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Alzheimer's disease biomarkers

The meaning of «alzheimer's disease biomarkers»

The Alzheimer's disease biomarkers are neurochemical indicators used to assess the risk or presence of the disease. The biomarkers can be used to diagnose Alzheimer's disease (AD) in a very early stage, but they also provide objective and reliable measures of disease progress. It is imperative to diagnose AD disease as soon as possible, because neuropathologic changes of AD precede the symptoms by years. It is well known that amyloid beta (Aβ) is a good indicator of AD disease, which has facilitated doctors to accurately pre-diagnose cases of AD. When Aβ peptide is released by proteolytic cleavage of amyloid-beta precursor protein,[1] some Aβ peptides that are solubilized are detected in CSF and blood plasma which makes AB peptides a promising candidate for biological markers. It has been shown that the amyloid beta biomarker shows 80% or above sensitivity and specificity, in distinguishing AD from dementia. It is believed that amyloid beta as a biomarker will provide a future for diagnosis of AD and eventually treatment of AD.[2]

Amyloid beta (Aβ) is composed of a family of peptides produced by proteolytic cleavage of the type I transmembrane spanning glycoprotein amyloid-beta precursor protein (APP). Amyloid plaque Aβ protein species ends in residue 40 or 42,[3] but it is suspected that Aβ42 form is crucial in the pathogenesis of AD. Although Aβ42 makes up less than 10% of total Aβ, it aggregates at much faster rates than Aβ40.[4] Aβ42 is the initial and major component of amyloid plaque deposits. While the most prevalent hypothesis for mechanisms of Aβ-mediated neurotoxicity is structural damage to the synapse, various mechanisms such as oxidative stress,[5] altered calcium homeostasis, induction of apoptosis, structural damage, chronic inflammation and neuronal formation of amyloid has been proposed. Observation of AB42/AB40 ratio has been a promising biomarker for AD. However, as AB42 fails to be a reliable biomarker in plasma, attention was drawn for alternative biomarkers.[6]

Various enzymatic digestion including beta secretase (β secretase), and gamma-secretase (γ-secretase) will cleave amyloid-beta precursor protein (APP) into various types of amyloid beta (Aβ) protein. Most β-secretase activity originates from an integral membrane aspartyle protease encoded by the β-site APP-cleaving enzyme 1 gene (BACE1). Dr. Zetterberg and his team used a sensitive and specific BACE1 assay to assess CSF BACE1 activity in AD. It was found that those with AD showed increased BACE1 expression and enzymatic activity. It was concluded that elevated BACE 1 activity may contribute to the amyloidgenic process in Alzheimer's disease. CSF BACE1 activity could be a potential candidate biomarker to monitor amyloidogenic APP metabolism in the CNS.[7]

APP is an integral membrane protein whose proteolysis generates beta amyloid ranging from 39- to 42- amino acid peptide. Although the biological function of APP are not known, it has been hypothesized that APP may play a role during neuroregeneration, and regulation of neural activity, connectivity, plasticity, and memory. Recent research has shown that large soluble APP (sAPP)[8] that are present in CSF may serve as a novel potential biomarker of Alzheimer's disease. In a article published in Nature, a group led by Lewczuk performed a test to observe the performance of a soluble form of APP α and β. A significant increase in sAPP α and sAPP β was found in people with AD as compared to normal subjects. However, the CSF level of α-sAPP and β-sAPP was found to be contradictory. Although many researchers have found that the CSF level of α sAPP increases in some people with AD, some report that there is no significant change, while Lannfelt argues that there is a slight decrease. Therefore, more studies are needed in order to confirm the validity of sAPP as a biological marker for AD.

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