# Accelerating Treatment Development for Psychosis in AD: MODEL-AD+P

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $787,106

## Abstract

Accelerating Treatment Development for Psychosis in AD: MODEL AD+P
 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. The goal of this renewal is to close several critical gaps in knowledge that
currently inhibit effective treatment development for psychosis in AD: delineation of the neurobiologic signature
distinguishing AD+P from AD-P; identification of drugs that reverse this signature, and; development of
construct and face valid models of AD+P in which to evaluate these drugs.
 We look to achieve this goal by building on a series of accomplishments from the current funding period,
in which we: 1) Identified a genome-wide significant locus for AD+P risk in SUMF1 and found reduced SUMF1
mRNA expression in excitatory neurons in AD+P; 2) Confirmed associations of AD+P with excess phosphotau
burden and newly demonstrated that AD+P is associated with excess loss of dorsolateral prefrontal cortex
glutamatergic neurons relative to AD-P; 3) Showed that AD+P (relative to AD-P) is further characterized by
reduced postsynaptic density (PSD) yield and profound loss of PSD proteins exceeding the loss of glutamate
neurons; 4) Characterized the PSD protein signature of AD+P relative to AD-P, finding reduced levels of a
network of protein kinases and regulators of the actin cytoskeleton, and; 5) Generated computational
predictions of drugs that may reverse the PSD protein signature of AD+P.
 We will now conduct a set of integrated experiments that will: Aim 1) more finely resolve signaling
alterations in AD+P by characterizing the PSD phosphoproteome and kinome signature of AD+P; Aim 2) test
computationally identified drugs for effects on the PSD protein and phosophoprotein signature in mouse
models of AD pathology, and; Aim 3) reduce SUMF1 expression in mouse models of AD pathology to evaluate
if this manipulation recapitulates the neurobiology of psychosis in AD and could thus serve as a construct and
face valid model to evaluate for predictive validity in future pharmacological studies.
 If successful, we will have more finely characterized the PSD biology of AD+P, validated several
available drugs as potential novel treatment candidates, and established the first construct and face valid
model of AD+P for drug testing. We will also share with the larger research community extensive data on the
PSD proteome and phosphoproteome of: AD+/-P, normal elderly, multiple mouse models of AD, and drug
treatments. These outcomes will help accelerate development of experimental therapeutics for AD+P.

## Key facts

- **NIH application ID:** 10896205
- **Project number:** 5R01MH116046-07
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Julia K Kofler
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $787,106
- **Award type:** 5
- **Project period:** 2018-09-25 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10896205

## Citation

> US National Institutes of Health, RePORTER application 10896205, Accelerating Treatment Development for Psychosis in AD: MODEL-AD+P (5R01MH116046-07). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/10896205. Licensed CC0.

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