CSF Biomarkers for Alzheimer's Disease Diagnosis

Abstract

Alzheimer's disease (AD) is the most common form of dementia that affects several million people worldwide. The major neuropathological hallmarks of AD are the presence of extracellular amyloid plaques that are composed of Abeta40 and Abeta42 and intracellular neurofibrillary tangles (NFT), which is composed of hyperphosphorylated protein Tau. While the amyloid plaques and NFT could define the disease progression involving neuronal loss and dysfunction, significant cognitive decline occurs before their appearance. Although significant advances in neuroimaging techniques provide the structure and physiology of brain of AD cases, the biomarker studies based on cerebrospinal fluid (CSF) and plasma represent the most direct and convenient means to study the disease progression. Biomarkers are useful in detecting the preclinical as well as symptomatic stages of AD. In this paper, we discuss the recent advancements of various biomarkers with particular emphasis on CSF biomarkers for monitoring the early development of AD before significant cognitive dysfunction.

Figure 1

Pathological cascades and potential biomarkers of AD. Proteolytic cleavage of APP first by β-secretase followed by γ-secretase can produce Aβ42 and other shorter Aβ fragments. The subsequent aggregation of Aβ42 results in oligomers and amyloid fibrils. Amyloid fibrils are eventually deposited as senile plaques as shown. The toxicity of oligomers and amyloid fibrils could lead to the cascade of tau-hyperphosphorylation, which is otherwise bound to microtubules, providing microtubule stability. Upon hyperphosphorylation, tau dissociates from microtubules and aggregates into NFT, which could eventually cause increased cytoskeleton flexibility and neuronal death.