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Page 326 Kapaki et al. Neuroimmunol Neuroinflammation 2020;7:319-29 I http://dx.doi.org/10.20517/2347-8659.2019.26

In case 4, a 59-year-old-female, clinically fulfilled the clinical criteria of an amnestic dementia of the AD
[1]
type . However, clinical presentation does not always predict brain pathology. For example, AD can present
with common amnestic dementia but also with a frontal behavioral-dysexecutive syndrome, the so-called
[4,5]
“frontal variant of AD” . Likewise, patients with FTLD pathologies may also present with an amnestic,
AD-like syndrome. The term limbic-predominant age-related TDP-43 encephalopathy (LATE) has been
recently introduced for at least some of these cases, and consensus-based recommendations and guidelines
[6]
for diagnosis and staging have been formulated . Thus, clinical, biochemical, neuropsychological and
imaging data, all should be considered. Of course, there is always the possibility of false-negative or false-
positive results. Since all biomarkers become abnormal during prodromal stages of AD, all would be
expected to be abnormal in a well-established AD dementia . However, in this patient, all biomarkers
[23]
were normal, dramatically reducing the possibility of false-negative results and pointing to a non-AD
pathology. Indeed, with all CSF biomarkers normal, AD is considered highly unlikely according to recent
[15]
recommendations . Clinically the patient is not compatible with dementia with Lewy bodies (DLB), and
to our knowledge, there are no robust, evidence-based data to support the use of standard AD treatments
in non-AD, non-DLB patients. Thus, correct diagnosis would also avoid possibly unnecessary treatment(s)
suitable for other diseases.

In case 5, TDP-43 proteinopathy was strongly considered from clinical presentation of combined
phenotype FTD-ALS in the family, which is known to be related to a TDP-43 histopathology [24,25] . The
CSF biomarker profile was compatible with non-AD pathology. In case 6, an AT(N) profile suggestive of
non-AD pathology was also observed. However, in this patient, τ P-181 was increased. Recently, it has been
suggested that in an FTD-like patient, with no AD biomarker profile, increased τ P-181 is more compatible
[19]
with tau-pathology, while low τ P-181 may be compatible with TDP-43 pathology . Thus, the tauopathy
observed in brain biopsy was in accordance with this notion.

Soon after its publication, the AT(N) system triggered a lot of discussion and criticism. The concept of a
disease viewed as a pathological/pathophysiological/biochemical entity unrelated to symptoms may not
[26]
be easily accepted by some clinicians or the community . However, given that the same disease may
present with different clinical syndromes and that the same clinical presentation may be caused by different
diseases, this new view is really a step forward, and this holds true not only for AD but also for many other
neurodegenerative disorders. Furthermore, since the AD pathological process starts even decades prior
to symptomatic onset, whilst CSF or imaging biomarkers become abnormal in the preclinical stage , the
[23]
need for adopting such a view/concept is further strengthened. However, many questions seek answers.
+
+ +
For example, what about an A T N patient with a clinical presentation suggestive of DLB. Is this due to
[28]
mixed pathology (synucleinopathy and AD) [5,27] or due to AD with atypical presentation ? Another related
question is a DLB-like patient with only amyloid biomarkers being positive. This is very common in DLB .
[29]
But, is this due to the synucleinopathy alone somehow triggering amyloid deposition unrelated to AD
mechanisms, or are such patients “destined” to develop full-blown AD pathology if they live long enough?
[20]
Furthermore, reduced Aβ levels have been observed in some patients with pure vascular dementia ,
42
[30]
including patients with inherited subcortical small vessel disease , who do not have additional AD
pathology, raising questions as to whether reduced Aβ always suggests Alzheimer’s pathological change.
42
Other CSF biomarkers may be of further help and improve the AT(N) system. Other forms of phospho-
tau such as τ P-217 may perform better, compared to τ P-181 [31] . TDP-43 combined with τ and τ P-181 could
T
enhance the diagnostic accuracy in the FTD spectrum [32,33] . CSF α-synuclein levels could be useful in
discriminating patients with AD from cognitively unimpaired subjects, patients with DLB and patients with
Parkinson’s disease dementia [34,35] . Blood-based biomarkers are quite promising as well, since classical AD
biomarkers may also be measured in plasma. Plasma τ P-181 could differentiate AD dementia from non-AD
[36]
neurodegenerative diseases with accuracy similar to that of CSF τ P-181 and tau-PET , while plasma Aβ /
42