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Paraskevas. Neuroimmunol Neuroinflammation 2020;7:183-93 I http://dx.doi.org/10.20517/2347-8659.2019.008 Page 185

HOW EARLY DO THE CLASSICAL BIOMARKERS BECOME ABNORMAL?
Currently, AD is viewed as a pathological or neurobiological entity, characterized by a continuum of
3 stages, starting as a preclinical (“asymptomatic at risk” or “presymptomatic”) stage, which later on
progresses to a symptomatic but pre-dementia stage (MCI) and finally to the dementia stage [11,45] . It seems
[45]
that in most cases CSF biomarkers become abnormal during the preclinical stage of AD , and on the basis
of studies in families with autosomal dominant AD, this may occur even 10-20 years prior to the expected
[46]
age of symptom onset . In patients with MCI, abnormalities are detected 5-10 years before progression
[47]
to dementia . Usually, the first abnormality detected is a decrease in Aβ , followed by an increase in
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[45]
τ P-181 and τ , but the reverse order may sometimes be observed . Sometimes, only the Aβ decrease is
42
T
seen in the preclinical stage, and the increase in τ P-181 and τ is observed in the pre-dementia (MCI) stage
T
of AD . Thus, in the vast majority of patients, all 3 classical biomarkers are already abnormal when
[48]
patients enter the dementia stage and in many (if not most), at the beginning of the MCI stage as well.
CSF levels may continue to change during disease progression [46,48,49] . Such changes may be important from
the neurochemical point of view, and it has been suggested that they may correlate with the stage of the
[48]
disease . However, from a diagnostic point of view, the changes compared to controls are small, and thus,
[49]
these biomarkers are considered as state and not stage markers .
DEFINITION OF THE ALZHEIMER’S CLASSICAL CSF BIOMARKER PROFILE (SIGNATURE)
In the research diagnostic criteria for AD of the International Working Group (IWG-2), both decreased
)are considered as in vivo evidence of AD pathology, with
Aβ and increased tau protein (either τ or τ P-181
T
42
[11]
sensitivities and specificities approaching or exceeding 90% . However, more recent recommendations
suggest that all 3 biomarkers should be abnormal . Indeed, this may increase specificity, and abnormality
[50]
of all 3 biomarkers is highly suggestive (and specific) of the presence of AD, while normal values of all 3
biomarkers is highly suggestive of the absence of AD pathology . In patients with MCI, the combination
[50]
of all 3 markers (τ and the Aβ /τ P-181 ratio) identified those harboring AD pathology with sensitivities and
T
42
[51]
specificities of 95% and 87%, respectively .
In pathologically verified cases, the combination of Aβ and τ identified AD patients, discriminating them
42
T
[52]
from other dementias or controls with sensitivity and specificity of 90% and 89%, respectively , while the
combination of Aβ with the more specific τ P-181 discriminated AD from other dementias with sensitivity
42
and specificity of 80%-88% and 93%-100%, respectively [52,53] .
The above indicates that, ideally, the AD CSF biomarker signature should be defined as abnormal values
of all 3 core biomarkers. However, the combination of Aβ with one of the tau forms (either total or
42
phosphorylated) may be sufficient in everyday practice.
ANSWERED AND UNANSWERED QUESTIONS
Classical AD biomarkers are useful in everyday practice since they can discriminate AD from normal
[43]
[54]
aging and psychiatric conditions . They offer an added diagnostic value in everyday differential
[41]
diagnosis of dementia patients, since they increase diagnostic confidence and correctly identify the
presence or absence of AD in 82% of patients with uncertain clinical diagnosis . They can be useful in the
[55]
[56]
differential diagnosis between AD and FTD , and they can identify the additional presence or absence of
AD in patients with cerebrovascular disease and dementia , including subcortical small vessel disease .
[44]
[57]
[58]
These biomarkers may also determine the additional presence of AD in patients with DLB and those
[59]
with normal pressure hydrocephalus . Additionally, they can identify the presence or absence of AD
biochemical process in patients with certain cognitive and/or parkinsonian syndromes such as primary
progressive aphasia , posterior cortical atrophy and corticobasal syndrome .
[60]
[13]
[12]