Cerebrospinal Fluid Biomarkers in Alzheimer’s Disease—From Brain Starch to Bench and Bedside

Abstract

Alzheimer’s disease is the most common cause of dementia. Over the last three decades, research has advanced dramatically and provided a detailed understanding of the molecular events underlying the pathogenesis of Alzheimer’s disease. In parallel, assays for the detection of biomarkers that reflect the typical Alzheimer’s disease-associated pathology have been developed and validated in myriads of clinical studies. Such biomarkers complement clinical diagnosis and improve diagnostic accuracy. The use of biomarkers will become even more important with the advent of disease-modifying therapies. Such therapies will likely be most beneficial when administered early in the disease course. Here, we summarise the development of the core Alzheimer’s disease cerebrospinal fluid biomarkers: amyloid-β and tau. We provide an overview of their role in cellular physiology and Alzheimer’s disease pathology, and embed their development as cerebrospinal fluid biomarkers into the historical context of Alzheimer’s disease research. Finally, we summarise recommendations for their use in clinical practice, and outline perspectives for novel cerebrospinal fluid candidate biomarkers.

Body Fluid Biomarkers for Alzheimer’s Disease—An Up-To-Date Overview

“…Among them, AD biomarkers have received a great deal of clinical interest, allowing for the depiction of AD pathology [35,39,40]. Furthermore, such biomarkers could also be applied for the diagnosis of mild cognitive impairment (MCI), the transitional phase from normal cognition to dementia, that generally manifests as a silent pre-clinical phase in 6-15% of AD patients [40][41][42].…”

“…The most effective strategy for developing a biomarker-based diagnostic tool is to combine both disease-specific and non-specific biomarkers. In this context, the decrease in Aβ 42 , and concomitant increase in Aβ 42 /Aβ 40 and Aβ 42 /Aβ 38 ratios and T-tau and P-tau levels is commonly referred to as the Alzheimer profile or signature, as it offers the possibility of detecting AD in its early stages [35,42,57,58]. Additionally, their combined use for AD diagnosis is characterized by sensitivity and specificity of approximately 85-95% [59].…”

Kynurenic Acid Levels are Increased in the CSF of Alzheimer’s Disease Patients

“…This analysis made it possible to establish these parameters as clinical biomarkers indicating that reduced Aβ levels and increased t-tau levels in CSF are distinctive of AD [2]. The inverse correlation between Aβ 42 levels in the CSF and the brain is explained because Aβ 42 in the AD brain is sequestered in the cerebral neuritic plaques, as it is their main component, with less Aβ being available to diffuse into the CSF, and therefore reduced levels of Aβ 42 in CSF from AD patients (reviewed in [3]). In the case of t-tau protein, CSF level probably reflects the intensity of neuronal damage and neurodegeneration (reviewed in [3]).…”

“…The inverse correlation between Aβ 42 levels in the CSF and the brain is explained because Aβ 42 in the AD brain is sequestered in the cerebral neuritic plaques, as it is their main component, with less Aβ being available to diffuse into the CSF, and therefore reduced levels of Aβ 42 in CSF from AD patients (reviewed in [3]). In the case of t-tau protein, CSF level probably reflects the intensity of neuronal damage and neurodegeneration (reviewed in [3]). Although highly studied, the exact initiating and pathophysiological AD-initiating factors remain unknown, but the majority of AD-related research is based on the amyloid cascade and tau hypotheses.…”

“…Although highly studied, the exact initiating and pathophysiological AD-initiating factors remain unknown, but the majority of AD-related research is based on the amyloid cascade and tau hypotheses. In addition to these theories, different pathological mechanisms, such as mitochondrial dysfunction, glutamate excitotoxicity, and neuroinflammation have been implicated in AD [2][3][4][5][6][7][8]. Neuroinflammation in AD is associated with the activation of microglia and astrocytes along with increased levels of neuroinflammatory mediators and modulators such as proinflammatory cytokines and chemokines [8,9].…”