Putative novel CSF biomarkers of Alzheimer’s disease based on the novel concept of generic protein misfolding and proteotoxicity: the PRAMA cohort

Alzheimer’s disease (AD) accounts for 60%–70% of cases of dementia worldwide (https://www.alz.org). The NIA-AA (American National Institute of Aging and Alzheimer’s Association) has proposed a research framework based on a biomarker-grounded biological, rather than syndromal, definition of AD, where the disease has to be regarded as a continuum. In this spectrum, seven biomarkers have attained widely recognized diagnostic relevance, including low levels of the 42-residue amyloid beta (Aβ42) and high concentrations of total tau (T-tau) and phosphorylated tau (P-tau) in the cerebrospinal fluid (CSF), high cortical amyloid deposition and tau deposition measured with positron emission tomography (PET), poor brain glucose metabolism measured with fluoro-deoxyglucose PET, and significant brain atrophy imaged with magnetic resonance imaging. Based on these biomarkers, the AT(N) system (A for Aβ deposition, T for pathologic tau, and N for neurodegeneration) has been proposed for biological characterization and staging of AD.