Schindler SE, Cruchaga C, Joseph A, McCue L, Farias FH, Wilkins CH, Deming Y, Henson RL, Mikesell RJ, Piccio L, Llibre-Guerra JJ, Moulder KL, Fagan AM, Ances BM, Benzinger TL, Xiong C, Holtzman DM, Morris JC. African Americans Have Differences in CSF Soluble TREM2 and Associated Genetic Variants. Neurol Genet. 2021 Apr;7(2):e571. Epub 2021 Mar 4 PubMed. Correction.

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  1. The work by Schindler and colleagues at the Knight ADRC adds to the growing number of studies showing CSF biomarker levels to differ between racial groups. Such studies—including our own—have been criticized in the past for highlighting how a social construction, i.e., race, can result in biological outcomes. The Knight ADRC investigators incorporated both self-reported race and genetic ancestry in their study, and found extremely high concordance between self-reported African American race and African genetic ancestry. This high level of concordance prevented a statistical determination of which was most strongly associated with lower CSF sTREM2 levels, but they further investigated the relationship between TREM2 genotype and sTREM2 levels. They found that more coding TREM2 variants in African Americans linked to lower sTREM2 levels, and less often than another variant associated with higher sTREM2 levels.

    I believe this study contributes to our understanding of AD disparities in three ways. First, the imbalance between African Americans and whites in gene variants related to Alzheimer’s disease risk supports the notion that genetic ancestry may selectively influence risk-conferring or protective pathways. If therapeutic strategies targeting TREM2 are to be tested in the future, sufficient numbers of African Americans must be included to adequately assess the treatment’s impact in this subgroup. Second, some CSF biomarkers and their associated genes are tightly connected, and we have seen a similar relationship between APOE genotype and CSF ApoE protein levels.

    Changes in these CSF biomarker levels will need to be adjusted for genotypes, which is not often done. Finally, it is not always straightforward to disentangle the social aspects of race from genetic ancestry using traditional statistical modeling, and more innovative methods are necessary to better understand Alzheimer’s disease risks from biological and sociological factors.

    View all comments by William Hu

  2. This Schindler et al. paper is an important and welcome contribution to the field for two reasons.

    First, it highlights the importance of understanding how genetic variations that influence risk for AD differ in African Americans as compared to non-Hispanic whites. A growing literature suggests that two other genetic risk factors for AD, APOE and ABAC7, function differently in those of African descent, both in terms of their direct linkage to AD as well as in their interaction with behavioral and health factors (for review, see our paper, Berg et al., 2019). The Schindler et al. paper, however, is the first to show that variations in TREM2 may also differ in African Americans. Based on their findings, we plan to add assessing for variations in TREM2 to our own ongoing studies of Pathways to Healthy Aging in African Americans in Newark, N.J. 

    Second, this paper further illuminates the intriguing, but still not fully understood, role of immune system dysfunction in AD. Although there is increasing evidence that AD involves disruption to the immune system, we do not sufficiently understand the degree to which AD pathology and risk are related to immune system dysfunction. The Schindler et al. study will encourage further work in this area, especially with regard to elucidating links between TREM2, immune health, cognitive and brain health, and AD risk. 

    References:

    Berg CN, Sinha N, Gluck MA. The Effects of APOE and ABCA7 on Cognitive Function and Alzheimer's Disease Risk in African Americans: A Focused Mini Review. Front Hum Neurosci. 2019;13:387. Epub 2019 Nov 5 PubMed.

    View all comments by Mark Gluck

  3. Alzheimer’s disease (AD) was reported to be ~14 percent to 100 percent more prevalent among African Americans (AAs) compared to non-Hispanic whites (NHWs). The increased AD risk in AA is partially attributed to high cholesterol, high blood pressure, Type 2 diabetes, and vascular dementia, which are present disproportionately in AA, and constitute significant risk factors for AD (African-Americans and Alzheimer's Disease: The Silent Epidemic). 

    Here, Schindler et al. provide original mechanistic and genetic insights into the higher prevalence of AD among AAs, and open the perspective of targeted therapeutics for AAs suffering from the disease.

    By studying two large cohorts of mixed ethnicity, Schindler et al. observed that cerebrospinal fluid (CSF) levels of soluble TREM2 (sTREM2) are almost 30 percent lower in AAs compared to NHWs.

    CSF sTREM2 is a highly relevant AD biomarker, because lower levels were previously linked to an increase in AD risk, a decrease in the age of AD onset, rapid loss of cortical and hippocampal volume in AD subjects, lower survival in symptomatic AD, higher rate of conversion from MCI to AD, and faster disease progression (Ewers et al., 2019; Gispert et al., 2016). 

