JAMA Sub-issue: Discover blood markers to evaluate the efficacy of Alzheimer's disease drugs!

*For medical professionals only

Donanemab, a monoclonal antibody that targets β amyloid (Aβ) N3pG, is one of
the few drugs that has shown potential therapeutic effects in patients with Alzheimer's disease (AD) in clinical trials.

In the Phase 2 clinical trial TRAILBLAZER-ALZ study (NCT03367403), Donanemab treatment met the primary endpoint that patients with AD had significantly less reduction in Alzheimer's Disease Composite Score Scale (iADRS, lower scores indicate more severe cognitive impairment) compared with placebo 1]
。 The study also led to Donanemab being granted breakthrough therapy designation
for AD by the FDA in June 2021.

In clinical trials, in addition to the use table (there is a certain subjectivity) to judge the therapeutic effect of AD drugs, a more objective evaluation method is positron emission computed tomography (PET) of neurofibrillary entanglements caused by excessive phosphorylation of Aβ plaques and Tau protein by tracer, but this method is obviously not very convenient
.
If readily available indicators such as plasma biomarkers can accurately and reliably reflect the extent of AD patients' condition, it is convenient to monitor the therapeutic effect
of drugs in clinical trials.

Recently, a research team led by Michael J.
Pontecorvo conducted a secondary analysis of the data of participants in the TRAILBLAZER-ALZ study to explore the plasma biomarkers Aβ42/40 (decreased in AD [2]), pTau217 (elevated in AD [3]), and glial fibrillary acidic protein after Donanemab treatment in patients with early symptomatic AD Changes in (GFAP, elevated in AD [4]) and neurofilament light chain (NfL, elevated in AD [5]), and the correlation of these markers with AD progression [6].

Studies have shown that plasma pTau217 and GFAP are significantly reduced in AD patients after treatment with Donanemab compared to placebo.

At the same time, plasma pTau217 and GFAP changes were also significantly positively correlated with changes in brain amyloid plaques shown by Aβ PET imaging after Donanemab treatment, and plasma pTau217 changes were significantly positively correlated
with changes in the normalized uptake value ratio of frontal lobe to temporal lobe Tau after Tau PET imaging after Donanemab treatment.

These readily available plasma biomarkers may become a convenient way to evaluate the efficacy of AD drug therapy in the future, and the relevant research results were published in
the prestigious journal JAMA Neurology.

Screenshot of the first page of the paper

TRAILBLAZER-ALZ is a randomized controlled phase 2 clinical trial conducted at 56 medical centers in the United States and Canada from December 18, 2017 to December 4, 2020, in patients with early symptomatic AD with gradual and progressive changes in memory function for at least 6 months
.

These participants had a mini-mental status test score of 20 to 28, and Aβ and Tau PET imaging showed increased amyloid plaques in the brain and moderately increased deposits of Tau protein (because Aβ-targeting drugs do not work well in patients with advanced AD [significantly elevated Tau protein], this trial excludes AD patients with significantly elevated Tau protein).

All participants were randomised to either Donanemab (700 mg for the first three Donanemab doses, subsequently increased to 1400 mg and reduced depending on amyloid plaque reduction) or placebo every 4 weeks for 72 weeks
.

A total of 245 participants were enrolled in this study, with a mean age of 75.
2 years, and 53.
3% (145) women, including 125 in the Donanemab group and 120 in the placebo group
.

At baseline, plasma levels of pTau217 in AD patients were positively correlated with brain amyloid plaques (P=0.
02) and Tau protein deposition (P<0.
001) on Aβ and Tau PET imaging, while plasma Aβ42/40, GFAP and NfL levels were not significantly correlated
.

At baseline, plasma pTau217 levels in AD patients were significantly positively correlated with brain amyloid plaques and Tau protein deposition on Aβ and Tau PET imaging

Next, the researchers analyzed changes in plasma biomarkers in AD patients after Donanemab treatment
.

After 12 weeks of treatment, plasma pTau217 levels were significantly reduced in AD patients in the Donanemab group compared to placebo and continued until week
76 of the study.
After completing all Donanemab treatments, the average plasma pTau217 level in AD patients decreased by 23%
from baseline.
In contrast, the average plasma level of pTau217 increased by 6%
in AD patients in the placebo group.

For plasma GFAP levels, they were also significantly reduced after 12 weeks of Donanemab treatment compared to placebo and continued until week
76.
After completing all Donanemab treatments, mean plasma GFAP levels decreased by 12% in AD patients from baseline, compared with 15%
in AD patients in the placebo group.

The other two plasma biomarkers Aβ42/40 and NfL levels were not significantly different
between the two groups after completion of treatment.
At week 76, mean Aβ42/40 levels increased by 4% in the Donanemab group compared with 2% in the placebo group; Average plasma NfL levels increased by 15% from baseline in the Donanemab group and 19%
in the placebo group.

Plasma pTau217 levels, GFAP levels, NfL levels, and Aβ42/40 levels varied during the test

Subsequently, the researchers analyzed the correlation between changes in plasma biomarker levels and Aβ and Tau PET imaging results
.

The results showed that the changes in plasma levels of pTau217 (P<0.
001) and GFAP (P<0.
001) were positively correlated with the changes in amyloid plaques observed in Aβ PET, and the changes in plasma pTau217 were significantly positively correlated
with the changes in the normalized uptake ratio of Tau in the frontal lobe (P=0.
02) and temporal lobe (P=0.
02).

Changes in plasma pTau217 and GFAP levels were positively correlated with amyloid plaque changes observed in Aβ PET

Plasma pTau217 and GFAP levels were significantly positively correlated at baseline (P<0.
001) and continued until week 76 (P<0.
001) at the end of the study, and plasma pTau217 and GFAP levels were similarly significantly correlated before and after treatment (P<0.
001
).

Plasma pTau217 and GFAP levels were significantly positively correlated at baseline and week 76 levels, as well as with changes before and after treatment

This suggests that plasma pTau217 and GFAP can reflect the degree of
AD pathology in the brain to a certain extent.

Immediately afterwards, the researchers also analyzed the relationship between plasma biomarkers and the volume of the whole brain, ventricles and hippocampus in MRI
.
At baseline, plasma pTau217, GFAP, NfL, and Aβ42/40 were not significantly correlated
with the above brain volume indicators.
However, after treatment, only changes in plasma NfL levels were significantly correlated with changes in whole brain volume (P=0.
03).

Finally, the researchers analyzed the relationship
between plasma biomarkers and iADRS scores.
At baseline, plasma levels of pTau217, GFAP, NfL, and Aβ42/40 were not significantly correlated
with iADRs scores.
After completion of treatment, only changes in GFAP were significantly correlated with changes in iADRS scores (P=0.
02).