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.
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.
Comments
Emory University
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 JohnsonIndiana University School Of Medicine
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.
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