# PET Imaging of SV2A and Other Biomarkers in Alzheimer's Disease

> **NIH NIH R01** · YALE UNIVERSITY · 2020 · $1,108,088

## Abstract

PROJECT SUMMARY/ABSTRACT
Alzheimer's disease (AD) has been called a synaptic failure. Indeed, synaptic loss is a prominent AD pathology
and the major structural correlate of cognitive impairment in AD. AD is characterized by a distinct pathology,
with plaques composed of amyloid-β (Aβ), neurofibrillary tangles (NFTs) composed of hyperphosphorylated
tau, and a loss of synapses. Synaptic damage is observed in the earliest stages of AD, with Mild Cognitive
Impairment (MCI) patients demonstrating a loss of synapses and several presynaptic proteins. Thus, the ability
to assess synaptic density in vivo is of high utility in studies of AD as well as in monitoring potential therapies.
Positron Emission Tomography (PET) imaging is increasingly employed in AD studies to measure glucose
metabolism (18F-fluorodeoxyglucose, 18F-FDG), Aβ, and NFTs. However, tracers for new molecular targets
are needed to directly monitor loss of synaptic density. One suitable target is the synaptic vesicle glycoprotein
2 (SV2), an essential vesicle membrane protein. One of its isoforms, SV2A, is ubiquitously expressed in
virtually all synapses and is involved in regulation of synaptic trafficking.
We recently developed 11C-UCB-J, a PET tracer for quantitative SV2A imaging in vivo and carried out the
first-in-human studies, which have shown high brain uptake and excellent reproducibility. Our preliminary
experience with 11C-UCB-J in early AD has demonstrated significant reductions (44%) in hippocampal SV2A
binding, consistent with the early degeneration of entorhinal cortical (ERC) cells that project to the
hippocampus (via the perforant path) and hippocampal SV2A reductions observed in postmortem studies.
However, we critically need to relate synaptic density with 11C-UCB-J to other markers of AD pathogenesis (in
particular, tau deposition) and to expand the study of synaptic loss to the earliest—preclinical—stages of
disease, using an established cohort. Thus, we propose the following Specific Aims:
Aim 1: To investigate in individuals with symptomatic AD the association of SV2A binding (using 11C-UCB-J)
with tau deposition (using 18F-MK6240).
Aim 2: To investigate the association of familial and genetic AD risk in cognitively normal (CN) middle-aged
individuals with: a) hippocampal SV2A binding and b) ERC-tau deposition.
Aim 3: To investigate the associations between SV2A binding and Aβ, as well as tau deposition in cognitively
normal middle-aged individuals at varying AD risk.
In vivo assessment of synaptic density will enable the study of the early emergence of synaptic loss and the
integration of this information with other biomarkers of disease, including Aβ and tau deposition, providing a
more comprehensive model of disease.

## Key facts

- **NIH application ID:** 9936355
- **Project number:** 5R01AG062276-03
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** CHRISTOPHER H VAN DYCK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,108,088
- **Award type:** 5
- **Project period:** 2018-09-30 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9936355

## Citation

> US National Institutes of Health, RePORTER application 9936355, PET Imaging of SV2A and Other Biomarkers in Alzheimer's Disease (5R01AG062276-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9936355. Licensed CC0.

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