Robust TREM2 Expression May Delay Alzheimer’s Disease

Loss-of-function mutations in the microglial protein TREM2 increase a person's risk for late-onset Alzheimer’s. Could boosting TREM2 expression protect against AD, even in those genetically destined to develop the disease? Yes, suggest scientists led by Christian Haass at the German Center for Neurodegenerative Diseases (DZNE), Munich. In the March 16 Lancet Neurology, they reported that among people who have an autosomal-dominant AD mutation, their cerebrospinal fluid Aβ42, cortical atrophy, and cognitive slippage all worsened less if their CSF level of the receptor's soluble stub, sTREM2, was high. Importantly, this is the first longitudinal study to compare changes in sTREM2 with other AD biomarkers over time.

  • In CSF, rapid rise in sTREM2 correlated with slower drop in Aβ42.
  • Plaque growth, cortical atrophy, and cognitive decline also slowed.
  • sTREM2 uptick could reflect early microglial response to amyloid.

“The very early microglial response is part of, not separate from, the amyloid cascade, so modulating microglia early enough in disease may preserve cognition,” Haass told Alzforum. Guojun Bu and Na Zhao of Mayo Clinic in Jacksonville, Florida, agreed. “These findings support a critical role of TREM2-mediated microglia response during AD, suggesting that sTREM2 can be a key biomarker for predicting AD-related outcomes in the early stages of the disease,” they wrote (full comment below).

Because some TREM2 mutations greatly increase a person’s risk of developing AD, researchers have been tracking how its expression correlates with AD biomarkers and with cognition (reviewed by Ulland and Colonna, 2018; Nov 2012 news). TREM2 activation releases the soluble, extracellular domain of the cell surface receptor into the interstitial fluid, whereupon it wends its way into the CSF, giving scientists a convenient marker of microglial activity (Feb 2017 news; Apr 2019 news).

Previous cross-sectional studies had tentatively linked high levels of CSF sTREM2 with slower disease progression. In two analyses of participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI), people with higher CSF sTREM2 accumulated less amyloid over two years and declined less on cognition tests over four years (Ewers et al., 2020; Aug 2019 news). Another cross-sectional study tied high CSF sTREM2 to less cortical atrophy in people with mild cognitive impairment (Aug 2016 conference news).

However, changes in sTREM2 during AD progression are less understood. In the only longitudinal study on CSF sTREM2 thus far, the protein rose slightly in the CSF of 268 cognitively normal ADNI participants over two years. Curiously, more sTREM2 was tied to greater shrinkage of the nucleus basalis of Meynert in the basal forebrain in volunteers deemed to have preclinical AD by their CSF Aβ42/p-tau ratio (Apr 2020 conference news).

To probe sTREM2 in familial AD, first and co-corresponding author Estrella Morenas-Rodríguez, now at the Hospital de Sant Pau in Barcelona, Spain, turned to the Dominantly Inherited Alzheimer Network (DIAN). She correlated CSF biomarkers, amyloid PET, structural MRI, and cognitive tests among 239 DIAN participants, most of whom were in their 30s and 40s. Of those, 48 carried pathogenic variants of PSEN1, PSEN2, or APP, and had been diagnosed with AD dementia. Another 100 had mutations but were not yet symptomatic; 91 carried no mutation and were controls. Each gave two to four CSF samples over an average of three years.

Morenas-Rodríguez measured their Aβ42, Aβ40, total tau, phosphotau-181, and sTREM2. In comparisons, she accounted for sex, age, years of education, and estimated age of AD onset. She found sTREM2 correlations in carriers, but not controls.

In all mutation carriers, regardless of symptoms, CSF sTREM2 began creeping up a whopping 21 years before their predicted symptom onset. This is 16 years earlier than Haass and colleagues had reported in a previous cross-sectional analysis of DIAN participants (Dec 2016 news). “I was surprised by this super early increase in microglial reactivity,” Haass said. He believes the stronger statistical power of longitudinal data and a new, highly sensitive, in-house meso-scale discovery immunoassay helped uncover the early rise in sTREM2. Their new detection antibody, 1H3, only binds to cleaved sTREM2 and not to other short isoforms that arise through alternative splicing. The assay could detect as little as 121 pg/mL sTREM2.

How did the CSF sTREM2 track with amyloid markers? First, the scientists looked at baseline data. Intriguingly, all mutation carriers whose CSF sTREM2 rose quickly had had less CSF Aβ42 and a lower ratio of Aβ42/40 at baseline than did those in whose CSF sTREM2 rose slowly. This implies that an activation of TREM2 processing might have been a response to formation of the first amyloid plaques. Haass thinks this microglial activation may slow plaque formation, because sTREM2 did not correlate with amyloid load judged by PiB PET signal.

