# Prediction of Psychosis in Alzheimer Disease

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $1,142,766

## Abstract

Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer
Disease (AD + Psychosis, AD+P), affecting ~ 40% to 60% of individuals with AD. Psychosis is a marker for a
subtype of AD associated with more rapid cognitive and functional decline, poor outcomes including premature
institutionalization, and elevated caregiver distress. Current treatments for AD+P have limited efficacy and
cause excess mortality. It is thus imperative to develop a translational approach to promote discovery
regarding the biology of AD+P and identify opportunities to intervene to prevent its adverse trajectory.
 We initially reported that AD+P aggregates in families with a heritability of ~61%, findings since replicated in
independent cohorts. These observations, and additional findings from our genetic studies, led us in the
current funding interval to hypothesize that AD+P results from a set of risk alleles that includes risk alleles for
schizophrenia (Sz), but not risk alleles for AD. Our findings during the current funding interval have further
illuminated the genetic architecture of AD+P: 1) We have independently replicated our finding of the
association of common genetic variation with AD+P; 2) We have similarly replicated our prior finding of a
significant association of AD+P with polygenic variation associated with Sz, including our prior, biologically
intriguing, observation that the direction of most allelic effects on risk are opposite for Sz and AD+P; 3)
Contrary to our hypothesis, we found that polygenic variation at loci associated with AD risk associate with
psychosis risk in AD, and this polygenic contribution is independently additive with the contribution of Sz risk
variants; 4) We have developed novel methods to map individual cognitive and cognitive-behavioral
trajectories that incorporate genetic variation in predicting the probability of transition to psychosis.
 These findings have led us to a revised hypothesis: AD+P results from risk alleles that include unique AD+P
risk alleles and subsets of alleles associated with Sz and AD; these alleles combine to yield a more rapidly
deteriorating cognitive trajectory and an increased probability of transition to psychosis. We will now test our
hypothesis by first performing an unbiased survey of the genome, including the use of innovative analytic
methods that we and others have developed to further identify genetic variants associated with AD+P (Aim 1);
then leveraging advances in the genomics of AD and Sz to refine the contribution of polygenic risk for these
disorders to AD+P (Aim 2); and validating across cohorts the prediction of the adverse cognitive and
behavioral trajectory of AD+P by variants identified in the preceding Aims (Aim 3).
 By identifying genetic variants that predict psychosis onset in AD, upon completion, these studies may
provide a means to identify individuals at risk for the poor outcomes associated with AD+P so they can be
targeted for ad...

## Key facts

- **NIH application ID:** 10153594
- **Project number:** 5R01AG027224-15
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** ROBERT A SWEET
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,142,766
- **Award type:** 5
- **Project period:** 2007-05-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10153594

## Citation

> US National Institutes of Health, RePORTER application 10153594, Prediction of Psychosis in Alzheimer Disease (5R01AG027224-15). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10153594. Licensed CC0.

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