BACKGROUND: The Clinical Dementia Rating–Sum of Boxes (CDR-SB) has been proposed as a primary outcome for use in prodromal AD trials. However, the psychometric properties of this, and of other commonly used measures, have not been well-established in this patient population. OBJECTIVE: To describe the psychometric properties of commonly used efficacy measures in a clinical trial of prodromal AD. SETTING: Data were gathered as part of a two-year clinical trial. PARTICIPANTS: Patients had biomarker confirmed prodromal AD. MEASUREMENTS: Clinical Dementia Rating (CDR), Functional Activities Questionnaire (FAQ), Alzheimer’s Disease Assessment Scale – Cognition Subscale 11 and 13 (ADAS-Cog), Mini Mental State Exam (MMSE), and Free and Cued Selective Reminding Test (FCSRT-IR [words]). Assessments were conducted at least every 24 weeks. RESULTS: For the CDR-SB, test-retest reliability was good (intra-class correlation coefficient [ICC]=0.83); internal consistency was 0.65 at baseline but above 0.8 at later assessments. Relationships between the CDR-SB and other measures were as expected (higher correlations with more closely related constructs), and the CDR-SB differentiated between patients with different severities of dementia (-2.9 points difference between CDR-Global Score 0.5 and 1, P<.0001). Floor and ceiling effects on the CDR-SB total score were minimal; however, at baseline there were ceiling effects in the personal care domain. Further detail is provided on the psychometric properties of ADAS-Cog, MMSE, FCSRT-IR and FAQ in this population. CONCLUSION: The psychometric properties of the CDR-SB are adequate in prodromal AD and continued use is warranted in clinical trials. However, there remains scope for improvement in the assessment of functional constructs and development of novel measures should continue.

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Background: We evaluated the Roche Elecsys ® NeuroToolKit (NTK) assay panel of 12 cerebrospinal fluid (CSF) biomarkers in patients from a total of six clinical trials of crenezumab and gantenerumab in sporadic Alzheimer's disease (AD), with respect to the correlations between individual biomarkers, and their associations with patient characteristics and disease severity. Additionally, we assessed their ability to measure and predict disease progression. Method: CSF samples were collected at baseline and follow-up (Phase II, 1.5 years; Phase III, 1 and 2 years) from a subset of patients enrolled in the Phase II ABBY (NCT01343966)/BLAZE (NCT01397578) studies of crenezumab in mild-to-moderate AD, the Phase III CREAD (NCT02670083)/CREAD 2 (NCT03114657) studies of crenezumab in prodromal-to-mild AD, the Phase III SCarlet RoAD (NCT01224106) study of gantenerumab in prodromal AD, and the Phase III Marguerite RoAD (NCT02051608) study of gantenerumab in mild AD. NTK assays included beta-amyloid (1-42), beta-amyloid (1-40), alpha-synuclein, GFAP, IL-6, neurogranin, neurofilament light chain (NfL), phospho-Tau (181P), S100B, sTREM2, total Tau, and YKL-40. Correlations between biomarkers, longitudinal changes in biomarkers, and correlation between baseline biomarker levels and cognitive progression were evaluated across all six studies.Result: All biomarkers except IL-6 positively correlated with each other; the highest correlations were between total Tau, phospho-Tau (181P), and neurogranin (Spearman's rho >0.9). NfL, GFAP, YKL-40, and sTREM2 biomarkers positively correlated with patient age. Analyses of ABBY, BLAZE, CREAD, and CREAD2 showed consistent findings across all studies. Levels of NfL, GFAP, and α-synuclein biomarkers increased at the 1 year and 1.5-year timepoints. NfL correlated with disease severity and progression in the prodromal-to-mild population. Additionally, results from NTK measurements in SCarlet RoAD and Marguerite RoAD CSF samples will also be presented. Conclusion:The NTK provided robust data and sufficient measuring range for the biomarkers tested. Further evaluation of these biomarkers is needed to understand their potential utility for clinical trials as pharmacodynamic biomarkers or for selecting patient populations. Elecsys is a trademark of Roche.

BackgroundSKYLINE is a new secondary prevention study in Alzheimer's disease (AD) enrolling amyloid‐positive, cognitively normal individuals at risk for clinical AD between 60 and 80 years and treating them with gantenerumab or placebo for 4 years. Based on available data from other studies, we expect only 15% of individuals to be amyloid‐positive in this screening population. We developed a blood‐based biomarker (BBBM) prescreening test to screen out participants who have a low likelihood of amyloid positivity by positron emission tomography (PET) or cerebrospinal fluid (CSF) testing before entering the main screening of SKYLINE.MethodWe explored multiple individual key AD BBBMs (measured with Elecsys® prototype assays) and combinations in three large cohorts (BioFINDER‐1, AIBL, A4) of cognitively unimpaired and subjective cognitive decline/mild cognitive impairment participants. We used predefined thresholds for amyloid PET and/or CSF pTau/Abeta42 as the reference standard for amyloid positivity. The performance of the BBBM was assessed by evaluating the positive and negative predictive value (PPV and NPV) for amyloid positivity, and screen‐out proportions based on a range of potential thresholds. Those metrics were translated into the total number of participants that need to be screened and the reduction of the number of participants that need to be screened with PET or CSF testing to reach the target sample size.ResultWe identified a combination of two key AD biomarkers expected to enable a high NPV at moderate PPV, screening out 40–50% of participants, amongst whom are only 3–5% true amyloid positives (falsely ruled out). This BBBM prescreening would reduce the need for PET or CSF testing by 40% while requiring screening of 8% more participants to compensate for the wrongly excluded amyloid positives.ConclusionThe implementation of Elecsys® blood‐based prescreening in SKYLINE will significantly reduce site and participant burden, accelerate the study enrollment, and save screening costs by reducing unnecessary downstream screening assessments such as cognitive batteries, magnetic resonance imaging, and PET or CSF testing.

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