# Synaptic Resilience to Psychosis in Alzheimer Disease

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $589,988

## Abstract

PROJECT SUMMARY: Psychotic symptoms occur in ~ 40-60% of individuals with Alzheimer Disease (AD with
psychosis, AD+P). Numerous studies have found that the AD+P phenotype is associated with more rapid
cognitive decline than AD subjects without psychosis (AD-P). Current, empirically developed, treatments for
psychosis in AD have limited efficacy, do not alter the more rapid disease progression, and are associated with
substantial toxicity, including excess mortality. Because the annual incidence of psychosis in AD is only ~ 10%,
there is a window of opportunity to intervene to prevent psychosis onset if resilience factors can be identified.
 Multiple brain imaging studies have shown that relative to AD+P, subjects with AD-P have preserved
indices of cortical synaptic function, especially in the dorsolateral prefrontal cortex (DLPFC). Our recent
genetic and proteomic findings in patients and model systems have converged on a possible mechanism to
explain this synaptic resilience in AD-P: Preservation of postsynaptic density (PSD) protein levels in DLPFC.
First, using targeted mass spectrometry (MS) in DLPFC grey matter homogenates from mild to moderate AD
subjects, we found a robust increase in homogenate levels of canonical PSD proteins in AD-P subjects relative
to both AD+P and Control subjects. Second, we identified and independently confirmed a polygenic protection
against psychosis in AD which included an allele associated with reduced DLPFC expression of TOM1L2.
TOM1L2 is an adaptor protein that facilitates degradation of synaptic proteins via actin-based endocytic
trafficking. Finally, in the APPswe/PSEN1dE9 mouse model of Aβ overproduction, we found that reduction of
Kalrn, a Rac1/RhoA guanine nucleotide exchange factor that regulates endocytic trafficking, elevated
canonical PSD protein levels in cortical homogenates, preserved these proteins' levels in PSD enrichments,
and protected against psychosis-associated behaviors. We thus hypothesize: resilience to psychosis onset
in AD is conferred by preservation of protein levels in PSD enrichments, due to reduced trafficking of
PSD proteins for degradation, and can be used to identify novel therapeutics. We will test this hypothesis
in three Aims: Aim 1) To determine if PSD proteome alterations and gene-protein interactions are associated
with resilience to AD+P; Aim 2) To test the effect of reduction in Tom1l2 on the synaptic proteome in a mouse
model, and; Aim 3) To use computational chemogenomics to identify drugs that induce synaptic proteome
compensations which confer resilience to AD+P, providing for rational prevention and/or treatment. The above
aims benefit from the tight integration and leveraging of Multiple PIs with expertise in the synaptic pathology of
psychosis (Sweet), the neuropathology of AD (Kofler), and the use of computation for novel therapeutic
discovery (Wang). Upon completion, we will have delineated the synaptic protein compensations associated
with resilience to psyc...

## Key facts

- **NIH application ID:** 9975225
- **Project number:** 5R01MH116046-03
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Julia K Kofler
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $589,988
- **Award type:** 5
- **Project period:** 2018-09-25 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9975225

## Citation

> US National Institutes of Health, RePORTER application 9975225, Synaptic Resilience to Psychosis in Alzheimer Disease (5R01MH116046-03). Retrieved via AI Analytics 2026-06-10 from https://api.ai-analytics.org/grant/nih/9975225. Licensed CC0.

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