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. (2018) proposed a new descriptive classification for AD biomarkers, AT(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 MCI to dementia. We will longitudinally follow normal aging, SCD, and MCI subjects, subclassifying the patients according to AT(N) classification: normal AD biomarkers (AD-) (AT-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 2 years: : a) structural and functional MRI; b) CSF and plasmatic high-sensitive analyses of: AD markers: A²40, A²42, p-Tau, t-Tau, ADAM-10; CSF analyses of synaptic dysfunctionmarkers: VILIP-1 and neurogranin; CSF and plasmatic analyses of neurofilament light chain; CSF and plasmatic analyses of inflammation: YKL-40, MCP-1, IL-6, IL-10, IL-12, IL-18and TNF-±; d) genetic factors: APOE; e) cognitive reserve. (AU)