Over time in asymptomatic mutation carriers, the faster their sTREM2 rose, the less their CSF Aβ42 dropped. This is another hint that TREM2 activation might be modulating the disease process. In this group, no correlation emerged with the rate of plaque accumulation. In contrast, in people whose sTREM2 rose slowly, CSF Aβ42 fell faster and plaques accumulated faster. Likewise, in symptomatic mutation carriers, rapid sTREM2 rise associated with less amyloid as judged by PET. There was no correlation with CSF Aβ42 (see image below), but many of these people already had low CSF Aβ42.

Taking all results together, the authors believe that the very first aggregates of Aβ that form before plaques can be detected by PET evoke activation of TREM2, and the quicker this happens, the more the disease process is held back. This fits with previous data that TREM2 drives microglia to cluster around small aggregates of Aβ in mice and hinders their growth into large plaques (Jan 2019 news).

More sTREM2, Less Amyloid. In presymptomatic ADAD mutation carriers (blue), more rapid rise in CSF sTREM2 correlated with slower fall of CSF Aβ42 (left). In symptomatic carriers (red) who already have low CSF Aβ42, this relationship was weaker. For PiB PET the correlations were reversed (right). Symptomatic carriers (red) who accrued sTREM2 most quickly accumulated amyloid plaques more slowly (right), while in presymptomatic carriers (blue), who had less amyloid, this relationship was weak. [Courtesy of Morenas-Rodríguez et al., Lancet Neurology, 2022.]

What about Other Markers?
Part of the appeal of the DIAN dataset is the comprehensive nature of biomarker measurement, so the scientists were able to ask how sTREM2 relates to tau. Changes in CSF sTREM2 did not track with baseline or change in CSF t-tau or p-tau181. However, a relationship did emerge after factoring in amyloid load. Then, faster sTREM2 rise correlated with slower rise in p-tau181 at the presymptomatic stage. The authors believe that when microglia most actively protect against amyloid, they also prevent downstream pathology of tau.

As for structural brain changes, hippocampal tissue shrank the least when baseline sTREM2 was highest. However, atrophy in this region did not correspond with sTREM2 change over time. In contrast, cortical thinning in the precuneus slowed when sTREM2 ticked up quickly in presymptomatic participants. A similar trend was seen in people who had symptoms (see image below). “The precuneus is where amyloid accumulates first, so this sTREM2/thinning association fits very well,” Morenas-Rodríguez told Alzforum.

More sTREM2, Less Atrophy. In presymptomatic ADAD mutation carriers (blue), cortical shrinkage crawled to almost a stop as sTREM2 levels rose. In symptomatic carriers (red) this relationship was weaker. [Courtesy of Morenas-Rodríguez et al., Lancet Neurology, 2022.]

Lastly, the scientists measured whether the rate of cognitive decline also correlated to sTREM2. In presymptomatic carriers, those whose sTREM2 rose fastest declined the least on DIAN cognitive composite, which includes the DIAN word list test, the Mini-Mental State Exam, a logical memory delayed-recall task, and a digit symbol coding test. In people who already had symptoms, sTREM2 trajectory and cognition no longer correlated.

sTREM2 and Cognition. In the years prior to symptoms, an ADAD mutation carrier's level of CSF sTREM2 can slow his or her slide toward dementia (blue). Once the symptomatic stage has been reached (red), this is no longer the case. [Courtesy of Morenas-Rodríguez et al., Lancet Neurology, 2022.]

All told, presymptomatic FAD mutation carriers had slower plaque deposition, cortical shrinkage, and cognitive decline if their CSF sTREM2 climbed quickly. This agrees with the idea that TREM2 peaks during prodromal or mild AD and slows plaque growth early in the disease, but not later (Mar 2016 news; Jan 2016 news; Apr 2020 conference news).

It also implies that person-to-person variation in the vigor of one's early microglial response to amyloid deposition may account for different rates of disease progression. This may help explain variation in disease onset of autosomal-dominant AD, but also play a role in the much more common late-onset AD. Clinical trials have struggled with the fact that some people progress rapidly while others hold relatively steady for years, complicating group-based outcome measures.

These sTREM2 changes early in the disease trajectory add nuance to a complex picture of microglial biology. Researchers are debating whether drugs should bump up TREM2 expression or tone it down (Jun 2020 news; Jul 2021 news). Haass believes the new findings support the idea of starting microglial-modulating treatment, including TREM2 immunotherapy, early in the disease trajectory.

