Alpha-synuclein measured in cerebrospinal fluid from patients with Alzheimer's disease, mild cognitive impairment, or healthy controls: a two year follow-up study

Background: alpha-Synuclein has been proposed as a potential biomarker for Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI). However, results from alpha-synuclein measurements in cerebrospinal fluid (CSF) have been inconclusive, and to our knowledge, longitudinal studies of changes prior to the AD diagnosis have not been investigated. Methods: Levels of alpha-synuclein at baseline and after one and two years were measured in CSF, by enzyme-linked immunosorbent assay. Twenty-six patients with early AD (AD-AD), 48 patients with aMCI, subdivided as 23 that developed AD during follow-up (MCI-AD), and 25 that did not (MCI-MCI), and 25 healthy control individuals, were included. One-way ANOVA was applied to compare mean alpha-synuclein baseline values between all four study groups, and a linear mixed model was used to compare mean change over time between the three patient groups. Linear associations between alpha-synuclein and amyloid-beta 1-42 (A beta 42), amyloid-beta 1-40 (A beta 40), total tau and phosphorylated tau were also examined. Results: A large variation in individual alpha-synuclein CSF levels was observed, particularly in the MCI-AD group. No significant differences were found in mean alpha-synuclein levels between all the study groups at baseline. When using a linear mixed model, no significant differences were found at follow-up for estimated mean changes between the patient groups. MCI-AD patients with short duration of symptoms prior to inclusion in the study (<= 2 years) had considerably higher mean CSF alpha-synuclein levels compared to patients with a longer symptom duration (802.2 vs. 442.8 pg/mL, p = 0.01). No such difference was seen in the MCI-MCI or AD-AD groups. Significant linear associations (p < 0.0005) between alpha-synuclein and A beta 40, total tau and phosphorylated tau were found. Conclusion: The observed difference in mean CSF alpha-synuclein level according to duration of symptoms in the MCI-AD group, may be an indication of changes related to disease progression. However, the lack of significant differences between groups, as well as the large individual variation in CSF levels of alpha-synuclein in the present study, suggest that alpha-synuclein is not a useful biomarker for AD.