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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
Project #
Application #
Study Section
Adult Psychopathology and Disorders of Aging Study Section (APDA)
Program Officer
Miller, Marilyn
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pittsburgh
Schools of Medicine
United States
Zip Code
Hu, Ziheng; Wang, Lirong; Ma, Shifan et al. (2018) Synergism of antihypertensives and cholinesterase inhibitors in Alzheimer's disease. Alzheimers Dement (N Y) 4:542-555
DeMichele-Sweet, M A A; Weamer, E A; Klei, L et al. (2018) Genetic risk for schizophrenia and psychosis in Alzheimer disease. Mol Psychiatry 23:963-972
Shah, Chintan; DeMichele-Sweet, Mary Ann A; Sweet, Robert A (2017) Genetics of psychosis of Alzheimer disease. Am J Med Genet B Neuropsychiatr Genet 174:27-35
Weamer, Elise A; DeMichele-Sweet, Mary Ann A; Cloonan, Yona K et al. (2016) Incident Psychosis in Subjects With Mild Cognitive Impairment or Alzheimer's Disease. J Clin Psychiatry 77:e1564-e1569
Seltman, Howard J; Mitchell, Shaina; Sweet, Robert A (2016) A Bayesian model of psychosis symptom trajectory in Alzheimer's disease. Int J Geriatr Psychiatry 31:204-10
Grubisha, Melanie J; Lin, Chien-Wei; Tseng, George C et al. (2016) Age-dependent increase in Kalirin-9 and Kalirin-12 transcripts in human orbitofrontal cortex. Eur J Neurosci 44:2483-2492
Sweet, Robert A; MacDonald, Matthew L; Kirkwood, Caitlin M et al. (2016) Apolipoprotein E*4 (APOE*4) Genotype Is Associated with Altered Levels of Glutamate Signaling Proteins and Synaptic Coexpression Networks in the Prefrontal Cortex in Mild to Moderate Alzheimer Disease. Mol Cell Proteomics 15:2252-62
Wang, Ting; Ren, Zhao; Ding, Ying et al. (2016) FastGGM: An Efficient Algorithm for the Inference of Gaussian Graphical Model in Biological Networks. PLoS Comput Biol 12:e1004755
Ismail, Zahinoor; Smith, Eric E; Geda, Yonas et al. (2016) Neuropsychiatric symptoms as early manifestations of emergent dementia: Provisional diagnostic criteria for mild behavioral impairment. Alzheimers Dement 12:195-202
Kirkwood, Caitlin M; MacDonald, Matthew L; Schempf, Tadhg A et al. (2016) Altered Levels of Visinin-Like Protein 1 Correspond to Regional Neuronal Loss in Alzheimer Disease and Frontotemporal Lobar Degeneration. J Neuropathol Exp Neurol 75:175-82

Showing the most recent 10 out of 54 publications