Neurology: The first large-scale prospective real-world study confirms that blood markers are feasible to predict Alzheimer's disease!

"Blood testing" is a vision that the medical community aspires to achieve, but the concentration of markers in the blood is usually low compared to the lesion site, and the reliability of the measurement results is doubtful
.

The good news is that the reliability and predictive value of blood markers of Alzheimer's disease (AD) is finally being analyzed
in a large prospective cohort study.

Recently, the research team of Vincent Planche from the Institute of Neurodegenerative Diseases in Bordeaux, France, published a study in the journal "Neurology" [1].

The researchers analyzed 2277 patients with mild cognitive impairment/subjective cognitive complaints and found a moderate correlation
between AD markers in most blood and similar markers in cerebrospinal fluid.
In particular, the p181-tau protein in the blood can better indicate the risk of
AD/AD combined dementia within 5 years.
However, the researchers also found that blood markers improved to existing AD prediction models to a limited
extent.

Using a cohort of patients with near-real-world characteristics, this study demonstrated the correlation
between AD marker concentrations in blood and cerebrospinal fluid, as well as AD markers in blood and PET results.
However, the rational application of blood markers in clinical practice and the construction of more complete AD prediction models still have a long
way to go.

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The deteriorating condition and limited treatment methods after the onset of AD have prompted researchers to analyze the pathological features before the onset, and the emerging AD markers have also made it feasible to identify high-risk groups [2].

However, the determination of these markers mostly relies on invasive, expensive, and inaccessible tests such as amyloid/tau positron emission tomography (PET) and cerebrospinal fluid biopsy [3,4], which limits the early diagnosis and preclinical immunotherapy of some patients
.

Studies have shown a correlation between AD markers detected in blood and cerebrospinal fluid/PET [5], blood phosphorylated tau protein can be used to distinguish AD from other neurodegenerative diseases, and blood markers are equally feasible for predicting the risk of AD-related dementia [6-7].

However, the high inclusion threshold, limited sample size and overlapping research subjects cast doubts over the generalizability of previous research conclusions and the clinical application value of blood markers
.

Planche's team wanted to know if AD/neurodegenerative markers measured in blood correlated with CSF measurements/PET findings in unscreened, people with mild cognitive impairment/subjective cognitive complaints; and how
effective blood markers were at predicting AD/AD with dementia at follow-up.
With these questions in mind, the Planche team explored with the help of the MEMENTO queue
.

The MEMENTTO cohort recruited patients with very mild to mild cognitive impairment (0-0.
5 on the Clinical Dementia Rating Scale 0-0.
5) or over 60 years of age with subjective cognitive complaints from 26 memory clinics in France, and blood samples were taken to measure
AD-related markers.
Stroke with or previous neurological deficit with a history of head trauma, stroke within the past three months or previous neurological deficit, brain tumors, epilepsy, schizophrenia, familial AD gene mutations, and illiteracy were excluded
.

During the subsequent 5-year follow-up, patients underwent multiple cognitive function assessments
at least once a year.
The researchers also analyzed AD-related magnetic resonance imaging features in patients, some of whom completed amyloid PET imaging or cerebrospinal fluid sampling
.

Between 2011 and 2014, a total of 2277 patients who underwent at least one blood marker test were included in the analysis
.
Of these, 357 patients underwent lumbar puncture biopsy within one year of blood collection, and 649 had available amyloid PET results
.
During the 5-year follow-up period, a total of 257 cases of AD/AD comorbid dementia were diagnosed
.

The researchers grouped the patients according to the results of amyloid PET examination and found that the Aß42/40 ratio, p181-tau protein concentration and nerve filament light chain protein concentration measured in the blood were associated
with the degree of lesion indicated by the PET examination.
After comparing different blood markers using the subject's working curve, the Planche team found that p181-tau protein concentration was the best indicator to identify amyloid PET positivity (area under the subject's working curve: 0.
74, 95% CI: 0.
69-0.
79).

