The neural signatures of psychoses in Alzheimer’s disease: a neuroimaging genetics approach

Psychoses in Alzheimer’s disease (AD) are associated with worse prognosis. Genetic vulnerability for schizophrenia (SCZ) may drive AD-related psychoses, yet its impact on brain constituents is still unknown. This study aimed to investigate the association between polygenic risk scores (PRSs) for SCZ and psychotic experiences (PE) and grey matter (GM) volume in patients with AD with (AD-PS) and without (AD-NP) psychosis. Clinical, genetic and T1-weighted MRI data for 800 participants were extracted from the ADNI database: 203 healthy controls, 121 AD-PS and 476 AD-NP. PRSs were calculated using a Bayesian approach and analysed at ten p-value thresholds. Standard voxel-based morphometry was used to process MRI data. Logistic regression models including both PRSs for SCZ and PE, and an AD-PRS were used to predict psychosis in AD. Associations between PRSs and GM volume were investigated in the whole sample and the three groups independently. Only the AD-PRS predicted psychosis in AD. Inconsistent associations between the SCZ-PRS and PE-PRS and GM volumes were found across groups. The SCZ-PRS was negatively associated with medio-temporal/subcortical volumes and positively with medial/orbitofrontal volumes in the AD-PS group. Only medio-temporal areas were more atrophic in the AD-PS group, while there was no significant correlation between psychosis severity and GM volume. Although not associated with psychoses, the SCZ-PRS was correlated with smaller medio-temporal and larger orbitofrontal volumes in AD-PS. Similar alterations have also been observed in SCZ patients. This finding suggest a possible disconnection between these regions associated with psychoses in more advanced AD.