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Page 184 Paraskevas. Neuroimmunol Neuroinflammation 2020;7:183-93 I http://dx.doi.org/10.20517/2347-8659.2019.008

WHY DO WE NEED BIOMARKERS?
[1]
Alzheimer’s disease (AD) is the most common type of dementia , followed by vascular cognitive
[4]
[3]
impairment (VCI) , dementia with Lewy bodies (DLB) , frontotemporal dementia (FTD) and others.
[2]
[5]
Until relatively recently, diagnosis of AD was made according to clinically based criteria . These criteria
[6]
may show high diagnostic accuracy, especially when typical cases are examined in specialized centers .
However, it is long known that in the community, in early, presenile or atypical cases and in the presence
of comorbidities, diagnostic accuracy may drop substantially, with clinicopathological concordance
rates sometimes as low as 62.5% [7-9] . Furthermore, it is now recognized that AD, typically presenting
as an amnestic dementia syndrome, may rarely have frontal (sometimes frontotemporal-like) [10,11] ,
posterior [10,11] , language [10-12] and even corticobasal-like presentations [13,14] . Thus, the same disease may
present with different phenotypes, and one phenotype may be caused by different diseases/pathologies.
[15]
Mixed pathologies are not infrequent in senile cases , especially AD mixed with various types of vascular
lesions , or DLB with concomitant AD pathology . Such mixed pathologies may modify the clinical
[16]
[17]
[20]
presentation [18,19] and the rate of disease progression . In addition, some patients present very early, in
a symptomatic but pre-dementia stage [mild cognitive impairment (MCI) and MCI due to AD] . On
[21]
the other hand, when the clinical impression is against AD, there is still a 39% chance for pathological
verification of AD (co)existence .
[22]
The above are not uncommon causes of diagnostic confusion in everyday practice. Of course, the gold
standard for diagnostic verification is post mortem pathological examination. However, correct ante
mortem diagnosis is necessary since it may help in predicting prognosis and it is likely to affect therapeutic
[23]
decisions . Thus, biomarkers are needed to serve as objective diagnostic tools during life. In the last
3 decades, various biomarkers have been developed (some being incorporated in various sets of diagnostic
criteria), including structural neuroimaging (pattern of atrophy as a marker of neuronal injury), functional
neuroimaging with positron emission tomography (PET), either as FDG-PET (hypometabolism as a
marker of neuronal injury) or PET at least for amyloid-beta (Aβ), and CSF biomarkers [10,11] . The last have
probably received the most attention.

ESTABLISHED (CORE) CSF BIOMARKERS OF AD
In an oversimplified scheme, there are two biochemical processes and pathological hallmarks of AD:
(1) misfolding, oligomerization and finally polymerization and extracellular aggregation of Aβ, in
the form of amyloid plaques, and (2) intracellular hyperphosphorylation and polymerization of the
microtubule-associated protein tau, forming paired helical filaments which in turn aggregate in the
form of neurofibrillary tangles [24,25] . The former process mobilizes various mechanisms that are toxic to
[26]
neurons , and the second results in destabilization of microtubules and dysfunction of the cytoskeleton
[27]
and of axonal transport . Both processes, acting synergistically, lead to neuritic, synaptic and neuronal
loss, through a vicious circle of interconnecting final pathways of oxidative stress, excitotoxicity,
2+
mitochondrial dysfunction, apoptosis and Ca -mediated cell death [28-30] , while prion-like spread and
[31]
neuroinflammation [32-34] are increasingly recognized as important early mechanisms.
[35]
[36]
Total tau protein (τ ) , hyperphosphorylated tau, especially at a threonine residue at position 181 (τ P-181 )
T
[37]
and Aβ peptide with 42 amino acids (Aβ ) can be quantified in the CSF. In AD, τ is increased, and
42
T
[38]
traditionally, this is viewed as a marker of neuronal/axonal injury ; τ P-181 is also increased and this is
considered a more specific marker of tangle formation . On the other hand, Aβ is decreased and this is
[39]
42
[40]
considered (inversely) a marker of amyloid burden . The above markers are useful in the discrimination
of AD from normal aging and other dementias, and even abnormal τ alone may show high sensitivity and,
T
[41]
in a few diagnostic questions, adequate specificity for the diagnosis of AD . Combinations of the above
biomarkers in the form of various formulas (including the Hulstaert formula ) or ratios (including τ /Aβ
[42]
42
T
or τ P-181 /Aβ 42 [43,44] ) further increase their diagnostic value.