Genetic Epidemiology of Psychotic Symptoms and their Treatment in Dementia

Abstract

There is an urgent need to develop safe and effective treatments for psychotic symptoms in dementia and make better use of current treatments. This will be aided by a better understanding of the mechanisms underlying both the symptoms and treatments. Thus, two lines of research were followed: 1) analysis of the prevalence and course of psychotic symptoms in Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB)/Parkinson’s disease dementia (PDD), and, 2) analysis of the response to treatments in AD. To address the former, the COMT val158met and 5HTTLPR polymorphisms were assessed with respect to the presence of persistent symptoms and the MAPT haplotype with respect to the course of symptoms. The 5HTTLPR LL genotype was associated with a significantly increased risk of persistent delusions in DLB/PDD and the MAPT haplotype with a significantly increased risk of worsening delusions in AD. Finally, the COMT val158met polymorphism was found to predict more rapid cognitive decline in mild AD patients.
The examination of point 2) above chiefly concerned histamine H1 receptor antagonism and antipsychotic mortality. Patients taking high affinity H1 antipsychotics had a significantly greater mortality risk compared with those taking no antipsychotics with evidence also suggesting effect modification by the HNMT gene polymorphism.
Collectively, in what are among the best characterised cohorts to date, these findings bring greater clarity to the current understanding of the role of 5HTTLPR and COMT val158met in contributing to psychotic symptoms in dementia, supporting the prioritisation of serotonin-acting treatments in DLB/PDD and suggesting that dopamine levels may indirectly influence the presentation of psychosis via more rapid cognitive decline in AD. New evidence was also found to support the hypotheses that tau pathology is associated with psychosis and histamine antagonism is a key harmful property of antipsychotics, with important implications for treatment strategies.

Date of Award	2014
Original language	English
Awarding Institution	King's College London
Supervisor	Clive Ballard (Supervisor) & Emma Jones (Supervisor)