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Page 188 araskevas. Neuroimmunol Neuroinflammation 2020;7:183-93 I http://dx.doi.org/10.20517/2347-8659.2019.008

Table 1. Levels of classical cerebrospinal fluid Alzheimer’s disease biomarkers in various cognitive disorders
Total tau (τ T ) Phospho-tau*
Aβ 42 or Aβ 42 /Aβ 40
Alzheimer’s disease Decreased Increased Increased
Vascular cognitive impairment May be decreased in some patients May be increased in some patients Normal
Frontotemporal dementia May rarely be decreased May be increased in some patients May be increased in some patients
Dementia with Lewy bodies Frequently decreased May be increased in some patients Normal
Creutzfeldt-Jakob disease May be decreased in some patients Extremely increased Normal
Normal aging Normal Normal Normal
Psychiatric disorders Normal Normal Normal

Based on the references cited throughout the text. *Usually for τ P-181 , others have also been suggested

aging, psychiatric disorders such as depression, pure vascular cognitive impairment, pure DLB and FTD,
and they can identify atypical and misleading clinical presentations of AD, or the coexistence of AD in
other primary (such as VCI or DLB) or secondary cognitive disorders [12,14,44,54,56-59] . However, they should
always be used in combination with clinical, neuropsychological and imaging data , and due to variability
[15]
[66]
of measurements, each laboratory should establish their own normal or cut-off values .
CSF biomarkers detect normal or abnormal biochemistry, offering (during life) an alternative to post-
[66]
mortem pathology and showing a very good concordance with pathological diagnosis . Thus, many, if
not most, of patients can be correctly diagnosed. However, borderline or inconclusive results may occur
in some patients, requiring repetition of measurements and/or use of additional biomarkers [50,96,102] .
Furthermore, classical CSF biomarkers cannot accurately detect mixed degenerative pathologies, which
are not unusual in older patients. For example, the identification of an AD biomarker profile in a patient
with dementia, parkinsonism and hallucinations, may indicate an atypical clinical presentation of AD, AD
with some additional Lewy bodies, DLB with some additional AD-type pathology, or a severe degree of
[58]
both pathologies . This further necessitates the use of additional biomarkers (in the above case, α-syn).
Unfortunately, methodological issues requiring further investigation prevent some of the newer biomarkers
such as α-syn and TDP-43 to be currently considered “established”.

The 3 classical AD biomarkers (τ , Aβ and τ P-181 ) become 4 by adding Aβ . Adding NFL, α-syn, TDP-43
40
42
T
and others increases the number to at least 7. Adding them to structural and functional neuroimaging and
possibly to genetic biomarkers, leads to a tempting increase of available data for patients; unfortunately,
there is an even more substantial increase in cost, while the diagnostic accuracy may not be equally
increased in some patients. Instead of an “all for all” approach, a personalized, precision medicine approach
may be more appropriate [106] , while blood biomarkers may be adequate for some patients [107] .

The ability to detect the AD CSF biochemical signature in pre-dementia and especially in pre-symptomatic
subjects, raises some ethical issues [108] . Communication of a positive result in a non-demented subject
may have adverse effects in quality of life and trigger significant emotional reactions [109] . Since the time
of appearance of the initial vague symptom(s) is usually unpredictable, many authorities consider it
inappropriate to perform such diagnostic tests in the majority of asymptomatic subjects (including families
with autosomal dominant AD). However, other subjects prefer disclosure of the results, so that they can
adjust their life accordingly (including measures for secondary prevention) or make important decisions
before dementia affects their judgment [110] . Such parameters should be taken into consideration before
determining CSF biomarkers and/or communicating results, especially in research settings [108] .

On the other hand, early detection is important in correct classification of subjects in trials of disease-
modifying approaches, which may be effective when given in pre-symptomatic stages of AD. Since
such trials are usually multicenter, stability, robustness and harmonization of methods and results,
regulatory guidance, operator training, quality control programs, strict adherence to recommendations for