Nature Medicine: Alzheimer's Early Screening Evidence Updated! The scientists found that two blood markers are closely related to early Aβ pathology

*For medical professionals only

Alzheimer's disease is one of the most common neurodegenerative diseases
.

Drug research on Alzheimer's disease has failed in recent years, and scientists have come to realize that it may be too late to treat the disease after it has occurred, because the early pathology of the disease precedes the symptoms [1].

Early detection of Alzheimer's disease requires a way to
monitor amyloid (Aβ) levels β the brain.
Because Alzheimer's disease is a disease of the central nervous system, current pathological examinations rely on invasive cerebrospinal fluid monitoring and expensive medical imaging technology
.
Both approaches are either poor patient compliance or are too costly to be used for early screening
for Alzheimer's disease.

Relatively speaking, blood samples are more convenient to collect and more suitable for early screening
of diseases.
In recent years, some blood markers (p-tau231, etc.
) have been found to reflect pathological levels of Aβ in the brain, but which markers can better predict the early development of the disease and whether these markers can be reproduced in larger populations have not been verified
.

Not long ago, a research team led by Marc Suárez-Calvet of the Barcelona βeta Brain Research Center and Kaj Blennow of the University of Gothenburg in Sweden published important research results
in the journal Nature Medicine.

They found abnormal changes in a number of plasma markers in the preclinical stage of Alzheimer's disease, among which the abnormalities of two markers, P-tau231 and P-tau217, were extremely significant
.
Their study provides potential screening markers for Aβ pathology in the early stages of Alzheimer's disease[2].

Screenshot of the front page of the paper

Let's take a look at how this study unfolded
.

This study analyzed cerebrospinal fluid (CSF) and blood samples from 397 subjects at high risk of Alzheimer's disease [3-4
].
These participants had all participated in the ALFA+ trial, in which 47.
4% of participants had parents with Alzheimer's disease and 34.
7% of participants carried the APOEε4 variant, but they all maintained normal cognitive function
at the time of the trial.

Of the participants in this trial, 135 were in the preclinical stages
of Alzheimer's disease, although positive for amyloid hydrolysate Aβ42/40 detected in cerebrospinal fluid [5].

The researchers performed a horizontal comparison of multiple Alzheimer's disease-related markers in their plasma, including three phosphorylated tau proteins (p-tau181, p-tau217, and p-tau231), glial fibrillary acidic protein (GFAP), neurofilament light chain protein (NfL), and Aβ42/40 [6-8].

Changes in individual plasma markers were compared in A+T- (Aβ-positive, tau-negative) and A+T+ (Aβ-positive, tau-positive).

The results of the study found significant changes
in all tested blood markers in subjects who were Aβ-positive (A+, CSF Aβ42/40 <0.
071) but tau protein-negative (T-).

Compared with other markers, the rates of elevated p-tau231, p-tau217, and Aβ42/40 were the largest (P<0.
0001; plasma p-tau231: Cohen's d=0.
76; plasma p-tau217 and Aβ42/40; Cohen's d=0.
74).

The markers were GFAP (P<0.
0001; Cohen's d=0.
55), p-tau181 (P=0.
001; Cohen's d=0.
45), and NfL (P=0.
031; Cohen's d=0.
33).

The changes of each plasma marker in different pathological reference (CSF, Aβ PET) groups were compared

Among the Aβ-positive subjects, the investigators subdivided a group of Aβ-positive subjects, that is, CSF Aβ42/40 abnormal, but Aβ PET< 30 centiloids
.
Among subjects with weak Aβ positives, there were also significant changes in plasma p-tau231 and Aβ42/40 (P < 0.
0001; Cohen's d = 0.
73).

Aβ PET (left) and CSF Aβ42/40 (right) represent the changes of markers in the regression model during disease progression, respectively

The researchers used Aβ positron emission tomography (Aβ PET) to record changes in Aβ deposition in the subjects' brains, and also measured changes
in the subjects' cerebrospinal fluid Aβ42/40 (CSF Aβ42/40).
In the results analysis, these two indexes were used to represent the pathological process of Aβ, and the changes
of each plasma marker with the change of Aβ PET and CSF Aβ42/40 were compared through a robust locally weighted regression model.
In this model, a marker with a z-score greater than 2 is considered an anomaly
.

They found that with the increase of Aβ load in Aβ PET, the z-scores of p-tau231, p-tau217 and GFAP all exceeded 2, and their corresponding Aβ PETs were 26.
4, 35.
4 and 65.
5 centiloids, respectively, and the z-scores of the remaining markers did not exceed 2
.
As CSF Aβ42/40 pathology progresses, only p-tau231 and p-tau217 have z-scores above 2
.

Changes in plasma markers associated with Aβ PET images of different brain regions

The researchers also found that elevated levels of p-tau231 and p-tau217 in Aβ PET image alignment strongly correlated
with increased Aβ deposition in disease-sensitive brain regions.

