Neurobiology of Aging 103 (2021) 158.e158–158.e5 Contents lists available at ScienceDirect Neurobiology of Aging journal homepage: www.elsevier.com/locate/neuaging.org Brief communication CSF sTREM2 is elevated in a subset in GRN-related frontotemporal dementia Emma L. van der Ende a, Estrella Morenas-Rodriguez b,c, Corey McMillan d, Murray Grossman d, David Irwin d, Raquel Sanchez-Valle e, Caroline Graff f,g, Rik Vandenberghe h, Yolande A.L. Pijnenburg i, Robert Laforce j, Isabelle Le Ber k,l, Alberto Lleo m, Christian Haass b,c,n, Marc Suarez-Calvet b, John C. van Swieten a, Harro Seelaar a,∗ a Alzheimer Center Rotterdam and Dept. of Neurology, Erasmus University Medical Center, Rotterdam, the Netherlands b German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany c Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximillians-Universität München, Munich, Germany d Dept. of Neurology, Penn Frontotemporal Degeneration Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA e Alzheimer’s Disease and Other Cognitive Disorders Unit, Hospital Clinic de Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain f Karolinska Institutet, Dept. NVS, Division of Neurogeriatrics, Bioclinicum, Stockholm, Sweden g Unit of Hereditary Dementia, Theme Aging, Karolinska University Hospital-Solna, Stockholm, Sweden h Laboratory for Cognitive Neurology, Department of Neurosciences, Leuven Brain Institute, Leuven, Belgium i Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands j Clinique Interdisciplinaire de Mémoire du CHU de Québec, Département des Sciences Neurologiques, Université Laval, Québec, Canada k APHP, Reference Centre for Rare or Early Onset Dementias, IM2A, Department of Neurology, Hôpital La Pitié-Salpêtrière, Paris, France l Sorbonne Université, Paris Brain Institute, Institut du Cerveau, ICM, Inserm U1127, CNRS UMR 7225, APHP, Hôpital Pitié-Salpêtrière, Paris, France m Neurology Department, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain n Munich Cluster for Systems Neurology (SyNergy), Munich, Germany a r t i c l e i n f o a b s t r a c t Article history: Excessive microglial activation might be a central pathological process in GRN-related frontotemporal Received 18 December 2020 dementia (FTD-GRN). We measured soluble triggering receptor expressed on myeloid cells 2 (sTREM2), Accepted 27 February 2021 which is shed from disease-associated microglia following cleavage of TREM2, in cerebrospinal fluid of Available online 4 March 2021 34 presymptomatic and 35 symptomatic GRN mutation carriers, 6 presymptomatic and 32 symptomatic Keywords: C9orf72 mutation carriers and 67 healthy noncarriers by ELISA. Although no group differences in sTREM2 Frontotemporal dementia levels were observed (GRN: symptomatic (median 5.2 ng/mL, interquartile range [3.9–9.2]) vs. presymp- Biomarker tomatic (4.3 ng/mL [2.6–6.1]) vs. noncarriers (4.2 ng/mL [2.6–5.5]): p = 0.059; C9orf72: symptomatic (4.3 Cerebrospinal fluid [2.9–7.0]) vs. presymptomatic (3.2 [2.2–4.2]) vs. noncarriers: p = 0.294), high levels were seen in a sub- Microglia set of GRN, but not C9orf72, mutation carriers, which might reflect differential TREM2-related microglial sTREM2 activation. Interestingly, 2 presymptomatic carriers with low sTREM2 levels developed symptoms after 1 year, whereas 2 with high levels became symptomatic after >5 years. While sTREM2 is not a promis- ing diagnostic biomarker for FTD-GRN or FTD-C9orf72, further research might elucidate its potential to monitor microglial activity and predict disease progression. © 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) 1. Introduction Although the exact mechanisms by which GRN mutations lead to FTD are poorly understood, accumulating evidence Frontotemporal dementia (FTD) is frequently caused by suggests a role for dysregulation of microglial homeostasis autosomal dominant genetic mutations in granulin (GRN). (Bright et al., 2019; Chitramuthu et al., 2017). GRN−/− mice display excessive microglial activation with subsequent re- lease of proinflammatory factors and neuronal loss (Lui et al., ∗ Corresponding author at: Erasmus Medical Center Rotterdam, Department of 2016; Martens et al., 2012; Tanaka et al., 2013), and sup- Neurology, PO Box 2040, 30 0 0 CA Rotterdam, the Netherlands. E-mail address: h.seelaar@erasmusmc.nl (H. Seelaar). pression of genes characteristic for homeostatic microglia 0197-4580/$ – see front matter © 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) https://doi.org/10.1016/j.neurobiolaging.2021.02.024 158.e2 E.L. van der Ende, E. Morenas-Rodriguez, C. McMillan et al. / Neurobiology of Aging 103 (2021) 158.e158–158.e5 (Götzl et al., 2019), whereas GRN overexpression reduces mi- croglial recruitment following nerve injury (Altmann et al., 2016). Biomarkers that accurately reflect microglial activity in vivo are currently lacking and might provide more insight into disease pathogenesis, as well as measure treatment effect in clinical trials aiming to restore immune dysregulation. Triggering receptor expressed on myeloid cells 2 (TREM2) is a membrane-bound receptor expressed by microglia which regulates the transition from homeostatic to disease-associated microglia (Keren-Shaul et al., 2017; Kleinberger et al., 2014; Schlepckow et al., 2017). Cleavage of its extracellular domain pro- duces a soluble fragment, sTREM2, which is measurable in cere- brospinal fluid (CSF) (Piccio et al., 2008). CSF sTREM2 levels likely reflect cerebral TREM2 expression and TREM2-triggered microglial activity (Ewers et al., 2020; Ewers et al., 2019; Keren-Shaul et al., 2017; Suárez-Calvet et al., 2019). Elevated sTREM2 levels have been observed mainly in the prodromal stages of Alzheimer’s disease (AD) (Liu et al., 2018; Ma et al., 2020; Suárez-Calvet et al., 2019). Reports of sTREM2 levels in FTD are inconsistent (Heslegrave et al., 2016; Kleinberger et al., 2014; Piccio et al., 2016), but high lev- els have been reported in a few FTD-GRN cases (Woollacott et al., 2018). Fig. 1. sTREM2 levels in presymptomatic and symptomatic mutation carriers and In the present study, we measured CSF sTREM2 in an interna- noncarriers. Error bars represent median ± interquartile range. Red and blue tri- tional cohort of presymptomatic and symptomatic GRN mutation angles indicate subjects with isolated or concomitant amyotrophic lateral sclero- carriers and noncarriers to determine its value as a biomarker in sis, respectively. Green squares indicate subjects who developed symptoms after CSF collection; subject 1 developed FTD with corticobasal syndrome after 7 years; FTD-GRN. To study potential gene-specificity, we additionally mea- subject 2 suffered cognitive decline after 5 years; subject 3 developed memory- sured sTREM2 in carriers of a C9orf72 repeat expansion, the most predominant FTD after 1.2 years; subject 4 developed behavioral variant FTD after common genetic cause of FTD. 1 year. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.) 2. Methods analyses. Bonferroni correction for multiple testing was applied Subjects were recruited from 8 research centers in Europe and where appropriate. the USA through familial FTD studies. We included 34 presymp- tomatic and 35 symptomatic GRN mutation carriers, 6 presymp- tomatic and 32 symptomatic C9orf72 mutation carriers, and 67 3. Results healthy noncarriers from GRN or C9orf72 mutation families. Sub- jects were classified as symptomatic if they met international 3.1. Demographics consensus criteria for behavioral variant FTD, primary progressive aphasia or amyotrophic lateral sclerosis (ALS) (Brooks et al., 20 0 0; Subject characteristics are shown in Table 1. In both genetic Gorno-Tempini et al., 2011; Rascovsky et al., 2011). Symptom onset groups (GRN and C9orf72), symptomatic mutation carriers