In ADAD, Plaque Removal Improves Synaptic and Inflammatory Biomarkers

Scientists still have much to learn about how Aβ immunotherapy affects downstream processes in the brain. In the April 29 JAMA Neurology, researchers led by Eric McDade at Washington University School of Medicine, St. Louis, offer some hints gleaned from the Dominantly Inherited Alzheimer Network’s first clinical trial. This study investigated the effects of gantenerumab and solanezumab in symptomatic and presymptomatic mutation carriers, finding no clinical benefit, but an improvement in amyloid and tau biomarkers on gantenerumab.

  • Fluid biomarkers neurogranin, sTREM2, and GFAP improved on gantenerumab.
  • Benefits were greater in presymptomatic than symptomatic participants.
  • Solanezumab worsened neurodegenerative marker NfL.

In the new paper, McDade and colleagues report results from markers of synaptic function, neuroinflammation, and neurodegeneration. In keeping with the main findings, the plaque-busting antibody gantenerumab nudged synaptic and inflammatory biomarkers toward normal. Solanezumab, which targets soluble, monomeric Aβ, had no effect on these biomarkers, but worsened the neurodegenerative marker neurofilament light.

In an accompanying editorial, Rik Ossenkoppele and Charlotte Teunissen at Vrije University Amsterdam, the Netherlands, noted that this is one of the first publications to describe the effects of amyloid removal on these downstream AD-related processes. They speculated the data could help explain the clinical benefits seen in some immunotherapy trials. “The activation of microglia and astrocytes, along with synaptic enhancement, could potentially influence the deceleration of cognitive decline associated with the removal of Aβ plaques,” they wrote.

Synaptic Benefit? On gantenerumab (blue), but not solanezumab (orange) or placebo (black), the synaptic degeneration marker neurogranin fell in cerebrospinal fluid over four years. [Courtesy of Wagemann et al., JAMA Neurology.]

The DIAN trial enrolled 142 mutation carriers. Fifty of them received solanezumab, 52 gantenerumab, and 40 placebo over the four years of the study. Though neither drug slowed cognitive decline, gantenerumab lowered plaque by one-fifth to a third, and suppressed p-tau181 and total tau in cerebrospinal fluid by about a third, as well. Gantenerumab was also reported to slightly slow the rise in CSF NfL (Feb 2020 news; Apr 2020 conference news; Jun 2021 news).

In the new paper, joint first authors Olivia Wagemann and Haiyan Liu analyzed several additional fluid biomarkers using Roche’s NeuroToolKit, a collection of fully automated CSF and plasma assays (Aug 2019 conference news; Dec 2019 conference news). Specifically, in CSF they measured neurogranin, sTREM2, GFAP, YKL-40, and NfL, and in plasma, GFAP and NfL. Henrik Zetterberg at Gothenburg University, Sweden, noted that NeuroToolKit assays are robust, with little analytic variation, allowing for high-precision measurements that can detect very small treatment effects.

Over the four years of the trial, gantenerumab brought down the postsynaptic marker neurogranin. CSF neurogranin rises as AD progresses, and is thought to reflect synaptic degeneration that releases this protein into the interstitial fluid (Aug 2019 conference news; Dec 2019 conference news).

Microglial and Astrocyte Effects. On gantenerumab (blue), the beneficial microglial marker sTREM2 rose, while the harmful astrocyte marker GFAP fell, compared with placebo (black). [Courtesy of Wagemann et al., JAMA Neurology.]

The NeuroToolKit included three inflammatory markers. Gantenerumab boosted sTREM2, a positive sign since higher levels of this microglial marker correlate with slower AD progression (Aug 2019 news; Mar 2022 news). The antibody nudged down the astrogliosis marker GFAP in plasma, but did not budge it in CSF. Plasma GFAP was previously shown to reflect amyloid plaque load better than does the CSF version, perhaps because astrocyte endfeet secrete this protein directly into the bloodstream (Mar 2021 conference news; Pereira et al., 2021; Benedet et al., 2021). Finally, gantenerumab had no effect on the astrocyte marker YKL-40, which correlates with p-tau and total tau rather than plaques.

Likewise, the NeuroToolKit found no effect of gantenerumab on CSF NfL, belying the previous results using a Simoa assay that suggested a slight check on this marker. McDade noted that both analyses trended in the same direction, but believes any effect on NfL is weak. This biomarker has also given inconsistent results in trials of other anti-amyloid antibodies such as lecanemab and donanemab, both of which cleared plaque more effectively than does gantenerumab. By contrast, solanezumab noticeably worsened CSF NfL in both analyses, suggesting increased degeneration.

Intriguingly, in people taking gantenerumab, but not solanezumab, lower GFAP and NfL in plasma and CSF correlated with healthier glucose metabolism in the precuneus, as seen by FDG-PET. Again, this hints at therapeutic effects on the brain.