Antibodies that activate TREM2 are in early clinical development (May 2019 conference news). Alector’s AL002 was deemed safe in a Phase 1 study of 56 healthy older adults, and a Phase 2 trial is testing monthly infusions in 265 people with early AD for 48 to 96 weeks (Jun 2020 news). A different Alector antibody, AL003, suppresses CD33, which diminishes TREM2 signaling. AL003 in May 2021 finished a Phase 1 study in 42 healthy adults and 12 with mild to moderate AD, but results are unpublished.

“Further investigation on the relationship and regulation of TREM2 signaling, sTREM2, and microglia activation in the context of Aβ should be conducted to guide the mechanism-based design of AD clinical trials targeting TREM2 or sTREM2,” Bu and Zhao wrote.—Chelsea Weidman Burke

Comments

  1. TREM2 is a cell surface receptor of the immunoglobulin superfamily that is expressed exclusively in the myeloid lineage cells, particularly microglia in the central nervous system. Engagement of TREM2 by ligands, such as lipoproteins or Aβ, initiates signaling through its adaptors DAP12 or DAP10 to trigger downstream signaling pathways. Importantly, TREM2 signaling is required for the sequential activation of microglia from a homeostatic to a disease-associated state in response to Aβ plaques. TREM2 also undergoes regulated proteolytic cleavage by ADAM10 and ADAM17 at the H157–S158 peptide bond, generating soluble TREM2 (sTREM2). We have reported previously that sTREM2 plays important roles in enhancing microglial functions such as proliferation, migration, survival, clustering around amyloid plaques, and the uptake and degradation of Aβ (Zhong et al., 2019), suggesting a beneficial role of sTREM2 against Aβ pathology.

    In this paper, Christian Haass and colleagues performed longitudinal analysis of CSF sTREM2 among patients from the Dominantly Inherited Alzheimer Network (DIAN) observational study, which includes presymptomatic and symptomatic AD patients. They found that the increase in CSF sTREM2 is correlated with diminished brain Aβ deposition, decreased cortical shrinkage in the precuneus, and diminished cognitive decline, whereas slower sTREM2 increase corelates with enhanced CSF p-tau and a boost in brain Aβ deposition.

    These findings support a critical role of TREM2-mediated microglial response during AD, suggesting that sTREM2 can be a key biomarker for predicting AD-related outcomes in the early stages of the disease.

    Although sTREM2 is abundant in CSF and its level negatively correlates with Aβ deposition, it is still unclear how CSF sTREM2 relates to TREM2 signaling and microglial functions and phenotypes in the brain. Could shedding of TREM2 to generate sTREM2 be a regulated response to pathogenic stimuli, allowing sTREM2 to work in harmony with cell surface TREM2 to provide stronger protection against Aβ pathology and related toxicity?

    In a Phase I study of the TREM2 agonist antibody AL002 (Wang et al., 2020), a dose-dependent decrease in CSF sTREM2 from baseline within two days was observed. This indicates that boosting TREM2 signaling may reduce the proteolytic shedding of TREM2. As such, whether a reduction of sTREM2 in the brain contributes to the beneficial effect of this TREM2 antibody remains unclear.

    Further investigation on the relationships and regulation among TREM2 signaling, sTREM2, and microglia activation in the context of Aβ should be conducted to guide mechanism-based design of AD clinical trials targeting TREM2 or sTREM2. Additionally, as single nuclei RNA-Seq of selected brains from these DIAN studies has been obtained (Brase et al., 2021), it will be very interesting and informative to analyze the correlation between CSF sTREM2 and the microglial transcriptional profiles in the same brains, to further understand the link between CSF sTREM2 as biomarker and the microglia function.

    References:

    Zhong L, Xu Y, Zhuo R, Wang T, Wang K, Huang R, Wang D, Gao Y, Zhu Y, Sheng X, Chen K, Wang N, Zhu L, Can D, Marten Y, Shinohara M, Liu CC, Du D, Sun H, Wen L, Xu H, Bu G, Chen XF. Soluble TREM2 ameliorates pathological phenotypes by modulating microglial functions in an Alzheimer's disease model. Nat Commun. 2019 Mar 25;10(1):1365. PubMed.

    Wang S, Mustafa M, Yuede CM, Salazar SV, Kong P, Long H, Ward M, Siddiqui O, Paul R, Gilfillan S, Ibrahim A, Rhinn H, Tassi I, Rosenthal A, Schwabe T, Colonna M. Anti-human TREM2 induces microglia proliferation and reduces pathology in an Alzheimer's disease model. J Exp Med. 2020 Sep 7;217(9) PubMed.

