Distinct CSF α-synuclein aggregation profiles associated with Alzheimer's disease phenotypes and MCI-to-AD conversion.

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Backgroundα-Synuclein (α-Syn) pathology is present in 30-50 % of Alzheimer's disease (AD) patients, and its interactions with tau proteins may further exacerbate pathological changes in AD. However, the specific role of different aggregation forms of α-Syn in the progression of AD remains unclear.ObjectivesTo explore the relationship between various aggregation types of CSF α-Syn and Alzheimer's disease progression.DesignWe conducted a retrospective analysis of data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to examine the association between different α-Syn aggregation forms-Syn0 (no detectable α-Syn aggregates) and Syn1 (α-Syn aggregates detected, resembling those found in Parkinson's disease)-with the pathological and clinical features of AD. Additionally, we evaluated their potential as predictors of conversion from mild cognitive impairment (MCI) to AD.SettingThe ADNI database.ParticipantsA total of 250 participants, including 70 cognitively normal controls, 119 patients diagnosed with MCI, and 61 patients diagnosed with AD.MeasurementsPearson correlation was employed to assess the relationship between α-Syn levels and cerebrospinal fluid (CSF) biomarkers, including total tau (T-tau), phosphorylated tau (p-tau), and amyloid-β42 (Aβ42). Multivariate Cox proportional hazards models were applied, adjusting for APOE4 status, age, and sex, to determine the association between α-Syn forms and AD-related pathological and clinical outcomes. Kaplan-Meier curves were used to evaluate the prognostic value of different α-Syn aggregation states in predicting the conversion from MCI to AD.ResultsCompared with controls, overall MCI and AD patients had elevated α-Syn levels. Notably, in the α-Syn0 group, α-Syn levels were increased in the MCI patients and further increased in AD patients, whereas in the α-Syn1 group, α-Syn levels did not significantly differ across diagnostic groups. Both in the α-Syn0 and α-Syn1 groups, α-Syn levels were found to correlate more strongly with CSF tau levels than with Aβ42, indicating a possible role for α-Syn in tau-related pathology in AD. Importantly, α-Syn0-AD patients exhibited more rapid cognitive decline and greater hippocampal atrophy than α-Syn1-AD patients. However, MCI patients with CSF α-Syn1 aggregation status had an increased risk of conversion to AD.ConclusionsCSF α-Syn is associated with tau pathology and neurodegeneration in Alzheimer's disease. The distinct aggregation profiles of α-Syn serve as valuable biomarkers, offering insights into differing prognoses in AD and aiding in the prediction of early disease progression.

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