Cerebrospinal Fluid Biomarkers of Alzheimer’s Disease: Current Evidence and Future Perspectives

Abstract

Alzheimer’s disease is a progressive, clinically heterogeneous, and particularly complex neurodegenerative disease characterized by a decline in cognition. Over the last two decades, there has been significant growth in the investigation of cerebrospinal fluid (CSF) biomarkers for Alzheimer’s disease. This review presents current evidence from many clinical neurochemical studies, with findings that attest to the efficacy of existing core CSF biomarkers such as total tau, phosphorylated tau, and amyloid-β (Aβ42), which diagnose Alzheimer’s disease in the early and dementia stages of the disorder. The heterogeneity of the pathophysiology of the late-onset disease warrants the growth of the Alzheimer’s disease CSF biomarker toolbox; more biomarkers showing other aspects of the disease mechanism are needed. This review focuses on new biomarkers that track Alzheimer’s disease pathology, such as those that assess neuronal injury (VILIP-1 and neurofilament light), neuroinflammation (sTREM2, YKL-40, osteopontin, GFAP, progranulin, and MCP-1), synaptic dysfunction (SNAP-25 and GAP-43), vascular dysregulation (hFABP), as well as CSF α-synuclein levels and TDP-43 pathology. Some of these biomarkers are promising candidates as they are specific and predict future rates of cognitive decline. Findings from the combinations of subclasses of new Alzheimer’s disease biomarkers that improve their diagnostic efficacy in detecting associated pathological changes are also presented.

From Cerebrospinal Fluid Neurochemistry to Clinical Diagnosis of Alzheimer’s Disease in the Era of Anti-Amyloid Treatments. Report of Four Patients

“…Classical CSF biomarkers are useful in identifying the AD biochemical fingerprint in typical and atypical AD cases [27,28]. Their diagnostic performance has been validated in autopsy-proven cases [56].…”

“…For in vivo diagnosis, various biomarkers have been studied during the last 25 years, including cerebrospinal fluid (CSF) biomarkers [27]. Among these, three are considered as classical or "core" biomarkers for AD [28]: Aβ 42 , which is decreased in AD and is inversely related to amyloid plaque burden [29]; tau protein phosphorylated to a threonine residue at position 181 (τ P-181 ) which is increased in AD and it is considered as a marker of tangle formation [30]; total tau protein (τ T ) which is increased in AD and it is a nonspecific marker of neuronal and/or axonal loss [31].…”

Cerebrospinal Fluid Biomarkers for Alzheimer’s Disease in the Era of Disease-Modifying Treatments

“…During the last two decades, various CSF biomarkers have been developed for the (differential) diagnosis of AD [25,26]. With sensitivities and specificities approaching or exceeding 90%, they have been incorporated into various guidelines and diagnostic criteria for Alzheimer's disease [12,27,28].…”

Brain-Derived Exosomal Proteins as Effective Biomarkers for Alzheimer’s Disease: A Systematic Review and Meta-Analysis

“…Generally, fluids [8], such as blood [9], saliva [9], urine [10], and cerebrospinal fluid (CSF) [11] and brain imaging techniques, such as structural MRI [12] and PET [13] have been used to establish a disease diagnosis and predict disease outcomes. Although CSF analysis is key in AD diagnosis, the moderately invasive nature of CSF collection limits its widespread use in routine primary clinical care practice, as the procedure is rarely performed by general practitioners [14].…”