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Page 186 Paraskevas. Neuroimmunol Neuroinflammation 2020;7:183-93 I http://dx.doi.org/10.20517/2347-8659.2019.008

Of course, CSF AD biomarkers are not standalone tools, and they should be used in conjunction with
[11]
clinical, imaging, neuropsychological and other biochemical data to reach the correct diagnosis . Keeping
[61]
that in mind, CSF Aβ , τ and τ P-181 fulfill most of the criteria required for valid biomarkers , since they
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reflect key biochemical mechanisms of AD, and combined, they provide sensitivities and specificities
greater than 80%-85%. Sampling needs lumbar puncture, which is less agreeable than urine or blood
sampling. However, it is a minimally invasive procedure, usually well-tolerated and with a low incidence of
post-lumbar puncture headache (< 4.5%) in dementia patients [43,62] . Thus, the 3 core CSF biomarkers were
gradually incorporated in research and/or clinical diagnostic criteria for AD in the dementia (typical or
[65]
atypical presentations) [10,11,63] , MCI [11,64] and preclinical stages , and if testing is available, they are currently
considered as part of the diagnostic workup of cognitive disorders, especially in ambiguous cases [66-68] . Since
new disease-modifying or preventive treatments are currently underway, CSF biomarkers may be used for
the selection of patients suitable for clinical trials across all stages of AD (including the preclinical stage)
and/or for monitoring treatment effects [69,70] .

With time, it has become evident that biomarkers can detect CSF signatures different from the one observed
in AD. The term “suspected non-Alzheimer pathophysiology” (SNAP) was introduced for a biomarker
profile with normal Aβ but an abnormal marker of neuronal injury or neurodegeneration, while the term
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“primary age-related tauopathy” has been used for the tau pathology picture in the medial temporal lobe
[71]
(hippocampus, entorhinal cortex), with or without minimal Aβ pathology . In patients with normal Aβ ,
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the Aβ /Aβ ratio may be used to confirm the absence of amyloid abnormality, since it “corrects” observed
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Aβ levels for the total level of Aβ (the most abundant form of Aβ peptide) [67,72] . When amyloid normality
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is confirmed, AD becomes unlikely and tauopathies, TDP-43 proteinopathies and other pathologies may
[50]
[73]
be considered to explain SNAP cases . Controversies and questions concerning the “non-AD” biomarker
profiles and the underlying pathologies have led to a modification of the 2011 National Institute on Aging
and Alzheimer’s Association separate recommendations [10,64,65] , to a unified biological definition of AD
across all stages and incorporating the various possible biomarker profiles and disease categories (AD or
[74]
non-AD) . This incorporation of “extended” biomarker profiles in diagnostic recommendations, may
prove useful in many atypical presentations, including patients resembling or even fulfilling criteria for AD,
but without the expected AD CSF biomarker signature, although biomarker levels may remain conflicting
in occasional patients.
Another profile which may be observed is characterized by abnormality (reduction) of only Aβ , while τ
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and τ P-181 being normal. In this case, the Aβ /Aβ may be used to confirm or exclude amyloid abnormality.
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If amyloid reduction is confirmed, AD pathology may be less likely in patients with full-blown dementia,
[50]
but it is still a possibility, especially in pre-dementia patients and may be compatible with the “AD
pathological change” . This profile may also be observed in vascular cognitive decline and in Lewy body
[57]
[74]
[75]
synucleinopathies, including PD, PDD and especially DLB .
Furthermore, there is always the problem of mixed pathologies, especially in the elderly. In a patient with
a clinical picture suggestive of DLB, the identification of the typical AD CSF signature, may indicate mixed
synucleinopathy with concomitant AD pathology [11,76] , but cases of AD with unusual DLB-like presentations
[77]
have been described . Even in the most common scenario of mixed pathology, the question arises as to
whether it represents DLB with some degree of AD pathology, AD with some degree of Lewy-pathology
[58]
or equally severe pathology of both types . Similarly, in a patient with a FTD-like clinical picture, the
[78]
identification of the typical AD CSF signature may serve as exclusion criterion for FTD , suggesting AD
with an atypical clinical presentation (frontal variant) , but mixed pathology cannot be excluded, since
[11]
[79]
patients with concomitant FTD and AD do exist .
Some patients may show borderline or gray-zone levels in one or more of the classical biomarkers. The
[12]
τ /Aβ and τ P-181 /Aβ ratios may be of some help in such patients , but not always. The “Erlangen Score”,
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