A Longitudinal Study of Total and Phosphorylated alpha-Synuclein with Other Biomarkers in Cerebrospinal Fluid of Alzheimer's Disease and Mild Cognitive Impairment

Alzheimer's disease (AD) features a dynamic sequence of amyloid deposition, neurodegeneration, and cognitive impairment. A significant fraction of AD brains also displays Lewy body pathology, suggesting that addition of classically Parkinson's disease-related proteins to the AD biomarker panel may be of value. To determine whether addition of cerebrospinal fluid (CSF) total alpha-synuclein and its form phosphorylated at S129 (pS129) to the AD biomarker panel [Amyloid-beta 1-42 (A beta(42)), tau, and phosphorylated tau (p-tau(181))] improves its performance, we examined CSF samples collected longitudinally up to 7 years as part of the Alzheimer's Disease Neuroimaging Initiative. From 87 AD, 177 mild cognitive impairment (MCI), and 104 age-matched healthy controls, 792 baseline and longitudinal CSF samples were tested for total alpha-synuclein, pS129, A beta(42), tau, and p-tau(181). pS129, but not total alpha-synuclein, was weakly associated with diagnosis at baseline when t-tau/A beta 42 was included in the statistical model (beta = 0.0026, p = 0.041, 95% CI [(0.0001)-(0.005)]). CSF alpha-synuclein predicted Alzheimer's Disease Assessment Scale-Cognitive (beta = -0.59, p = 0.0015, 95% CI [(-0.96)-(-0.23)]), memory (beta = 0.4, p = 0.00025, 95% CI [(0.16)-(0.59)]), and executive (0.62,< 0.0001, 95% CI [(0.31)-(0.93)]) function composite scores, and progression from MCI to AD (beta = 0.019, p = 0.0011, 95% CI [(0.002)-(0.20)]). pS129 was associated with executive function (beta = -2.55, p = 0.0085, 95% CI [(-4.45)-(-0.66)]). Lower values in the mismatch between alpha-synuclein and p-tau181 predicted faster cognitive decline (beta = 0.64, p = 0.0012, 95% CI [(0.48)-(0.84)]). Longitudinal biomarker changes did not differ between groups, and may not reflect AD progression. The alpha-synuclein-p-tau(181)-Mismatch could better predict longitudinal cognitive changes than classical AD markers alone, and its pathological correlates should be investigated further.