    Schindler et al. also noted that rare TREM2 coding genetic variants and an MS4A4A noncoding genetic variant known to be associated with lower CSF sTREM2 levels are respectively five- and two- to fourfold more frequent in AAs, and showed that such higher prevalence of those variants in AA may explain the lower CSF sTREM2 levels observed in this population.

    TREM2 and MS4A4A are key risk genes for AD that regulate the survival, proliferation, migration, and functionality of microglia, the disease-fighting, innate immune cells in the AD brain (Ulland and Colonna, 2018; Deming et al., 2019). The levels of sTREM2 are believed to reflect TREM2 and/or MS4A4A activity in microglia (Ewers et al., 2019; Deming et al., 2019). 

    Low levels of sTREM2 in the CSF of AA thus likely reflect a decreased functionality of the disease-fighting microglia. Fewer and/or disabled microglia are in turn less likely to counteract multiple AD pathogenic events, including the accumulation of Aβ and Tau, neuronal dystrophy, synaptic loss, and micro-hemorrhages.

    The findings of likely defects in TREM2 and MS4A4A functions in AA, as manifested by the low levels of sTREM2, not only provide a possible mechanistic explanation for the prevalence of AD in AAs, but also suggest that AAs may respond differently, and possibly more robustly, to both TREM2 activation therapy and to MS4A4A therapies that would increase the level of sTREM2. The findings may thus open a new and exciting chapter in precision medicine for AD that is based on a deep understanding of human genetics and disease mechanisms.

    A TREM2-activating investigational therapeutic is currently in a Phase 2 clinical trial for AD (INVOKE-2), and an MS4A4A investigational therapeutic is advancing toward the clinic in AD. Both investigational therapeutics are sponsored by Alector Inc. as part of the company’s broad immuno-neurology platform.

    For both our TREM2 and MS4A (did not start yet) trials, we intend to retrospectively analyze for the presence of the TREM2 and MS4A4A mutations and stratify mutation carriers as well as the levels of sTrem2 at baseline to the magnitude of drug efficacy. This will help with the design and patient stratification of our Phase 3. 

    The participation of AA in AD trials was historically low (Donanemab Phase 2: 3 percent; Aducamab Emerge/Engage: ~5 percent, they only report white and Asian; Solanezumab: ~1.7 percent), but Glenn Morrison, VP, our lead clinician for TREM2, is looking for ways to change that with our Phase 2 Trem2 (INVOKE-2) trial by opening additional clinical sites in places such as  Atlanta and Baltimore, to make access easier.

    References:

    Ewers M, Franzmeier N, Suárez-Calvet M, Morenas-Rodriguez E, Caballero MA, Kleinberger G, Piccio L, Cruchaga C, Deming Y, Dichgans M, Trojanowski JQ, Shaw LM, Weiner MW, Haass C, Alzheimer’s Disease Neuroimaging Initiative. Increased soluble TREM2 in cerebrospinal fluid is associated with reduced cognitive and clinical decline in Alzheimer's disease. Sci Transl Med. 2019 Aug 28;11(507) PubMed.

    Gispert JD, Suárez-Calvet M, Monté GC, Tucholka A, Falcon C, Rojas S, Rami L, Sánchez-Valle R, Lladó A, Kleinberger G, Haass C, Molinuevo JL. Cerebrospinal fluid sTREM2 levels are associated with gray matter volume increases and reduced diffusivity in early Alzheimer's disease. Alzheimers Dement. 2016 Dec;12(12):1259-1272. Epub 2016 Jul 14 PubMed.

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

    View all comments by Hervé Rhinn

  4. Differences in the levels of CSF Aβ and tau biomarkers in African Americans vs. non-Hispanic whites have been previously reported. This article from Schindler et al. provides evidence that CSF sTREM2 levels are lower in African Americans compared to non-Hispanic whites, and that this may be due to a higher frequency in African Americans of TREM2 variants that are associated with lower CSF sTREM2.

    Taken together these findings underscore the importance of studying cohorts from diverse populations to ensure that effective therapies are developed by taking these differences into consideration.

    In addition, this article is very encouraging for those of us conducting research focused on health disparities in underrepresented groups, as it demonstrates that, through carefully designed studies, it is possible to obtain valuable insight into the pathophysiology of disease, despite the challenge of having access to relatively smaller sample sizes.

