Cerebrospinal Fluid α-Synuclein and Lewy Body-Like Symptoms in Normal Controls, Mild Cognitive Impairment, and Alzheimer's Disease

Background: Reduced cerebrospinal fluid (CSF) alpha-synuclein has been described in synucleinopathies, including dementia with Lewy bodies (DLB). Common symptoms of DLB include visual hallucinations and visuospatial and executive deficits. Co-occurrence of Lewy body pathology is common in Alzheimer's disease (AD) patients, but it is unknown if reduced CSF alpha-synuclein is associated with Lewy body-like symptomatology in AD. Objective: Determine associations between CSF alpha-synuclein and Lewy body-like symptomatology. Methods: We included 73 controls (NC), 121 mild cognitive impairment (MCI) patients, and 61 AD patients (median follow-up 3.5 years, range 0.6-7.8). We tested associations between baseline CSF alpha-synuclein and visual hallucinations and (longitudinal) cognition. Models were tested with and without co-varying for CSF total tau (T-tau), which is elevated in AD patients, and believed to reflect neurodegeneration. Results: Hallucinations were reported in 20% of AD patients, 13% of MCI patients, and 8% of NC. In AD, low CSF alpha-synuclein was associated with hallucinations. When adjusting for CSF T-tau, low CSF alpha-synuclein was associated with accelerated decline of executive function (NC, MCI, and AD), memory (MCI and AD), and language (MCI). Conclusion: The associations of low CSF alpha-synuclein with hallucinations and poor executive function, which are hallmarks of DLB, indirectly suggest that this biomarker may reflect underlying synuclein pathology. The associations with memory and language in MCI and AD suggests either that reduced CSF alpha-synuclein also partly reflects global impaired neuronal/synaptic function, or that non-specific overall cognitive deterioration is accelerated in the presence of synuclein related pathology. The findings will require autopsy verification.