Fig. 1

Pathophysiological hallmarks of Alzheimer’s disease and its associated biomarkers in either blood or cerebrospinal fluid. Alzheimer's disease is characterized by amyloid plaques, neurofibrillary tangles, axonal damage, microglial activation, and synaptic dysfunction. These pathophysiological hallmarks are responsible for significant modification of CSF Amyloid-β42/40 ratio, levels of tau with abnormal phosphorylation at positions 181, 231, and 217, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) levels. These variations are also detected in the blood of AD patients. The levels of numerous proteins involved in synaptic function vary in CSF in (preclinical) AD. Proteins originating from the central nervous system are often present in low concentrations that are difficult to detect. A fraction of synaptic proteins is also expressed in other tissues and are therefore not suitable as specific blood biomarkers for synaptic dysfunction. To date, β-synuclein, whose expression is brain-specific, is the only synaptic protein that is determined to be significantly increased in the blood of AD patients