Lewy Bodies, Vascular Risk Factors, and Subcortical Arteriosclerotic Leukoencephalopathy, but not Alzheimer Pathology, are Associated with Development of Psychosis in Alzheimer’s Disease

Abstract

Background The neuropathological correlates of psychosis in Alzheimer’s disease (AD) is unclear, with some studies reporting a correlation between psychosis and increased AD pathology while others have found no association. Objective To determine the demographic, clinical, and neuropathological features associated with psychotic symptoms in clinically attributed and neuropathologically proven AD. Method We separately reviewed two overlapping groups of clinically diagnosed (cAD) AD patients with neuropathology data and neuropathologically definite (npAD) cases (regardless of clinical diagnosis) from the NACC database, and explored the relationships between psychosis and clinical variables, neuropathologic correlates, and vascular risk factors. Delusions and hallucinations, defined according to the NPI-Q, were analyzed separately. Results 1,073 subjects in the database fulfilled our criteria (890 cAD and 728 npAD patients). 34% of cAD and 37% of npAD had psychotic symptoms during their illness. Hallucinations were associated with greater cognitive and functional impairments on the MMSE and CDR, while delusional patients showed less impairment on CDR, consistent across cAD and npAD groups. Burden of AD pathology appears to relate to presence of psychotic symptoms in the clinical AD group, but this result is not confirmed in the neuropathologically confirmed group suggesting the findings in the clinical group were due to misdiagnosis of AD. Lewy body pathology, subcortical arteriosclerotic leukoencephalopathy, and vascular risk factors, including a history of hypertension and diabetes, were associated with the development of psychosis. Conclusions Vascular and Lewy body pathologies and vascular risk factors are important modifiers of the risk of psychosis in AD.

Advanced cerebral amyloid angiopathy and small vessel disease are associated with psychosis in Alzheimer’s disease

“…Patients clinically misdiagnosed with a certain type of dementia may be an important subgroup inflicting errors in trials and mixed AD with vascular dementia are often misdiagnosed as pure LDB 1. Our findings of vascular pathology and severe psychosis introduce a possible understanding of this subgroup and may improve diagnostic accuracy.…”

“…Subcortical arteriosclerotic leukoencephalopathy (SVD-related pathology) and vascular risk factors, but not specific vascular pathologies, were found associated with psychosis ever present 1. Vascular changes on MRI have also been associated with late onset schizophrenia, and there is an overlap between late onset schizophrenia and early psychotic symptoms in dementia.…”

“…The mechanisms of psychotic symptoms are largely unknown. Psychosis has been found to be associated with more severe AD and Lewy body pathology in patients with AD and cerebrovascular disease-related vasculopathy 1. One form of vascular pathology, cerebral amylod angiopathy (CAA), is defined as deposits of amyloid in the vessel walls that increase risk of haemorrhage and ischaemia.…”

Association Between Psychosis Phenotype and APOE Genotype on the Clinical Profiles of Alzheimer's Disease

“…Moreover, most studies relied on a clinical diagnosis of AD, which is more prone to error, rather than the gold standard neuropathological diagnosis of AD. In our previous study, we found that using a clinical diagnosis can result in false associations due to the high rates of misdiagnosis [36, 37]. …”

Clinical and neurocognitive aspects of hallucinations in Alzheimer’s disease

“…A study has demonstrated that AD patients tend to develop visual hallucinations significantly later than patients with Dementia with Lewy bodies [28]. Thus, visual hallucinations may characterize the advanced stages of AD and the co-occurrence of vascular pathology rather than AD pathology [29, 30]. …”