Mapping the progression of subjective cognitive decline to mild cognitive impairment and Alzheimer´s disease dementia with multimodal biomarkers

Abstract

Alzheimer´s disease (AD) is the most common neurodegenerative disorder and its prevalence is increasing mainly due to the aging of the population. Recent clinical trials with anti-amyloid and other drugs in AD dementia and Mild Cognitive Impairment (MCI) have failed, and one possible explanation is that diagnosis is made too late, when subjects have already relevant clinical symptoms. Thus, the concept of Subjective Cognitive Decline (SCD), when subjects have cognitive complaints but normal neuropsychological performance, has emerged and gained more relevance over the last few years. Recently, Jack et al. (2016) proposed a new descriptive classification for AD biomarkers, A/T/N (alterations in amyloid, tau and neurodegeneration), that can be used in the whole spectrum of the AD pathophysiology continuum (including SCD). In this project, our objective is to determine which are the best biomarkers to predict the conversion from SCD to MCI and from amnestic MCI (aMCI) to dementia. We will longitudinally follow normal aging, SCD, and aMCI subjects, sub classifying the patients according to A/T/N classification: normal AD biomarkers (AD-) (A-T-N-); suspected non-Alzheimer pathophysiology (SNAP) (A-T+N-, A-T-N+, or A-T+N+) and AD pathophysiologic continuum (AD+) (any A+ combination). We will longitudinally evaluate new and well-established multimodal biomarkers in baseline and annually for 4 years: : a) structural and functional MRI; b) FDG-PET brain glucose metabolism; c) CSF analyses of: - AD markers: A²40, A²42, A² oligomers, p-Tau, t-Tau, ADAM-10; - Synaptic dysfunction markers: VILIP-1 and neurogranin; neurofilament light chain; - Neuroinflammation: YKL-40, MCP-1, IL-6, IL-10, IL-12, IL-18 and TNF-±; d) genetic factors: APOE, CLU, PICALM and CR1; e) cognitive reserve; f) white matter disease observed in MRI. (AU)