Dementia is a major global cause of disability and dependency worldwide. By 2030,the growing number of patients with dementia is estimated to reach 135.5 million to 2050. Much of the increase will be in the developing countries with the fastest growth in the elderly population. On the contrary,recent trends in dementia in several western countries,however, depict a gradual decline in prevalence and incidence. This decrease has been attributed to an improvement in education and living environments,engagement in healthy behaviors,and reduction in the prevalence of vascular risk factors^[1]. On the contrary,in Asian countries,there is a stable trend of increase in dementia cases. People with dementia living in the developing countries account for 62% of all patients,but by 2050 this will rise to 71%. The total estimated global societal direct and indirect cost of global dementia in 2010 was $604 billion^[2].

Alzheimer’s disease (AD) is a heterogeneous and slowly progressive illness characterized by extracellular amyloid‐β (Aβ) deposits and intracellular hyper‐ phosphorylated tau protein aggregates. Aggregation of Aβ into oligomers,fibrils,and plaques is central in the molecular pathogenesis of AD. Although it is still unclear,multiple lines of evidence suggested that Aβ oligomers may be more toxic than fibrillary Aβ aggregates^[3]. Accumulating evidence from studies on transgenic mouse models demonstrated that AD brain‐derived and synthetically prepared Aβ oligomers can cause early synaptic toxicity,long‐term potentiation (LTP) deficits,tau phosphorylation,and neurofibrillary tangles.

Biomarkers for the stratification,follow‐up,and monitoring of safe and effective therapeutic responses of Aβ disease‐modifying therapies (DMT) represent a research priority in this rapidly developing field. In particular,immunotherapy trials have underlined the urgent need of safety biomarkers to avoid,or at least enable the early detection of severe side effects of treatment termed amyloid‐related imaging abnor‐ malities. The cerebrospinal fluid biomarkers Aβ,total tau,and hyperphosphorylated tau reflect the main pathological changes of AD with several novel biomarkers,such as,β‐site APP cleaving enzyme 1, soluble amyloid precursor proteins α and β,soluble Aβ oligomers,and others,which are associated with the occurrence and progression of this disease.

The main goal of research communities worldwide is to find several ideal biomarkers to improve the diagnosis of Alzheimer’s diseases,standardize biomarkers,and optimize the respective treatments. In addition to extracellular Aβ deposits,AD involves neurofibrillary tangles,another validated histopatholo‐ gical feature,which consist of intracellular aggregates of hyperphosphorylated tau protein (p‐tau). Tau,a microtubule associated protein,participates in the microtubule stabilization and organization system, which regulates cellular morphogenesis,cytoskeleton functionality,and axonal transport. It is comprehensible that high levels of tau in the cerebrospinal fluid (CSF) of patients with AD can reflect the intensity of the neuronal damage and degeneration in the brain. The most commonly used measurement method for t‐tau and p‐tau is the enzyme‐linked immunosorbent assay (ELISA) using monoclonal antibodies that detect all isoforms of tau independently of phosphorylation state for t‐tau and antibodies that are specific for phosphorylation at either threonine181 (p‐tau181) or threonine231 (p‐tau231) for p‐tau. P‐tau231 is useful for distinguishing AD and frontotemporal dementia, and p‐tau181 can enhance classification between AD and dementia with Lewy bodies. Numerous studies have used this assay,and consistently report a pro‐ minent increase in CSF total tau protein (t‐tau) and p‐tau in AD compared to control levels.

In order to provide more objective diagnosis,suitable radiotracers have been used over the past decades for imaging the Aβ aggregates^[4]. For these purposes, neuroimaging techniques have been modified to achieve high specificity by using generated Aβ antibodies and peptide fragments that can be labeled with a suitable tracer^[5]. The neuroimaging techniques are capable of detecting the amyloid plaques that are known to be formed several years prior to the actual manifestation of cognitive decline and amnesia that are characteristic of AD.

Briefly,biomarkers could be classified and used according to the requirements for evaluating therapy, clinical course,or some defined outcomes such as cog‐ nitive outcome,behavior outcome,or socio‐economic outcomes. However,although many biomarkers have been proposed,the exact role of each biomarker should be fully understood before its application.