pre- and postsynapse subtype-specific mechanisms of injury at
unprecedented scale, and further highlight new therapeutic targets for AD and ADRD.

## Key facts

- **NIH application ID:** 10590045
- **Project number:** 1RF1AG077443-01A1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Nima Aghaeepour
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $2,155,924
- **Award type:** 1
- **Project period:** 2022-12-15 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10590045

## Citation

> US National Institutes of Health, RePORTER application 10590045, Neuropathology of synapses in AD and ADRD (1RF1AG077443-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10590045. Licensed CC0.

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