The relationship of excess cognitive impairment in MCI and early Alzheimer's disease to the subsequent emergence of psychosis

Abstract

Background: Psychotic symptoms in Alzheimer disease (AD + P) identify a heritable phenotype associated with greater cognitive impairment. Knowing when the cognitive course of AD + P subjects diverges from that of subjects without psychosis would enhance understanding of how genetic variation results in AD + P and its associated cognitive burden. This study seeks to determine whether the degree of cognitive impairment and cognitive decline in early AD predicts subsequent AD + P onset.

Methods: 361 subjects with possible or probable AD or mild cognitive impairment (MCI) without psychosis were evaluated every 6 months until psychosis onset.

Results: Severity of cognitive dysfunction was a strong predictor of AD + P up to two years prior to psychosis onset. Cognition did not decline more rapidly prior to onset of AD + P.

Conclusions: Individuals who will develop AD + P already demonstrate excess cognitive impairment during the mild stages of disease. Genetic variation and brain pathophysiology may lead to a cognitive risk phenotype which is present prior to dementia onset.

Figure 1. Possible Trajectories of Greater Cognitive Impairment Relative to Onset of Psychosis in AD, and Implications for the Relationship of Genetic Variation to AD+P

Genetic variation may contribute to the risk of psychosis onset, with greater cognitive burden only emerging as a result of the psychotic process, i.e. after the onset of psychotic symptoms (Trajectory A). Alternatively, genetic variation may accelerate the neurodegenerative process leading to greater cognitive decline and onset of AD+P (Trajectory B). Finally, genetic variants may act during neurodevelopment or normal aging to create a “cognitive risk” phenotype that will manifest as AD+P after the independent onset of neurodegeneration (Trajectory C).