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 additional interventions. Among the identified SNPs will be those predicting brain transcript expression, providing strong mechanistic hypotheses of AD+P for future translational studies.

Public Health Relevance

Individuals who develop psychotic symptoms such as delusions or hallucinations during Alzheimer disease have a more rapid deterioration and worse outcomes. We have found that the risk for developing psychosis during Alzheimer disease is influenced by genetic factors. In this grant we will conduct a large scale genetic analysis of individuals with Alzheimer disease (both with and without psychosis), in an effort to identify the specific combinations of genetic markers that predispose to psychotic symptoms in Alzheimer disease. We will further test whether these genetic markers can be used for personalized prediction of more rapid deterioration and psychosis onset.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG027224-14
Application #
9925165
Study Section
Adult Psychopathology and Disorders of Aging Study Section (APDA)
Program Officer
Miller, Marilyn
Project Start
2007-05-01
Project End
2022-04-30
Budget Start
2020-05-01
Budget End
2021-04-30
Support Year
14
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Psychiatry
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15260
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