Alzheimer’s Disease Biomarkers Revisited From the Amyloid Cascade Hypothesis Standpoint

Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disease worldwide. Amyloid beta (Aβ) is one of the proteins which aggregate in AD, and its key role in the disease pathogenesis is highlighted in the amyloid cascade hypothesis, which states that the deposition of Aβ in the brain parenchyma is a crucial initiating step in the future development of AD. The sensitivity of instruments used to measure proteins in blood and cerebrospinal fluid has significantly improved, such that Aβ can now successfully be measured in plasma. However, due to the peripheral production of Aβ, there is significant overlap between diagnostic groups. The presence of pathological Aβ within the AD brain has several effects on the cells and surrounding tissue. Therefore, there is a possibility that using markers of tissue responses to Aβ may reveal more information about Aβ pathology and pathogenesis than looking at plasma Aβ alone. In this manuscript, using the amyloid cascade hypothesis as a starting point, we will delve into how the effect of Aβ on the surrounding tissue can be monitored using biomarkers. In particular, we will consider whether glial fibrillary acidic protein, triggering receptor expressed on myeloid cells 2, phosphorylated tau, and neurofilament light chain could be used to phenotype and quantify the tissue response against Aβ pathology in AD.

scaDA: A Novel Statistical Method for Differential Analysis of Single-Cell Chromatin Accessibility Sequencing Data

“…Consequently, the performance of all methods has been demonstrated by enrichment in 10 significant GO terms (FDR < 0.05) (Fig 10), which include “cognition” and “learning or memory” related to clinical phenotype of AD involves progressive cognitive decline and memory loss [27]; “regulation of trans-synapic signaling” and “moderation of chemical synaptic transmission” related to synaptic transmission that promotes neurodegeneration [28]; “regulation of amyloid-beta formation” and “amyloid-beta metabolic process” related to Amyloid beta, which is one protein crucial to AD development [29]; “immunological memory process” and “negative regulation of adaptive immune response” related to microglia ‘s role in the pathogenesis of AD by generating adaptive immune response [24].…”

“…Microglia from "Human AD" is selected for the GO analysis. lated to synaptic transmission that promotes neurodegeneration [28]; "regulation of amyloid-beta formation" and "amyloid-beta metabolic process" related to Amyloid beta, which is one protein crucial to AD development [29]; "immunological memory process" and "negative regulation of adaptive immune response" related to microglia's role in the pathogenesis of AD by generating adaptive immune response [24].…”

Longitudinal decline of plasma neurofilament light levels after antiretroviral initiation in people living with HIV

“…In addition to residual CNS immune activation, some antiretroviral drugs may have neurotoxic effects [43], which could be objectively assessed using a biomarker. Plasma NfL may also be useful for detecting neuronal injury caused by other non‐HIV‐related events or co‐morbidities (e.g., substance use or other CNS diseases, such as Alzheimer's and dementia) [44–46]. Moreover, symptomatic CSF escape, although a rare condition, can potentially lead to neuronal injury and is important to identify [47, 48].…”

Linking the Amyloid, Tau, and Mitochondrial Hypotheses of Alzheimer’s Disease and Identifying Promising Drug Targets

“…Potential novel AD biomarkers include neurogranin and visinin-like protein 1 (VILIP-1) (promising synaptic and neuronal degeneration biomarkers of AD) [ 105 , 118 ], neurofilament light polypeptide (NfL, a possible tau-independent marker of neuroaxonal degeneration) [ 107 ], glial fibrillary acidic protein (a promising plasma biomarker of AD) [ 119 , 120 ], and soluble triggering receptor expressed on myeloid cells 2 (TREM2) (a possible biomarker of microglial activation) to which ApoE can bind [ 121 , 122 ]. A multistep neurodiagnostic process starting with the examination of blood biomarkers of AD and other neurodegenerative diseases has been explored and discussed [ 123 ].…”