Atrophy in dopaminergic pathways is associated with emergence of delusions in patients with Alzheimer’s disease

Background People with advanced Alzheimer’s disease (AD) may present with delusions that are associated with worse quality of life and prognosis. However, early markers of delusions have not been identified yet. The present study aimed to investigate whether differences in cognitive and grey matter (GM) volume decline can be detected in the year before symptom onset between patients with AD who will and will not develop delusions. Method Two samples of patients with AD, 63 who will (AD‐D) and 63 who will not develop delusions (AD‐ND) over a year as recorded by means of the NPI, were identified from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database and matched for diagnosis, cognitive status, age, education, sex, handedness and APOE genotype. Sixty‐three additional matched healthy controls (HC) were selected. Group‐by‐time models were used to compare cognitive and clinical data across groups, as well as GM maps by means of VBM. Change in NPI scores was used as covariate. Post hoc analyses were performed to investigate AD‐D vs AD‐ND differences in volume decline in areas found to be more atrophic in the AD‐D group and in brainstem nuclei connected to these areas. Result No neurocognitive differences were observed between patient groups either prior to or at symptom onset. When the two patient groups were compared to HC, the AD‐ND showed no greater atrophy over time while greater atrophy in the left caudate was observed in the AD‐D group. Post hoc analyses revealed greater GM loss in the AD‐D group in both caudate bodies and dopaminergic nuclei (i.e. the substantia nigra and the ventral tegmental area), but not in serotoninergic nuclei. Conclusion Patients with AD who will develop delusion showed faster neurodegeneration prior to symptom onset in dopaminergic systems, especially in the nigrostriatal pathway. Therefore, alterations in dopamine neurotransmission due to AD‐related pathology may explain the emergence of delusional thoughts in this population, consistently with the dopaminergic hypothesis of positive symptoms in schizophrenia.