Clinical Utility of the Pathogenesis-Related Proteins in Alzheimer's Disease

Abstract

Research on the Aβ cascade and alternations of biomarkers in neuro-inflammation, synaptic dysfunction, and neuronal injury followed by Aβ have progressed. But the question is how to use the biomarkers. Here, we examine the evidence and pathogenic implications of protein interactions and the time order of alternation. After the deposition of Aβ, the change of tau, neurofilament light chain (NFL), and neurogranin (Ng) is the main alternation and connection to others. Neuro-inflammation, synaptic dysfunction, and neuronal injury function is exhibited prior to the structural and metabolic changes in the brain following Aβ deposition. The time order of such biomarkers compared to the tau protein is not clear. Despite the close relationship between biomarkers and plaque Aβ deposition, several factors favor one or the other. There is an interaction between some proteins that can predict the brain amyloid burden. The Aβ cascade hypothesis could be the pathway, but not all subjects suffer from Alzheimer's disease (AD) within a long follow-up, even with very elevated Aβ. The interaction of biomarkers and the time order of change require further research to identify the right subjects and right molecular target for precision medicine therapies.

Keywords: Alzheimer’s disease; biomarkers dynamics; interaction; time order.

Figure 1

Hypothesis of Alzheimer’s disease (AD) pathogenesis. HFABp: heart-type fatty acid binding protein, CAA: cerebral amyloid angiopathy, CBF: cerebral blood flow, CGM: cerebral glucose metabolism, FDG-PET: 18F-positron emission tomography-computed tomography, CSF Aβ: cerebral spinal fluid beta amyloid, CSF Tau: cerebral spinal fluid Tau protein, PET-Aβ: Amyloid-beta assessed by florbetapir PET. Ng: neurogranin; SNAP-25: synaptosomal-associated protein 25; YKL-40: chitinase-3-like protein 1; NFL: neurofilament light chain; VILIP-1:visinin-like protein 1.

Figure 2

Association among the proteins based on studies published. Aβ: beta amyloid; Ng: neurogranin; SNAP-25: synaptosomal-associated protein 25; YKL-40: chitinase-3-like protein 1; NfL: neurofilament light chain; VILIP-1: visinin-like protein 1; Blue: association; Green: negative association.