were and disease duration were based on caregivers’ estimations of the older at CSF collection than presymptomatic carriers and noncar- emergence of first symptoms. Subjects had no known neurological riers (p < 0.001). sTREM2 levels were positively correlated with or immunological co-morbidities. Global cognitive functioning was age across the entire cohort (rs = 0.271, p < 0.001) and in non- scored using the Mini Mental State Examination (MMSE). carriers alone (rs = 0.247, p = 0.044) but not in symptomatic GRN CSF was collected in polypropylene tubes, centrifuged and or C9orf72 mutation carriers (GRN: rs = 0.020, p = 0.911; C9orf72: stored at -80°C within 2 hours after withdrawal. sTREM2 lev- rs = 0.206, p = 0.258) (supplementary Fig. 1). No differences were els were measured using an ELISA as previously described found in sTREM2 levels between males and females (p = 0.470). (Kleinberger et al., 2014). Samples were randomly distributed across plates and measured in duplicate; the median coefficient of 3.2. sTREM2 levels in GRN mutation carriers variation (CV) of duplicate samples was 3.6%. One sample with a duplicate CV > 15% was excluded. Samples were measured in 2 No significant differences in sTREM2 levels were seen in symp- batches (median between-batch CV 4%) in the German Center for tomatic GRN mutation carriers (median 5.2 ng/mL, interquartile Neurodegenerative Diseases (DZNE), Munich, Germany. Laboratory range [3.9–9.2]) compared to presymptomatic carriers (4.3 ng/mL technicians were blinded to all clinical and genetic information. [2.6–6.1]) and noncarriers (4.2 ng/mL [2.6–5.5]) (p = 0.059 by Statistical analyses were performed in IBM SPSS Statistics 24 Kruskal-Wallis test; p = 0.513 by ANCOVA) (Fig. 1). sTREM2 lev- applying a significance level of 0.05 (2-sided). Demographic vari- els did not correlate with disease duration (rs = 0.210, p = 0.226) ables were compared using Kruskal-Wallis tests for numerical vari- or MMSE score (rs = -0.364, p = 0.057, n = 28) among symp- ables and χ 2 tests for categorical variables. Group comparisons tomatic carriers. Furthermore, no significant differences in sTREM2 of sTREM2 levels were performed by Mann Whitney U tests or levels were seen between the various FTD phenotypes (p = 0.830) Kruskal-Wallis tests as the data were not normally distributed. Af- (Table 1). ter log-transformation, sTREM2 levels were normally distributed, Three presymptomatic GRN mutation carriers developed FTD re- as confirmed by the Shapiro-Wilk test, and group comparisons spectively 1 year, 1.2 years, and 7 years after CSF collection (Fig. 1). were additionally performed by ANCOVA with correction for age, In addition, one presymptomatic GRN carrier developed mild be- gender and assay batch. Spearman’s rho was used for correlative havioral abnormalities and cognitive deficits 5 years after CSF col- E.L. van der Ende, E. Morenas-Rodriguez, C. McMillan et al. / Neurobiology of Aging 103 (2021) 158.e158–158.e5 158.e3 Table 1 Subject characteristics. All continuous variables are reported as medians (interquartile range). GRN mutation carriers C9orf72 mutation carriers Noncarriers p Symptomatica Presymptomatic Symptomaticb Presymptomatic N 35 34 32 6 67 - Gender, male (%) 16 (46%) 15 (44%) 18 (56%) 0 (0%) 27 (40%) 0.132c Age at CSF collection, years 61 (57–65) 51 (41–59) 62 (54–67) 34 (26–43) 54 (42–59) <0.001d Disease duration, years 2.0 (1.5–3.1) - 1.9 (0.7–5.1) - - 0.672 MMSE 23 (18–27) 29 (29–30) 26 (22–28) 29 (29–30) 30 (29–30) <0.001d sTREM2 (ng/mL) 5.2 (3.9–9.2) 4.3 (2.6–6.1) 4.3 (2.9–7.0) 3.2 (2.2–4.2) 4.2 (2.6–5.5) 0.090e Abbreviations: CSF, cerebrospinal fluid; MMSE, mini mental state examination. a Phenotypes: behavioral variant FTD (bvFTD) (n = 20), primary progressive aphasia (PPA) (n = 8), dementia not otherwise specified (n = 4), memory-predominant FTD (n = 2), and FTD with corticobasal syndrome (CBS) (n = 1). b Phenotypes: bvFTD (n = 13), PPA (n = 3), FTD with amyotrophic lateral sclerosis (AL S) (n = 9), AL S (n = 5), memory-predominant FTD (n = 1), and FTD with CBS (n = 1). c By χ 2 test. d In both genetic groups, symptomatic mutation carriers were older and had lower MMSE scores than presymptomatic carriers and noncarriers (all comparisons p < 0.001). There were no significant differences in age or MMSE between symptomatic GRN and C9orf72 carriers (by Mann-Whitney U tests). e By Kruskall-Wallis test across all groups. lection, although clinical diagnostic criteria for FTD were not ful- correlation between brain sTREM2 levels and microglial activity filled. on TSPO-PET imaging in mouse models (Brendel et al., 2017). Our Visual inspection of Fig. 1 revealed high sTREM2 levels in 8 findings might therefore reflect a variable degree of microglial in- symptomatic GRN mutation carriers (>10 ng/mL). We did not iden- volvement specifically among GRN mutation carriers. The identifi- tify any association with specific clinical or genetic features in cation of subsets of carriers with more or less microglial activation these subjects (i.e., disease severity or duration, phenotype, age at would be highly valuable for patient stratification in inflammation- symptom onset, genetic mutation) (supplementary Table 1). directed clinical trials. Interestingly, much variability has also been observed for the microglia-derived proteins YKL-40 and chitotriosi- 3.3. sTREM2 levels in C9orf72 mutation carriers dase (CHIT-1) in FTD (Abu-Rumeileh et al., 2019; Oeckl et al., 2019; Woollacott et al., 2020) and future studies that elucidate the rela- No significant differences in sTREM2 levels were seen between tionship between these proteins in FTD-GRN would be of interest. symptomatic (median 4.3 ng/mL [2.9–7.0])) and presymptomatic Three presymptomatic GRN mutation carriers developed FTD (3.2 ng/mL [2.2–4.2]) C9orf72 mutation carriers or noncarriers after CSF collection, and cognitive decline was reported in one. (p = 0.294 by Kruskal-Wallis test; p = 0.433 by ANCOVA) (Fig. 1). Interestingly, 2 of these subjects with very high sTREM2 levels Results were unchanged after exclusion of subjects with isolated only developed symptoms several years after CSF collection, while ALS (n = 4) or FTD with ALS (n = 9). sTREM2 levels did not corre- 2 subjects with low sTREM2 levels declined within 2 years. It is late with disease duration (rs = 0.199, p = 0.275) or MMSE score tempting to speculate that increased microglial activity and ac- (rs = -0.037, p = 0.856, n = 27) among symptomatic carriers. cordingly, high sTREM2 levels, in the late-presymptomatic stage might delay disease onset. In mild cognitive impairment and AD, 3.4. Comparison between GRN and C9orf72 mutation carriers higher CSF sTREM2 levels have been associated with reduced rates of clinical decline and attenuated amyloid-β accumulation on amy- sTREM2 levels did not differ between symptomatic GRN and loid PET imaging, suggesting that TREM2-related processes might C9orf72 mutation carriers (p = 0.196) or between presymptomatic play a protective role (Ewers et al., 2020; Ewers et al., 2019; GRN and C9orf72 mutation carriers (p = 0.288) (both by Mann- Franzmeier et al., 2020). In line with these findings, increased mi- Whitney U tests). croglial activation on TSPO-PET imaging predicted slower disease progression in (prodromal) AD (Hamelin et al., 2018). Such associ- 4. Discussion ations require further study in a much larger cohort of FTD-GRN patients, and could be highly relevant for clinical trial design as The present study revealed no significant differences in CSF they could potentially confound outcome measures, i.e., slow pro- sTREM2 levels between presymptomatic and symptomatic GRN or gression rates could falsely be attributed to the study drug. C9orf72 mutation carriers and noncarriers. Although the