This means that in the preclinical stage of Alzheimer's disease, p-tau231 and p-tau217 have great potential to become plasma markers for screening for Aβ pathology
.

CSF Aβ42/40 represents the ROC curve of each marker during pathological progression

The researchers also used recipient operant characteristic curve (ROC) analysis to further verify the predictive accuracy
of different plasma markers for Aβ pathology.

In the correlation analysis, they introduced a basic risk model to aid judgment, including the risk factors that have been shown to influence the onset of Alzheimer's disease, namely sex, age, and APOEε4 carryover
.

The researchers then compared several plasma markers in the trial with the model individually or comprehensively to explore whether it could improve the predictive power of the model and provide further evidence
for whether it could become a disease marker.

The results showed that when using CSF Aβ42/40 as a pathological marker, the addition of any other plasma marker except NfL could improve the predictive power of this model, the most significant of which were plasma p-tau231 (AUC=0.
810), plasma Aβ42/40 (AUC=0.
798), and plasma p-tau217 (AUC=0.
797).

Changes in association between p-tau231 and cognitive decline (left) and Aβ PET (right) at 3-year follow-up

In order to verify the relationship between each marker and the cognitive ability and Aβ pathology of the subjects, the investigators also followed some subjects for 3 years
.

During follow-up, they found a significant association between p-tau181 and cognitive decline, the only one of all that showed a significant association with CSF Aβ42/40
.
In comparison with Aβ PET pathology, all markers showed correlation, but only p-tau231 was significantly associated
.

However, this study also has certain limitations, that is, the subjects themselves have a high risk of disease, so the trial lacks a control group of subjects with normal aging, so more follow-up studies are needed to explore the possibility
of clinical translation of these markers.

Overall, this study showed abnormalities in plasma in preclinical Alzheimer's disease patients with Aβ pathology, among which plasma abnormalities of p-tau231 and p-tau217 were particularly significant
.
These abnormally elevated plasma markers have great potential to become markers of early Aβ pathology and help doctors screen for
early Alzheimer's disease.

The discovery of p-tau231 and p-tau217 as potential plasma markers for Aβ pathology of Alzheimer's disease will greatly promote the development of preclinical screening and intervention, and also provide new ideas
for subsequent treatment strategies of the disease.

References:

[1] Jack CR Jr, Bennett DA, Blennow K, et al.
NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease.
Alzheimers Dement.
2018; 14(4):535-562.
doi:10.
1016/j.
jalz.
2018.
02.
018

[2] Milà-Alomà M, Ashton NJ, Shekari M, et al.
Plasma p-tau231 and p-tau217 as state markers of amyloid-β pathology in preclinical Alzheimer's disease [published online ahead of print, 2022 Aug 11] [published correction appears in Nat Med.
2022 Sep 13; :].
Nat Med.
2022; 10.
1038/s41591-022-01925-w.
doi:10.
1038/s41591-022-01925-w

[3] Milà-Alomà M, Salvadó G, Gispert JD, et al.
Amyloid beta, tau, synaptic, neurodegeneration, and glial biomarkers in the preclinical stage of the Alzheimer's continuum.
Alzheimers Dement.
2020; 16(10):1358-1371.
doi:10.
1002/alz.
12131

[4] Molinuevo JL, Gramunt N, Gispert JD, et al.
The ALFA project: A research platform to identify early pathophysiological features of Alzheimer's disease.
Alzheimers Dement (N Y).
2016; 2(2):82-92.
Published 2016 Mar 3.
doi:10.
1016/j.
trci.
2016.
02.
003

[5] Blennow K, Hampel H.
CSF markers for incipient Alzheimer's disease.
Lancet Neurol.
2003; 2(10):605-613.
doi:10.
1016/s1474-4422(03)00530-1

[6] Palmqvist S, Janelidze S, Quiroz YT, et al.
Discriminative Accuracy of Plasma Phospho-tau217 for Alzheimer Disease vs Other Neurodegenerative Disorders.
JAMA.
2020; 324(8):772-781.
doi:10.
1001/jama.
2020.
12134

[7] Ashton NJ, Pascoal TA, Karikari TK, et al.
Plasma p-tau231: a new biomarker for incipient Alzheimer's disease pathology.
Acta Neuropathol.
2021; 141(5):709-724.
doi:10.
1007/s00401-021-02275-6

[8] Karikari TK, Pascoal TA, Ashton NJ, et al.
Blood phosphorylated tau 181 as a biomarker for Alzheimer's disease: a diagnostic performance and prediction modelling study using data from four prospective cohorts.
Lancet Neurol.
2020; 19(5):422-433.
doi:10.
1016/S1474-4422(20)30071-5

Responsible EditorBioTalker