Blood Testing Reveals Amyloid-Lowering Effect of Alzheimer’s Meds

ByLois C

Apr 16, 2022 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

Reduced stages of phosphorylated (P)-tau217 and glial fibrillary acidic protein (GFAP) in the blood point out downstream procedure outcomes of beta amyloid (Aβ) clearance from the mind, new investigation exhibits.

Investigators found that changes in degrees of these plasma biomarkers have been positively correlated with p.c change in amyloid plaque ranges as revealed on positron-emission tomography (PET).

The effects recommend these biomarkers could be used as an alternative of the additional costly, and not usually commonly readily available, PET scans to observe people having anti-amyloid brokers.

“We possibly can’t evaluate complete amyloid elimination with a blood exam, but we can see that something’s going on and we know no matter whether or not we’ve bought engagement,” analyze investigator Michael Pontecorvo, PhD, vice president of medical enhancement at Avid Radiopharmaceuticals, the biomarker arm of Lilly, advised Medscape Health care News.

The findings were offered at the American Academy of Neurology (AAN) 2022 Annual Meeting.

New Choices

The period 2 trial of donanemab (TRAILBLAZER-ALZ) is a randomized, double-blind, placebo-managed study in clients with early, symptomatic Alzheimer’s disorder (Advertisement). The research integrated 257 people. Of these, 131 have been randomly assigned to receive donanemab and 126 to get placebo.

The study, posted previous yr in The New England Journal of Drugs, confirmed that the modify from baseline in the main endpoint of built-in Alzheimer’s Condition Rating Scale rating at 76 months was −6.86 with donanemab and −10.06 with placebo, for a change of 3.20 (95% CI, .12 – 6.27 P = .04).

The evaluation also confirmed robust amyloid plaque reduction and slowing of tau accumulation, as measured working with PET, in sufferers treated with donanemab.

“By the close of the study, amyloid concentrations in practically 70% of people experienced returned to regular ― the kind of levels you would see in an amyloid-unfavorable, cognitively unimpaired aged person,” explained Pontecorvo.

Through the demo, researchers consistently gathered plasma samples. The biomarkers they analyzed integrated the ratio of Aβ 42/40, GFAP, neurofilament mild chain (NfL) and P-tau217.

It’s hypothesized that in Advert, amyloid triggers a cascade of occasions, starting with an enhance in phosphorylation of tau, then accumulation of neurofibrillary tangles, with the amyloid and neurofibrillary tangles subsequently foremost to swelling and, finally, neuronal death.

The investigation showed that plasma concentrations of P-tau217 and GFAP (a marker of swelling) ended up appreciably reduced following 12 weeks of donanemab treatment method in comparison with placebo.

The reduction in concentrations of these biomarkers was preserved for the period of the research. This was the case even for members who realized amyloid reduction and discontinued using donanemab, mentioned Pontecorvo.

The variations in plasma P-tau217 and GFAP ranges have been positively correlated with percent improve in amyloid plaque stages on PET (P < .0001 and P < .0001, respectively).

There was a significant positive correlation between the change in plasma P-tau217 and change in tau deposition on PET in the frontal (P = .0019) and temporal (P = .0247) lobes at 76 weeks and a trend toward significance in the parietal lobe (P = .0516).

“What we are showing with these plasma biomarkers is that we can see downstream effects of amyloid we can see that the amyloid has stopped the new generation of P-tau and has reduced the amount of inflammation going on in the brain,” said Pontecorvo.

“This is perhaps contributing to more than a symptomatic effect but rather to a disease-modifying effect, interfering with the chain that eventually leads to neurodegeneration,” he added.

There were no significant differences in plasma levels of Aβ 42/40 and NfL between treatment arms at 76 weeks. Pontecorvo believes that for Aβ 42/40, “that’s just a commentary on the quality of the particular assay” used during the study.

In addition, the issue with NfL, a marker of neurodegeneration, is that such damage occurs “significantly farther downstream,” said Pontecorvo. “We need longer studies to see an effect on NfL is my hypothesis.”

These new results “open possibilities” for wider use of these blood tests, said Pontecorvo. For example, they could be used to determine when to remove patients from therapy once certain amyloid levels are reached.

They could also be used to check whether a patient who has stopped therapy needs to restart it, he added. “When the blood P-tau starts going up, you probably have significant levels of amyloid starting to come into play, and you may want to get a scan and consider restarting the drug.” However, he added, at this point this is “all speculation.”

Donanemab has been deemed a “breakthrough” medication by the US Food and Drug Administration. The company has initiated a rolling submission under the accelerated approval pathway. A phase 3 confirmatory trial is ongoing.

Tracking Efficacy

Commenting for Medscape Medical News, Rebecca Edelmayer, PhD, Alzheimer’s Association senior director of scientific engagement, said the new data support the idea that a panel of plasma biomarkers may be used in future to more precisely predict biological brain changes in AD.

“While these results aren’t necessarily surprising, the blood biomarker data analyzed together with amyloid PET, tau PET, and cognition outcomes help to support validation of these tools for future clinical use,” said Edelmayer.

Blood biomarkers may also be useful for tracking treatment effects, she added. “The more we learn about plasma biomarkers, the more we understand about their utility in not only detecting Alzheimer’s-related pathology but also in tracking the effectiveness of newly developed therapies that target that biology.”

American Academy of Neurology (AAN) 2022 Annual Meeting: Abstract 1087. Presented April 5, 2022.

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By Lois C