The dynamics of Alzheimer's disease biomarkers in the Alzheimer's Disease Neuroimaging Initiative cohort

Abstract

The aim of this study was to investigate the dynamics of four of the most validated biomarkers for Alzheimer's disease (AD), cerebro-spinal fluid (CSF) Abeta 1-42, tau, hippocampal volume, and FDG-PET, in patients at different stage of AD. Two hundred twenty-nine cognitively healthy subjects, 154 mild cognitive impairment (MCI) patients converted to AD, and 193 (95 early and 98 late) AD patients were selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. For each biomarker, individual values were Z-transformed and plotted against ADAS-cog scores, and sigmoid and linear fits were compared. For most biomarkers the sigmoid model fitted data significantly better than the linear model. Abeta 1-42 time course followed a steep curve, stabilizing early in the disease course. CSF tau and hippocampal volume changed later showing similar monotonous trends, reflecting disease progression. Hippocampal loss trend was steeper and occurred earlier in time in APOE epsilon4 carriers than in non-carriers. FDG-PET started changing early in time and likely followed a linear decline. In conclusion, this study provides the first evidence in favor of the dynamic biomarker model which has recently been proposed.

Fig. 1

Schematic representation of the generic sigmoid curve (y = asym/ (1+exp (xmid-x)/scal)). Asym is the asymptote, xmid the inflection point x-value (distance from origin), and one/scal is the angular coefficient of the tangent (i.e. the slope) at point of inflection.

Fig. 2

For each biomarker, individual Z scores are plotted against ADAS-Cog scores, and the fitted sigmoid curve is displayed. Full circles denote healthy controls, full squares MCI patients converted to AD, empty circles early AD, and full triangles late AD patients. Sigmoid fitting was better than linear fitting for Tau, Aβ 1–42 and hippocampus (for the latter: sigmoid nonsignificantly better than linear); linear fitting was better for FDG-PET.

Fig. 3

Individual hippocampal volume Z scores are plotted against ADAS-Cog for both APOE ε4 carriers (full circles), and non-carriers (empty circles). The fitted sigmoid curves for the whole population (thin dotted), APOE ε4 carriers (thick solid), and non-carriers (thick dashed) are displayed. The parameters of each of the three fitted sigmoids are reported in the bottom table. Values are fitted parameters [95% confidence interval], and * denotes significant difference in APOE ε4 carriers vs non-carriers.