    View all comments by Minerva Carrasquillo

  5. Schindler et al. compared the levels of CSF soluble TREM2 (sTREM2) between African Americans (AA) and non-Hispanic whites (NHW), based on self-reported race and ethnicity. Interestingly, they found that CSF sTREM2 was lower in AA compared to NHW. This difference was probably explained by the fact that coding TREM2 variants associated with lower CSF sTREM2 (Piccio et al., 2016; Suárez-Calvet et al., 2019) were more frequent in AA. On the contrary, AA were less likely to carry the rs1582763 minor allele (A), located near MS4A4A, which is associated with higher CSF sTREM2 (Deming et al., 2019). 

    CSF sTREM2 reflects the amount of TREM2 competent signaling on the surface of microglia (Kleinberger et al., 2014) and higher CSF sTREM2 concentrations are associated with reduced cognitive decline in patients with Alzheimer’s disease (Ewers et al., 2019). The heterogeneity in CSF sTREM2 levels (and TREM2 function and microglial activity) may contribute to the clinical heterogeneity in Alzheimer’s disease, irrespective of self-identified race and ethnicity. Therapies that target TREM2 are currently being developed and it will be important to assess whether these therapies have a different effect in participants with a lower TREM2 function.

    This study also reminds us about the importance of investigating the associations between biomarkers and race, and that race is a social construct with profound effects on health, including Alzheimer’s disease. Although some genetic variants are more frequently found in certain self-identified racial and ethnic groups, there are non-biological factors (e.g., social, economic, environmental) that also need to be considered. We must strengthen diversity in Alzheimer’s observational studies and clinical trials. The racial diversity of the Knight ADRC cohort can serve as an excellent model for other observational AD cohorts.

    References:

    Deming Y, Filipello F, Cignarella F, Cantoni C, Hsu S, Mikesell R, Li Z, Del-Aguila JL, Dube U, Farias FG, Bradley J, Budde J, Ibanez L, Fernandez MV, Blennow K, Zetterberg H, Heslegrave A, Johansson PM, Svensson J, Nellgård B, Lleo A, Alcolea D, Clarimon J, Rami L, Molinuevo JL, Suárez-Calvet M, Morenas-Rodríguez E, Kleinberger G, Ewers M, Harari O, Haass C, Brett TJ, Benitez BA, Karch CM, Piccio L, Cruchaga C. The MS4A gene cluster is a key modulator of soluble TREM2 and Alzheimer's disease risk. Sci Transl Med. 2019 Aug 14;11(505) PubMed.

    Ewers M, Franzmeier N, Suárez-Calvet M, Morenas-Rodriguez E, Caballero MA, Kleinberger G, Piccio L, Cruchaga C, Deming Y, Dichgans M, Trojanowski JQ, Shaw LM, Weiner MW, Haass C, Alzheimer’s Disease Neuroimaging Initiative. Increased soluble TREM2 in cerebrospinal fluid is associated with reduced cognitive and clinical decline in Alzheimer's disease. Sci Transl Med. 2019 Aug 28;11(507) PubMed.

    Kleinberger G, Yamanishi Y, Suárez-Calvet M, Czirr E, Lohmann E, Cuyvers E, Struyfs H, Pettkus N, Wenninger-Weinzierl A, Mazaheri F, Tahirovic S, Lleó A, Alcolea D, Fortea J, Willem M, Lammich S, Molinuevo JL, Sánchez-Valle R, Antonell A, Ramirez A, Heneka MT, Sleegers K, van der Zee J, Martin JJ, Engelborghs S, Demirtas-Tatlidede A, Zetterberg H, Van Broeckhoven C, Gurvit H, Wyss-Coray T, Hardy J, Colonna M, Haass C. TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis. Sci Transl Med. 2014 Jul 2;6(243):243ra86. PubMed.

    Piccio L, Deming Y, Del-Águila JL, Ghezzi L, Holtzman DM, Fagan AM, Fenoglio C, Galimberti D, Borroni B, Cruchaga C. Cerebrospinal fluid soluble TREM2 is higher in Alzheimer disease and associated with mutation status. Acta Neuropathol. 2016 Jun;131(6):925-33. Epub 2016 Jan 11 PubMed.

    Suárez-Calvet M, Morenas-Rodríguez E, Kleinberger G, Schlepckow K, Araque Caballero MÁ, Franzmeier N, Capell A, Fellerer K, Nuscher B, Eren E, Levin J, Deming Y, Piccio L, Karch CM, Cruchaga C, Shaw LM, Trojanowski JQ, Weiner M, Ewers M, Haass C, Alzheimer’s Disease Neuroimaging Initiative. Early increase of CSF sTREM2 in Alzheimer's disease is associated with tau related-neurodegeneration but not with amyloid-β pathology. Mol Neurodegener. 2019 Jan 10;14(1):1. PubMed.

    View all comments by Alberto Lleó

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  1. TREM2 Variants and CSF sTREM2 Levels Differ by Race