    Brase L, You SF, del Aguila J, Dai Y, Novotny BC, Soriano-Tarraga C, Dykstra T, Fernandez MV, Budde JP, Bergmann K, Morris JC, Bateman RJ, Perrin RJ, McDade E, Xiong C, Goate A, Farlow M, Chhatwal JP, Schofield P, Chui H, Dominantly Inherited Alzheimer Network (DIAN), Sutherland GT, Kipnis J, Karch CM, Benitez BA, Cruchaga C, Harari O. A landscape of the genetic and cellular heterogeneity in Alzheimer disease. medRxiv 2021.11.30. medRxiv

    View all comments by Guojun Bu View all comments by Na Zhao

  2. In this fascinating work from the Haass group, a longitudinal analysis links higher levels of sTREM2 in CSF to apparent slowing of neurodegeneration. This mirrors our own work in amyotrophic lateral sclerosis, where we showed that higher levels of CSF sTREM2 in late disease correlated with prolonged survival (Cooper-Knock et al., 2017). Our work was discussed in a previous Alzforum news piece.

    This supports the idea that a TREM2-mediated microglial response is protective, and that sTREM2 in CSF is a potential biomarker, for multiple neurodegenerative diseases.

    References:

    Cooper-Knock J, Green C, Altschuler G, Wei W, Bury JJ, Heath PR, Wyles M, Gelsthorpe C, Highley JR, Lorente-Pons A, Beck T, Doyle K, Otero K, Traynor B, Kirby J, Shaw PJ, Hide W. A data-driven approach links microglia to pathology and prognosis in amyotrophic lateral sclerosis. Acta Neuropathol Commun. 2017 Mar 16;5(1):23. PubMed.

    View all comments by Johnathan Cooper-Knock View all comments by Winston Hide

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References

Mutation Interactive Images Citations

  1. TREM2

News Citations

  1. Enter the New Alzheimer’s Gene: TREM2 Variant Triples Risk
  2. Does Soluble TREM2 Rile Up Microglia?
  3. Cut Loose, Soluble TREM2 Beckons Microglia to Mop Up Plaques
  4. In Alzheimer’s, More TREM2 Is Good for You
  5. Refining Models of Amyloid Accumulation in Alzheimer’s Disease
  6. Does Alzheimer’s Start in the Heart of the Cholinergic System?
  7. Paper Alert: Slotting TREM2 into Alzheimer’s Pathogenesis
  8. Without TREM2, Plaques Grow Fast in Mice, Have Less ApoE
  9. Microglial Marker TREM2 Rises in Early Alzheimer’s and on Western Diet
  10. TREM2 Goes Up in Spinal Fluid in Early Alzheimer’s
  11. With TREM2, Timing Is Everything
  12. Boost or Block TREM2? Either Way, Therapy May Need Careful Timing
  13. New Ways to Target TREM2 Beg the Question: Up or Down?
  14. Antibodies Against Microglial Receptors TREM2 and CD33 Head to Trials
  15. In Mice, Activating TREM2 Tempers Plaque Toxicity, not Load

Therapeutics Citations

  1. AL002
  2. AL003

Paper Citations

  1. Ulland TK, Colonna M. TREM2 - a key player in microglial biology and Alzheimer disease. Nat Rev Neurol. 2018 Nov;14(11):667-675. PubMed.
  2. 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.

External Citations

  1. Phase 1
  2. Phase 2

Further Reading

Papers

  1. Bartl M, Dakna M, Galasko D, Hutten SJ, Foroud T, Quan M, Marek K, Siderowf A, Franz J, Trenkwalder C, Mollenhauer B, Parkinson’s Progression Markers Initiative. Biomarkers of neurodegeneration and glial activation validated in Alzheimer's disease assessed in longitudinal cerebrospinal fluid samples of Parkinson's disease. PLoS One. 2021;16(10):e0257372. Epub 2021 Oct 7 PubMed.

Primary Papers

  1. Morenas-Rodríguez E, Li Y, Nuscher B, Franzmeier N, Xiong C, Suárez-Calvet M, Fagan AM, Schultz S, Gordon BA, Benzinger TL, Hassenstab J, McDade E, Feederle R, Karch CM, Schlepckow K, Morris JC, Kleinberger G, Nellgard B, Vöglein J, Blennow K, Zetterberg H, Ewers M, Jucker M, Levin J, Bateman RJ, Haass C, Dominantly Inherited Alzheimer Network. Soluble TREM2 in CSF and its association with other biomarkers and cognition in autosomal-dominant Alzheimer's disease: a longitudinal observational study. Lancet Neurol. 2022 Apr;21(4):329-341. PubMed.

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