Comparison of different blood markers between amyloid PET-positive and negative groups

In addition to total tau protein, homogeneous markers measured in blood and cerebrospinal fluid were significantly correlated
.
The researchers also grouped markers in blood and cerebrospinal fluid by quartile and compared the risk of
AD/AD comitant dementia between different groups.
The results showed that p181-tau protein, neurofilament light chain protein and Aß42/40 ratio in blood and cerebrospinal fluid were dose-effect associated
with the risk of AD/AD and dementia.

After different markers were grouped by quartile, the risk of events in each group was compared

p181-tau protein has the best predictive performance of AD/AD combined dementia risk (C-index: 0.
731, 95% CI: 0.
694-0.
768).

However, compared with models that included common clinical variables (age, sex, education level, memory and cognitive test performance, C-index: 0.
884) or scientific variables (clinical data, ApoE genotype, MRI cortical thickness, etc.
, C-index: 0.
907), the prediction effect was not small
.
After adding the ratio of blood p181-tau to Aß42/40 to the aforementioned model, the prediction efficiency was only slightly improved
.

Comparison of outcome event prediction performance of different indicators

Considering the association between disease progression and blood marker concentration, the researchers divided the patients according to the results of the Clinical Dementia Rating Scale and the presence or absence of amnesia, and the results showed that the p181-tau protein in the blood had a better predictive effect in the patient population with a clinical dementia rating scale score of 0 (C-index: 0.
830).

It is understood that this study by Planche's team is the first to demonstrate a moderate association between AD markers measured in blood and similar markers in cerebrospinal fluid in a large prospective cohort close to real-world characteristics; The concentrations of p181-tau protein and neurofilament light chain protein in blood and cerebrospinal fluid had similar predictive efficacy
for AD/AD combined with dementia at 5-year follow-up.
Compared with other blood AD markers, p181-tau protein is the best predictor of AD/AD combined dementia within 5 years
.

It is worth mentioning that p181-tau protein has a better predictive effect in patients with low baseline dementia scores during a relatively short follow-up period of 5 years, indicating that p181-tau protein may be more suitable for predicting rapidly progressing AD patients
.

In addition, the limited clinical predictive value of AD markers in blood and the moderate correlation of similar markers in blood and cerebrospinal fluid also suggest that blood test results in patients with cognitive impairment should be interpreted with caution
.
The significance of markers in the blood should also be considered
in the context of the patient's stage of disease.
Future researchers should also explore how to combine blood markers with clinical, imaging and other features to achieve the best clinical application results
.

At the same time, this study also has certain limitations: for example, there are differences in the measurement methods used by different markers, which may affect the accuracy and consistency of the results; The diagnostic value of AD may be better than that of p181-tau protein for p217-tau, but it was not measured in this study; Blood markers are grouped by quartiles, and reasonable cut-off values remain to be given in future studies.
There are also deficiencies
in the collection of data characteristics related to patient health.

In general, blood AD markers are expected to be further used
in future outpatient clinics for memory disorders.
Combined with clinical and radiographically suggestive AD prodromal stage manifestations, the disease prediction performance
of blood AD markers can be better exerted.

References

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Validity and Performance of Blood Biomarkers for Alzheimer Disease to Predict Dementia Risk in a Large Clinic-Based Cohort [published online ahead of print, 2022 Oct 19].
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0000000000201479

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[3] Scheltens P, De Strooper B, Kivipelto M, et al.
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[4] Villemagne VL, Fodero-Tavoletti MT, Masters CL, Rowe CC.
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[6] Karikari TK, Pascoal TA, Ashton NJ, et al.
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[7] Janelidze S, Mattsson N, Palmqvist S, et al.
Plasma P-tau181 in Alzheimer's disease: relationship to other biomarkers, differential diagnosis, neuropathology and longitudinal progression to Alzheimer's dementia.
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