Pontecorvo MJ, Lu M, Burnham SC, Schade AE, Dage JL, Shcherbinin S, Collins EC, Sims JR, Mintun MA. Association of Donanemab Treatment With Exploratory Plasma Biomarkers in Early Symptomatic Alzheimer Disease: A Secondary Analysis of the TRAILBLAZER-ALZ Randomized Clinical Trial. JAMA Neurol. 2022 Dec 1;79(12):1250-1259. PubMed.

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  1. Plasma p-tau217 measured by immunoassay or mass spectrometry has emerged as a tremendously valuable biomarker for AD pathology. Alone, or in combination with Aβ42/20 ratio by mass spec, plasma p-tau217 is an accurate predictor of amyloid PET and tau PET results, facilitating recruitment into early stage AD trials. Early, robust decline in plasma p-tau217 as a result of amyloid-reducing immunotherapy suggests that longitudinal assessment of this biomarker is also valuable as a trial outcome measure, perhaps predicting clinical benefit and facilitating early phase dose selection. Along with the treatment effect on GFAP, it suggests downstream effects of amyloid removal on AD neurobiology.

    Results expected soon from the Phase 3 trials of lecanemab, gantenerumab, and donanemab will further clarify these issues. Why no effect on NfL and Aβ ratios? NfL, which is a relatively nonspecific marker of neurodegeneration, may reflect aspects of brain disease that do not change, or take longer to change, with amyloid-reducing therapy. Immunoassays of Aβ ratios are not as accurate as mass spec and may be influenced directly by immunotherapy, confounding interpretation. Again, the huge amount of data expected soon will be very helpful to our understanding.

    View all comments by Paul Aisen

  2. This paper examined the course of plasma biomarker changes in an exploratory analysis of the TRAILBLAZER Phase 2 trial targeting pyroglutamate amyloid isoforms using the donanemab antibody. The striking findings are the early, significant decreases of both plasma p-tau217 and GFAP levels, already at 12 weeks after treatment began. This suggests quite direct effects of amyloid lowering on two major players in the amyloid cascade, namely tau pathology and astrocyte activation. The changes in GFAP fit into prior findings of an association of this plasma biomarker with amyloid, such as the previously reported increased GFAP levels in amyloid-positive individuals. Nevertheless, even longitudinal increase of a biomarker along the disease trajectory is not proof of good potential for treatment monitoring. But here, both markers pass the proof-of-concept for treatment monitoring response.

    Another striking finding is the lack of an effect on NfL. NfL is being used to monitor treatment responses in several neurological diseases, such as multiple sclerosis (MS) and several pediatric diseases, such as spinal muscular atrophy (SMA). What could be the reason for such a lack of effect in AD? It may be due to the less-pronounced increase observed for NfL in AD compared to, e.g., relapsing-remitting MS and SMA, providing less room for reduction. Another reason could be that NfL may rather reflect atrophy and white-matter alterations in AD, and the protective effects of amyloid lowering on these features have more long-term and more subtle temporal dynamics. This contrasts the rapid effects of anti-inflammatory treatments in MS, which lower NfL elevations caused by acute inflammatory-mediated axonal damage.

    The next step is to prove that plasma p-tau217 and GFAP changes act as surrogates for cognitive change. These relations were weak in the current study, but, given cognitive outcome measures are usually variable, we need to await outcomes of Phase 3 trials to get a better sense of these relationships. On the other hand, the road to acceptance of these two plasma biomarkers as treatment monitoring markers is well paved by their correlation with amyloid reduction in the present study.

    View all comments by Lisa Vermunt

  3. These results complete the amyloid, tau, and neurodegeneration triad of biomarkers for TRAILBLAZER, demonstrating the utility of anti-amyloid immunotherapy. Although the percent reductions might seem small (12 percent for GFAP), the lack of a cognitively unimpaired group in the trial makes it hard to know what the baseline level of GFAP would be. In other work, cognitively unimpaired, amyloid-negative, older adults appear to have 50 percent less plasma GFAP than AD do cases, so the reduction is possibly 25 percent of the way back to "normal” (Benedet et al., 2021). This would appear to be in line with the roughly 30 percent slowing of cognitive decline with the anti-amyloid antibodies. This might be all that is expected given the observations that postmortem amyloid accounts for about a third of the variance in the rate of premorbid cognitive decline (Yu et al., 2021). 

    Although longer treatment exposure may cause even greater reductions in neurodegeneration markers, there are factors other than amyloid which contribute to brain aging that most likely need to be addressed separately. As for most therapies, anti-amyloid immunotherapy might be more effective as prevention instead of treatment.