The researchers also stratified the findings by disease stage. This exploratory analysis found that gantenerumab moved biomarkers most strongly in the presymptomatic group, adding to the evidence that earlier treatment with anti-amyloid antibodies might help people more.

What’s next for these DIAN participants? Gantenerumab’s benefit on biomarkers had led researchers to continue treatment in an open-label extension, which ended in August 2023. At last year’s Clinical Trials on Alzheimer’s Disease conference in Boston, Randall Bateman of WashU reported that asymptomatic participants who had been on gantenerumab since the beginning of the trial, about eight years of exposure, were half as likely to develop symptoms as were those who started on solanezumab or placebo (Nov 2023 conference news).

Nonetheless, amyloid removal on gantenerumab in this autosomal-dominant AD population was slow, and many participants remain amyloid-positive, McDade told Alzforum. DIAN researchers recently announced that they will begin a new five-year, open-label study for this group, where all participants will receive lecanemab. This antibody was chosen for its proven effectiveness and favorable safety profile, McDade noted. The goal of the study is to determine if complete plaque removal can delay symptom onset or disease progression. Researchers will also examine the effects on downstream biomarkers. Zetterberg speculated that because lecanemab removes plaque more effectively than does gantenerumab, it might have a greater effect on biomarkers such as NfL.—Madolyn Bowman Rogers

Comments

  1. This is a very nice study from the DIAN-TU team, reporting the effects of anti-amyloid therapy with gantenerumab and solanezumab on CSF and plasma biomarkers as measured by the Roche NeuroToolKit in dominantly inherited Alzheimer’s disease. Although the significant dose escalations halfway through the trials make interpretation of time-dependent changes in these markers challenging, it is clear that, even with significant dose escalation, solanezumab did not move the needle in a beneficial direction on any of these markers and the pathways they represent.

    However, with gantenerumab, it is encouraging to see that removing fibrillar Aβ had positive effects on the synaptic marker neurogranin and the astrocytic marker plasma GFAP, indicating that these markers could be useful readouts for other anti-amyloid therapies that target fibrillar Aβ. Future studies with these markers in trials that meet, or have already demonstrated, a positive clinical endpoint will be informative.

    One of the main questions in my mind that arises from these results is the relationship between the neuroinflammatory markers GFAP and YKL-40.  Although they are both highly expressed in astrocytes and are elevated in AD, gantenerumab treatment decreases GFAP but increases YKL-40, perhaps suggesting that YKL-40 is marking a beneficial compensatory astrocytic response to amyloid plaques. Mechanistic studies that dissect this opposing response in astrocytes in the context of anti-amyloid therapy, and validate that the increased YKL-40 signal is truly coming from astrocytes, will be helpful to clarify.

    View all comments by Erik Johnson
    • User Profile Image Jeffrey Dage
      Indiana University School Of Medicine
    • Posted:

    In this study by Wagemann et. al, gantenerumab and solanezumab have been studied in the context of dominantly inherited Alzheimer disease (DIAD), and they have shown different effects on downstream biomarkers. Previously reported results (Salloway et al., 2021) have demonstrated a lack of clear clinical benefits for both treatments; however, post hoc biomarker studies can often shed light on the pathways and mechanisms associated with investigational treatments. This study leverages the robust prototype assays developed within Roche’s NeuroToolKit and represents another example of how the DIAN observational and therapeutic studies advance our understanding of AD. Interestingly, this seems to be the first use of the plasma NeuroToolKit assays. None of these assays describe the specific antibodies or epitopes involved in the assay design and there are limited studies showing correlations between these and other commercially available assays, which makes comparisons to other literature difficult.

    One of the most interesting features to me was the CSF sTrem2 data.  First, the downward arrow showing the direction of worsening is opposite to the direction of the increase seen with disease stage. The disease associated increase in sTrem2 has been published specifically for these assays (Johnson et al., 2023).  It is clear, CSF sTrem2 levels increase with disease.  However, the authors point out in the discussion that the higher levels might have different interpretations as far as worsening due to the complex correlation with amyloid and tau PET accumulation rates (Ewers et. al, 2020).  This is a very complicated argument due to measurement properties of PET ligands and there needs to be much more research into the meaning of sTrem2 levels in CSF along with other glial cell specific markers. Obtaining data on CSF sTREM2, along with amyloid and tau PET, from early onset AD and late-onset AD patients who have been treated with solanezumab, gantenerumab, lecanemab, or donanemab would further enhance our understanding of the relationship throughout the entire process of amyloid removal, including before, during, and after the treatment.  The sTrem2 increases seen with gantenerumab treatment may be related to the mechanism of amyloid removal, however, the exact mechanisms and relationship still need a lot more research.

