The effect of diagnostic criteria on outcome measures in preclinical and prodromal Alzheimer's disease: Implications for trial design

Daniela Bertens, Betty M Tijms, Lisa Vermunt, Niels D Prins, Philip Scheltens, Pieter Jelle Visser, Daniela Bertens, Betty M Tijms, Lisa Vermunt, Niels D Prins, Philip Scheltens, Pieter Jelle Visser

Abstract

Introduction: We investigated the influence of different inclusion criteria for preclinical and prodromal Alzheimer's disease (AD) on changes in biomarkers and cognitive markers and on trial sample size estimates.

Methods: We selected 522 cognitively normal subjects and 872 subjects with mild cognitive impairment from the Alzheimer's Disease Neuroimaging Initiative study. Compared inclusion criteria were (1) preclinical or prodromal AD (amyloid marker abnormal); (2) preclinical or prodromal AD stage-1 (amyloid marker abnormal, injury marker normal); and (3) preclinical or prodromal AD stage-2 (amyloid and injury markers abnormal). Outcome measures were amyloid, neuronal injury, and cognitive markers.

Results: In both subjects with preclinical and prodromal AD stage-2, inclusion criteria resulted in the largest observed decline in brain volumetric measures on magnetic resonance imaging and cognitive markers.

Discussion: Inclusion criteria influence the observed rate of worsening in outcome measures. This has implications for trial design.

Keywords: Alzheimer's disease; Biomarkers; Clinical trial; Cognitive markers; Longitudinal; Preclinical; Prodromal; Sample size estimates.

Figures

Fig. 1
Fig. 1
Schematic overview of the groups according to subclassification, applying the research criteria. Abbreviations: ADNI, Alzheimer's Disease Neuroimaging Initiative; MCI, mild cognitive impairment; AD, Alzheimer's disease. Subject classification based on AD biomarkers: Preclinical AD, n = 146; 49 based on CSF measures only, 80 based on PET, and 17 subjects with both modalities present. Preclinical AD stage-1, n = 110; 33 based on CSF measures only, 60 based on PET, and 17 with both modalities present. Preclinical AD stage-2, n = 34; 16 based on CSF measures only, 17 based on PET, and 1 with both modalities present. For two cognitively normal subjects, we did not have any information of their injury status so they could not be further classified into stage-1 or stage-2. Prodromal AD, n = 420; 149 based on CSF measures only, 148 based on PET, and 123 with both modalities present. Prodromal AD stage-1, n = 216; 63 based on CSF measures only, 88 based on PET, and 65 with both modalities present. Prodromal AD stage-2, n = 197; 85 based on CSF measures, 59 based on PET, 53 with both modalities present. For seven MCI subjects, we did not have any information of their injury status, so they could not be further classified into stage-1 or stage-2.

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