    References:

    Benedet AL, Milà-Alomà M, Vrillon A, Ashton NJ, Pascoal TA, Lussier F, Karikari TK, Hourregue C, Cognat E, Dumurgier J, Stevenson J, Rahmouni N, Pallen V, Poltronetti NM, Salvadó G, Shekari M, Operto G, Gispert JD, Minguillon C, Fauria K, Kollmorgen G, Suridjan I, Zimmer ER, Zetterberg H, Molinuevo JL, Paquet C, Rosa-Neto P, Blennow K, Suárez-Calvet M, Translational Biomarkers in Aging and Dementia (TRIAD) study, Alzheimer’s and Families (ALFA) study, and BioCogBank Paris Lariboisière cohort. Differences Between Plasma and Cerebrospinal Fluid Glial Fibrillary Acidic Protein Levels Across the Alzheimer Disease Continuum. JAMA Neurol. 2021 Dec 1;78(12):1471-1483. PubMed.

    Yu L, Boyle PA, Wingo AP, Yang J, Wang T, Buchman AS, Wingo TS, Seyfried NT, Levey AI, De Jager PL, Schneider JA, Bennett DA. Neuropathologic Correlates of Human Cortical Proteins in Alzheimer Disease and Related Dementias. Neurology. 2022 Mar 8;98(10):e1031-e1039. Epub 2021 Dec 22 PubMed.

    View all comments by Dave Morgan

  4. The development of blood biomarkers for Alzheimer’s disease has been one of the most important advances in our field in recent years. We can now affirm that we have several blood biomarkers that accurately detect Alzheimer’s disease. In other words, blood biomarkers appear to be useful as diagnostic biomarkers or, in preclinical stages, as state biomarkers that indicate amyloid and tau pathology. This opens the door for using blood biomarkers for participant selection in clinical trials. Yet, blood biomarkers may also play other roles in drug development. Could blood biomarkers be used as pharmacodynamic/response biomarkers in clinical trials? The results of this study suggest so.

    In this post hoc analysis of the TRAILBLAZER-ALZ Phase 2 randomized clinical trial, Pontecorvo et al. investigate the association of the anti-amyloid drug donanemab with the plasma biomarkers Aβ42/40, GFAP, NfL, and p-tau217 in early symptomatic Alzheimer’s disease. Plasma p-tau217 and GFAP were significantly lower in the donanemab treatment arm compared to the placebo one as early as 12 weeks after the start of the treatment, and their changes were associated with amyloid burden reduction as measured by positron emission tomography (PET). Of note, plasma p-tau217 and GFAP were still lower throughout the 76 weeks of the study even in those patients in whom treatment with donanemab was stopped at week 24 because amyloid PET levels dropped below 11 centiloids (CL).

    These results indicate that plasma p-tau217 and GFAP could be used as target engagement biomarkers in clinical trials, that is, assessing whether the investigated drug has an effect on the target pathology (herein, Aβ pathology). In the future, these plasma biomarkers might also be helpful to select the dose to use in an eventual Phase 3 trial. These data are also in line with the notion that plasma p-tau217 and GFAP probably reflect Aβ dyshomeostasis and, albeit counterintuitive, it arises the question of whether these biomarkers should be part of the “A” (Aβ pathology) of the widely used ATN classification.

    No significant changes were observed in plasma Aβ42/40 or NfL between the two study arms, except for an enigmatical increase in plasma Aβ42/40 in the treatment arm only at week 36. Plasma Aβ42/40 was measured with the Simoa Kit from Quanterix. One might ask whether using other Aβ42/40 assays (e.g., mass spectrometry-based assays) may lead to the same results. That plasma NfL does not correlate with amyloid or tau PET is not unexpected, since plasma NfL is a biomarker of neuronal injury that is not specific for AD. However, one would expect that if donanemab has an effect of halting neurodegeneration, plasma NfL would also decrease in the active treatment arm.

    And here the big question arises: Could we also use blood biomarkers as surrogate endpoints in clinical trials? This study gives us a hint. A decline of plasma p-tau217 was associated with lower odds of exhibiting a meaningful worsening on the iADRS scale. The authors acknowledge the post hoc and explorative nature of this study. Larger and longer studies will be needed to test whether blood biomarkers are associated with slowing cognitive decline.

    View all comments by Marc Suárez-Calvet

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  1. In TRAILBLAZER, Plasma GFAP Falls, but NfL Continues to Rise

Therapeutics

  1. Donanemab