    References:

    Salloway S, Farlow M, McDade E, Clifford DB, Wang G, Llibre-Guerra JJ, Hitchcock JM, Mills SL, Santacruz AM, Aschenbrenner AJ, Hassenstab J, Benzinger TL, Gordon BA, Fagan AM, Coalier KA, Cruchaga C, Goate AA, Perrin RJ, Xiong C, Li Y, Morris JC, Snider BJ, Mummery C, Surti GM, Hannequin D, Wallon D, Berman SB, Lah JJ, Jimenez-Velazquez IZ, Roberson ED, van Dyck CH, Honig LS, Sánchez-Valle R, Brooks WS, Gauthier S, Galasko DR, Masters CL, Brosch JR, Hsiung GR, Jayadev S, Formaglio M, Masellis M, Clarnette R, Pariente J, Dubois B, Pasquier F, Jack CR Jr, Koeppe R, Snyder PJ, Aisen PS, Thomas RG, Berry SM, Wendelberger BA, Andersen SW, Holdridge KC, Mintun MA, Yaari R, Sims JR, Baudler M, Delmar P, Doody RS, Fontoura P, Giacobino C, Kerchner GA, Bateman RJ, Dominantly Inherited Alzheimer Network–Trials Unit. A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer's disease. Nat Med. 2021 Jul;27(7):1187-1196. Epub 2021 Jun 21 PubMed.

    Johnson SC, Suárez-Calvet M, Suridjan I, Minguillón C, Gispert JD, Jonaitis E, Michna A, Carboni M, Bittner T, Rabe C, Kollmorgen G, Zetterberg H, Blennow K. Identifying clinically useful biomarkers in neurodegenerative disease through a collaborative approach: the NeuroToolKit. Alzheimers Res Ther. 2023 Jan 28;15(1):25. PubMed.

    Ewers M, Biechele G, Suárez-Calvet M, Sacher C, Blume T, Morenas-Rodriguez E, Deming Y, Piccio L, Cruchaga C, Kleinberger G, Shaw L, Trojanowski JQ, Herms J, Dichgans M, Alzheimer's Disease Neuroimaging Initiative (ADNI), Brendel M, Haass C, Franzmeier N. Higher CSF sTREM2 and microglia activation are associated with slower rates of beta-amyloid accumulation. EMBO Mol Med. 2020 Sep 7;12(9):e12308. Epub 2020 Aug 10 PubMed.

    View all comments by Jeffrey Dage

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References

Therapeutics Citations

  1. Gantenerumab
  2. Solanezumab
  3. Leqembi
  4. Donanemab

News Citations

  1. Topline Result for First DIAN-TU Clinical Trial: Negative on Primary
  2. In DIAN-TU, Gantenerumab Brings Down Tau. By a Lot. Open Extension Planned
  3. Paper Alert: DIAN-TU Solanezumab and Gantenerumab Data Published
  4. Proteomics Uncovers Potential Markers, Subtypes of Alzheimer’s
  5. Fluid AD Biomarkers Link P-Tau to Synapses, Inflammation
  6. Synaptic Proteins in CSF: New Markers of Cognitive Decline?
  7. In Alzheimer’s, More TREM2 Is Good for You
  8. Robust TREM2 Expression May Delay Alzheimer’s Disease
  9. Astroglial Markers Poised for Stardom?
  10. Treat Before ‘Aβ Bothers Tau,’ Scientists Say at CTAD

Paper Citations

  1. Pereira JB, Janelidze S, Smith R, Mattsson-Carlgren N, Palmqvist S, Teunissen CE, Zetterberg H, Stomrud E, Ashton NJ, Blennow K, Hansson O. Plasma GFAP is an early marker of amyloid-β but not tau pathology in Alzheimer's disease. Brain. 2021 Dec 16;144(11):3505-3516. PubMed.
  2. 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.

External Citations

  1. announced 

Further Reading

Primary Papers

  1. Wagemann O, Liu H, Wang G, Shi X, Bittner T, Scelsi MA, Farlow MR, Clifford DB, Supnet-Bell C, Santacruz AM, Aschenbrenner AJ, Hassenstab JJ, Benzinger TL, Gordon BA, Coalier KA, Cruchaga C, Ibanez L, Perrin RJ, Xiong C, Li Y, Morris JC, Lah JJ, Berman SB, Roberson ED, van Dyck CH, Galasko D, Gauthier S, Hsiung GR, Brooks WS, Pariente J, Mummery CJ, Day GS, Ringman JM, Mendez PC, St George-Hyslop P, Fox NC, Suzuki K, Okhravi HR, Chhatwal J, Levin J, Jucker M, Sims JR, Holdridge KC, Proctor NK, Yaari R, Andersen SW, Mancini M, Llibre-Guerra J, Bateman RJ, McDade E, Dominantly Inherited Alzheimer Network–Trials Unit. Downstream Biomarker Effects of Gantenerumab or Solanezumab in Dominantly Inherited Alzheimer Disease: The DIAN-TU-001 Randomized Clinical Trial. JAMA Neurol. 2024 Jun 1;81(6):582-593. PubMed.
  2. Ossenkoppele R, Teunissen CE. Fluid Biomarker Changes After Amyloid-β-Targeting Drugs. JAMA Neurol. 2024 Jun 1;81(6):579-581. PubMed.

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