Longitudinal change of CSF tau and Aβ42.

<p>The figure shows the mean baseline and follow-up levels of CSF tau (panel A) and CSF Aβ42 (panel B) in healthy controls (HC), that were followed for 4 years (y), and in two cohorts of patients with Alzheimer's disease (AD) that were followed for one or two years, respectively. Error bars represent standard errors of the mean. The figure illustrates that differences between controls and AD patients by far surpass the within-group differences over time.</p

Demographic characteristics of the AD patients and the age-matched controls at baseline and follow-up.

<p>Values are means±SD, except as noted otherwise.</p>a<p>p<0.001 vs Controls.</p><p>Abbreviations: 1-year AD cohort, AD patients with approximately one year between baseline and follow-up lumbar puncture; 2-year AD cohort, AD patients with approximately two years between baseline and follow-up lumbar puncture; Controls, healthy controls followed for 4 years; APOE ε4 carrier, at least one apolipoprotein E ε4 allele; MMSE, Mini-Mental State Examination.</p

Baseline and follow-up levels of CSF tau and Aβ42 in the AD patients and age-matched controls.

<p>Values are means±SD except if noted otherwise.</p>a<p>p<0.001 vs Controls.</p>b<p>p<0.05 vs baseline.</p><p>Abbreviations: CSF, cerebrospinal fluid; 1-year AD cohort, subjects with Alzheimer's disease with an interval between baseline and follow-up lumbar puncture of approximately one year; 2-year AD cohort, subjects with Alzheimer's disease with an interval between baseline and follow-up lumbar puncture of approximately two years. Controls, healthy controls followed for 4 years.</p

ELISA method for Aβ oligomers in cerebrospinal fluid.

<p>A) Schematic drawing of the principle for the method. Left: The Aβo ELISA is based on the use of the same N-terminal anti-Aβ monoclonal antibody twice. The ELISA plate is coated with 82E1 to capture all forms of Aβ, while biotinylated 82E1 is used for detection. A synthetic Aβ dimer, with two N-termini, is used as standard. Middle: Aβos, with several free N-terminals, are detected in the assay. Right: monomeric Aβ will have their epitopes blocked by the capture antibody and are thus not detected by the detection antibody. B) Example of a typical standard curve from the Aβo assay. The standard curve ranges from 200–102,400 fg/mL. The assay has a lower limit of quantification of 200 fg/mL. C) Measurement of synthetic Aβo formation by the Aβo ELISA. Synthetic Aβ_1–42 was allowed to aggregate into Aβ oligomers. The signal in the Aβo ELISA was compared with a Thioflavin-T (ThT) assay for aggregated Aβ. The Aβo ELISA detects the formation of synthetic Aβo at an earlier stage than the ThT assay, while following the increase of oligomerization in parallel with the ThT assay after 5 hours.</p

Cerebrospinal fluid Aβ oligomers in independent clinical samples.

<p>A) First AD study (Malmö). Increased CSF levels of Aβo in the AD group (n = 42) compared to the control group (n = 31), p<0.0001. Bars indicate median with interquartile range. B) Second AD study (Piteå and Stockholm). Increased CSF levels of Aβo in the group of patients with AD (n = 51) compared to the control group (n = 22), p<0.001. Bars indicate median with interquartile range. C) MCI study. Increased CSF levels of Aβo in the group of MCI patients who converted to AD during the follow-up period (n = 58) as compared to the control group (n = 62), p<0.01. No significant difference in CSF Aβo between stable MCI (p = 0.059) and controls. Bars indicate median with interquartile range. D) Clinical study on AD with different severity of dementia. Increased CSF levels of Aβo in the group of AD patients with mild (n = 44, p<0.01) and moderate (n = 51, p<0.001) dementia as compared to the control group (n = 33). No significant change was found in the AD group with severe dementia (n = 11) compared to the control group. Bars indicate median with interquartile range.</p

Summary of patients’ baseline characteristics.

<p>SD = single dose; RD = repeat dose; SE = standard error.</p><p>³Three patients participated in two dose levels of the single dose study and therefore the PGx sample was collected at the first dosing level in which they participated and not the second dosing level. <i>APOE</i> ε4 overall carriage frequency was calculated using the PGx population (n = 15), i.e., patients who participated in more than one dosing level were only taken into account once.</p><p>²Six patients participated in part A and re-entered part B. Therefore the pharmacogenetic (PGx) sample was collected when the patients participated in part A and no PGx sample was collected during part B. <i>APOE</i> ε4 overall carriage frequency was calculated using the PGx population (n = 44), i.e., patients who participated in both parts were only taken into account once.</p><p>¹Values ranged from 20 to 26 for all patients except one, who scored 28.</p><p>Summary of patients’ baseline characteristics.</p

Summary of most frequently reported adverse events.

<p>SD = single dose; RD = repeat dose.</p><p>²Amyloid-related imaging abnormality-hemorrhage (ARIA-H)</p><p>¹Amyloid-related imaging abnormality-edema (ARIA-E);</p><p>Summary of most frequently reported adverse events.</p

GSK933776 plasma pharmacokinetics.

<p>Time-course of plasma concentrations of GSK933776 by dose: medians (lines) and individual data (dots). LLQ is 100 ng/mL for the 0.1 mg/kg dose and 5 μg/mL for the 1, 3, and 6 mg/kg doses. SD = single dose; RD = repeat dose. Maximum plasma concentrations increased with dose.</p

GSK933776 plasma pharmacodynamics.

<p>A) Geometric mean plasma Aβ concentration–time plots over the three dosing intervals (semi-log plot). Plasma levels of total Aβ42 and Aβ increased whereas plasma levels of free Aβ decreased in dose-dependent manner. Peak:trough ratios for Aβ decreased with increasing dose of GSK933776. B) Week 12 ratio to baseline for CSF Aβ (Aβ1–42 and AβX–42) concentrations. Presented as individual values and mean (95%CI). There were no significant changes from baseline for Aβ1–42 or AβX–42.</p