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

Abstract

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 α-synuclein and its form phosphorylated at S129 (pS129) to the AD biomarker panel [Amyloid-β1-42 (Aβ42), tau, and phosphorylated tau (p-tau181)] 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 α-synuclein, pS129, Aβ42, tau, and p-tau181. pS129, but not total α-synuclein, was weakly associated with diagnosis at baseline when t-tau/Aβ42 was included in the statistical model (β= 0.0026, p = 0.041, 95% CI [(0.0001)-(0.005)]). CSF α-synuclein predicted Alzheimer's Disease Assessment Scale-Cognitive (β= -0.59, p = 0.0015, 95% CI [(-0.96)-(-0.23)]), memory (β= 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 (β= 0.019, p = 0.0011, 95% CI [(0.002)-(0.20)]). pS129 was associated with executive function (β= -2.55, p = 0.0085, 95% CI [(-4.45)-(-0.66)]). Lower values in the mismatch between α-synuclein and p-tau181 predicted faster cognitive decline (β= 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 α-synuclein-p-tau181-Mismatch could better predict longitudinal cognitive changes than classical AD markers alone, and its pathological correlates should be investigated further.

Keywords: Alzheimer’s disease; biomarkers; cerebrospinal fluid; mild cognitive impairment; pS129-α-synuclein; α-synuclein.

Fig. 1

Correlation among CSF biomarkers. (A) correlation matrix with Pearson correlation coefficient values between all CSF biomarker pairs (red shading indicates positive correlation and blue shading negative correlation). (B-G) Scatterplots depicting values of the different biomarker pairs. Blue lines represent LOESS lines (LOcal regrESSion).

Fig. 2

Cross-sectional values of biomarkers by diagnosis group. Baseline biomarker values are reported for (A) total α-syn, (B) pS129, and (C) α-syn-p-tau₁₈₁-Mis for control, MCI, and AD subjects.

Fig. 3

ROC curves for separation of subjects by diagnosis for each biomarker. Cross-sectional (A) total α-syn, (B) pS129, and (C) α-syn–p-tau₁₈₁-Mis performed poorly in distinguishing diagnoses.

Fig. 4

α-syn–p-tau₁₈₁-Mis is associated with AD progression. A-C) Association of baseline α-syn–p-tau181-Mis with clinical progression during follow-up. Modeled progression by quartile shows faster progression for those with lower (i.e., more negative) α-syn–p-tau₁₈₁-Mis values. D) Association of the α-syn–p-tau181-Mis with progression from MCI to AD. Cox hazard model results were calculated using quantitative values, but for graphical representation we present results for α-syn–p-tau181-Mis tertiles.