Alzheimer’s disease (AD) and other dementia (OD) are major and increasing global health
challenges. The World Health Organization (WHO) estimates that around 50 million people
worldwide have dementia, of which AD is the most common form, potentially contributing
to 60 to 70% of these cases. The alarming global burden of dementia is projected to
reach 82 million by 2030 and 152 million people by 2050.1
AD biomarkers play an essential role in detecting the disease in its early stages,
thus allowing initiation of treatment. Being in direct contact with the brain and
spinal cord, cerebrospinal fluid (CSF) has been known to act as a valuable source
of biomarkers that are representative of various biochemical and metabolic profiles
of the brain. The established CSF biomarkers for diagnosis of AD are the 42-amino
acid form of amyloid-beta (Aβ42) and the total and phosphorylated fractions of tau
protein (T-tau and P-tau, respectively). CSF Aβ42 levels are low in patients with
AD when compared with healthy controls, due to increased amyloid deposition in the
brain of these patients. Tau protein is a microtubule-associated protein expressed
in neurons, and is considered as an important biomarker of several disorders in which
axonal damage is implicated. In AD, T-tau and P-tau concentrations in the CSF are
elevated due to cortical neuronal loss and cortical tangle formation, respectively.
The most recent well-established biomarker for AD diagnosis is the neurofilament light
chain (NFL) protein. NFL is a marker of neuroaxonal damage, and its levels are elevated
in the CSF of patients with AD and other neurological conditions as compared with
healthy controls. These high NFL levels in the CSF are due to prominent axonal destruction
triggered by neurodegeneration. A recent systematic review and meta-analysis by Olsson
et al. recommends using CSF Aβ42, T-tau, P-tau, and NFL levels as a panel of diagnostic
biomarkers for AD in clinical practice and research2 (Figure 1).
In this issue of the Brazilian Journal of Psychiatry, Radanovic et al. evaluated Aβ1-42,
P-tau, and T-tau in the CSF of healthy controls (n=54), patients with mild cognitive
impairment (MCI) (n=82), patients with AD (n=46), and patients with OD (n=26), and
tested for correlation with Mini-Mental State Examination (MMSE) scores. CSF from
patients with AD contained higher levels of P-tau and T-tau and lower levels of Aβ1-42,
as well as a lower Aβ1-42/P-tau ratio, as compared to healthy controls and those with
MCI, but not to the OD group. By evaluating the coefficient of correlation between
CSF biomarkers and MMSE, the authors found that the Aβ1-42 levels in the CSF and MMSE
scores correlated weakly in the MCI (0.247), moderately in the OD (0.440), and weakly
and inversely (-0.145) in the AD group. T-tau CSF levels had a weak, inverse correlation
with MMSE scores in the control (-0.284) and MCI (-0.241) groups; this correlation
was moderate to high in the OD (-0.665) group. P-tau CSF levels presented a weak negative
correlation with the AD group (-0.343) and moderate negative correlation with the
OD group (-0.540).3 The authors did not find a strong correlation between CSF biomarkers
and MMSE scores; however, an important contribution of this study was to reaffirm
the importance of the CSF biomarkers Aβ1-42, P-tau, and T-tau to distinguish patients
with AD from controls and OD in the Brazilian population.
The limitations of adopting MMSE scores in AD clinical trials was demonstrated by
Chapman et al., who examined the diagnostic accuracy of MMSE and Logical Memory (LM)
cutoffs used in AD trials and diagnostic studies, tested using subjects from the NACC
database diagnosed with normal cognition (n=10,741), MCI (n=5,883), or AD dementia
(n=6,814). The results from this large-cohort study revealed that MMSE and LM scores
might not be appropriate tools for the selection of subjects to enroll in multicenter
studies designed to develop therapeutics and diagnostic methods for AD.4
Another study, by Olsson et al., demonstrated the association between cognition and
CSF-NFL levels. Their wide-ranging sample included healthy controls (n=75) and patients
with MCI (n=114), AD (n=397), frontotemporal dementia (FTD) (n=96), amyotrophic lateral
sclerosis (n=68), Parkinson’s disease (PD) (n=41), PD with MCI (n=19), PD dementia
(n=29), dementia with Lewy bodies (n=33), corticobasal syndrome (n=21), and progressive
supranuclear palsy (n=20). The patients were followed longitudinally for cognitive
testing over a period of 1 to 18 years. The CSF biomarkers evaluated included Aβ1-42,
P-tau, T-tau, and NFL. Compared to other markers, CSF levels of NFL gradually increased
among the control, MCI, and AD groups. These results delineate the increased positive
association of NFL with cognitive impairment. As expected, the AD group presented
low levels of Aβ42 and high levels of P-tau, T-tau, and NFL compared to the control
group. As this study included patients with neurodegenerative disorders, the outcome
also emphasizes that CSF NFL levels appear to reflect the intensity of neurodegeneration,
and that NFL has the potential to assist in differentiation of AD from FTD.5
To date, the biosignature of AD has comprised CSF levels of T-tau, P-tau, and Aβ42,
as well as plasma T-tau. However, a growing body of evidence suggests NFL is a strong
CSF biomarker that should be included in this biosignature.
Disclosure
The authors report no conflicts of interest.