Biomarkers associated with the pathogenesis of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a progressive degenerative neurological illness with insidious onset. Due to the complexity of the pathogenesis of AD and different pathological changes, the clinical phenotypes of dementia are diverse, and these pathological changes also interact with each other. Therefore, it is of great significance to search for biomarkers that can diagnose these pathological changes to improve the ability to monitor the course of disease and treat the disease. The pathological mechanism hypothesis with high recognition of AD mainly includes the accumulation of β-amyloid (Aβ) around neurons and hyperphosphorylation of tau protein, which results in the development of neuronal fiber tangles (NFTs) and mitochondrial dysfunction. AD is an irreversible disease; currently, there is no clinical cure or delay in the disease process of drugs, and there is a lack of effective early clinical diagnosis methods. AD patients, often in the dementia stages and moderate cognitive impairment, will seek medical treatment. Biomarkers can help diagnose the presence or absence of specific diseases and their pathological processes, so early screening and diagnosis are crucial for the prevention and therapy of AD in clinical practice. β-amyloid deposition (A), tau pathology (T), and neurodegeneration/neuronal damage (N), also known as the AT (N) biomarkers system, are widely validated core humoral markers for the diagnosis of AD. In this paper, the pathogenesis of AD related to AT (N) and the current research status of cerebrospinal fluid (CSF) and blood related biomarkers were reviewed. At the same time, the limitations of humoral markers in the diagnosis of AD were also discussed, and the future development of humoral markers for AD was prospected. In addition, the contents related to mitochondrial dysfunction, prion virology and intestinal microbiome related to AD are also described, so as to understand the pathogenesis of AD in many aspects and dimensions, so as to evaluate the pathological changes related to AD more comprehensively and accurately.

Keywords: Alzheimer’s disease; Aβ; NFTs; biomarkers; tau.

FIGURE 1

Amyloid metabolic pathway: the N-terminal extracellular domain portion of APP is first cleaved by β-secretase to produce soluble sAPPβ fragments and C99. C99 is further processed by β-secretory enzymes at multiple sites to release Aβ. Aβ proteins aggregate into oligomers and fibrils and eventually form plaques that damage neurons, leading to the occurrence of AD.

FIGURE 2

In the AD brain, hyperphosphorylated tau protein disrupts the stability of neuronal microtubules and forms NFTs, resulting in impaired neuronal function. (A) Tau proteins bind to microtubule binding domains to stabilize microtubules. (B–F) In the brain neurons of AD patients, phosphorylated kinases such as CDK5 and GSK-3β overphosphorylated tau protein, hyperphosphorylated tau protein separated from microtubules, and the microtubule depolymerized to produce insoluble tau oligomers, tau monomers aggregated to form oligomers, which then intertwine with each other to form pairs of spiral filaments, eventually forming NFTs.