Development of a prediction model of conversion to Alzheimer’s disease in subjects with mild cognitive impairment: the statistical analysis plan of the INTERCEPTOR project

Abstract

Background In recent years, considerable efforts have been directed towards the research and development of disease-modifying therapies for dementia. These drugs focus on prodromal (Mild Cognitive Impairment, MCI) and/or early stages of Alzheimer's disease. Evidence from literature demonstrates that a considerable proportion of MCI subjects never progress to dementia. Therefore it is of utmost importance to identify those individuals who are at a higher risk of developing dementia. Methods The ongoing INTERCEPTOR study is a multicenter, longitudinal, interventional, non-therapeutic cohort study designed to enroll 500 subjects with MCI aged 50–85 years. The primary aim is to identify a biomarker or a set of biomarkers able to accurately predict the conversion from MCI to AD within 3 years of follow-up. The biomarkers investigated in this study are neuropsychological tests (mini-mental state examination MMSE and delayed free recall), brain glucose metabolism ([¹⁸F]FDG-PET), MRI volumetry of the hippocampus, EEG brain connectivity, cerebrospinal fluid (CSF) markers (p-tau, t-tau, Aβ1–42, Aβ1–42/1–40 ratio, Aβ1–42 /p-Tau ratio) and APOE genotype. The baseline visit includes a full cognitive and neuropsychological evaluation, as well as the collection of clinical and socio-demographic information. Prognostic models will be developed using Cox regression, incorporating patient characteristics and biomarkers through stepwise selection. Model performance will be evaluated in terms of discrimination and calibration and subjected to internal validation using the bootstrapping procedure. The final model will be visually represented as a nomogram. Discussion This paper contains a detailed description of the statistical analysis plan to ensure the reproducibility and transparency of the analysis. The prognostic model developed in this study aims to identify the population with MCI at higher risk of developing dementia, potentially eligible for drugs prescriptions. The nomogram could provide a valuable tool for clinicians for risk stratification and early treatment decisions. Trial registration ClinicalTrials.gov NCT03834402. Registered on January 10, 2019