lack of The positive correlation between sTREM2 levels and age is group differences and overlap in sTREM2 levels between groups in line with previous studies (Ma et al., 2020; Piccio et al., preclude its value as a diagnostic biomarker, a remarkable degree 2016; Suárez-Calvet et al., 2016; Suárez-Calvet et al., 2019; of variability in sTREM2 levels was observed among GRN mutation Woollacott et al., 2018) and is thought to reflect physiological age- carriers, which warrants further study. related microglial activity (Heneka et al., 2014; Kleinberger et al., Several GRN mutation carriers had very high sTREM2 levels, 2017). Although we cannot rule out that co-existence of other whereas sTREM2 levels among C9orf72 carriers and noncarriers ap- (asymptomatic) neurodegenerative diseases such as AD might peared to be more consistent, which is in line with previous find- have affected sTREM2 levels in our cohort, several studies have ings (Woollacott et al., 2018). These high levels are unlikely to found no correlation between sTREM2 levels and CSF amyloid-β be measurement errors given the favorable assay characteristics (Piccio et al., 2016; Suárez-Calvet et al., 2016; Suárez-Calvet et al., (Kleinberger et al., 2014) and low inter-plate and duplicate CVs. El- 2019); therefore, the effect of concomitant amyloid pathology on evated CSF sTREM2 levels are thought to reflect increased TREM2- sTREM2 levels in the present study is probably limited. dependent microglial activation, a hypothesis that is supported by Neuroinflammation is thought to be the result of a highly com- more convincingly elevated levels in typical neuroinflammatory plex and dynamic interaction between many factors (Bright et al., diseases such as multiple sclerosis (Piccio et al., 2008) and by a 2019). Different disease stages might be characterized by variable 158.e4 E.L. van der Ende, E. Morenas-Rodriguez, C. McMillan et al. / Neurobiology of Aging 103 (2021) 158.e158–158.e5 degrees of microglial activation and subsequent sTREM2 shedding, Altmann, C., Vasic, V., Hardt, S., Heidler, J., Häussler, A., Wittig, I., Schmidt, M.H.H., making group comparisons difficult to interpret. This is exemplified Tegeder, I, 2016. Progranulin promotes peripheral nerve regeneration and rein- nervation: role of notch signaling. Mol Neurodegener 11 (1), 69. by findings of elevated sTREM2 levels in preclinical and early-stage Brendel, M., Kleinberger, G., Probst, F., Jaworska, A., Overhoff, F., Blume, T., Al- AD, followed by slightly attenuated levels in later disease stages bert, N.L., Carlsen, J., Lindner, S., Gildehaus, F.J., Ozmen, L., Suárez-Calvet, M., (Liu et al., 2018; Ma et al., 2020; Suárez-Calvet et al., 2019). Lon- Bartenstein, P., Baumann, K., Ewers, M., Herms, J., Haass, C., Rominger, A., 2017. Increase of TREM2 during aging of an Alzheimer’s disease mouse model is par- gitudinal measurements of sTREM2 in FTD-GRN might provide in- alleled by microglial activation and amyloidosis. Front Aging Neurosci 9, 8. sights into its dynamics over the course of disease as well as de- Bright, F., Werry, E.L., Dobson-Stone, C., Piguet, O., Ittner, L.M., Halliday, G.M., termine its value as a disease monitoring marker. Hodges, J.R., Kiernan, M.C., Loy, C.T., Kassiou, M., Kril, J.J., 2019. Neuroinflam- mation in frontotemporal dementia. Nat Rev Neurol 15 (9), 540–555. A major strength of this study is the inclusion of presymp- Brooks, B.R., Miller, R.G., Swash, M., Munsat, T.L.World Federation of Neurology Re- tomatic and symptomatic carriers of GRN and C9orf72 mutations, search Group on Motor Neuron, D, 20 0 0. El Escorial revisited: revised criteria as opposed to clinically diagnosed FTD patients, enabling investi- for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 1 (5), 293–299. gation of well-defined, pathologically homogeneous cohorts. Lim- Chitramuthu, B.P., Bennett, H.P.J., Bateman, A, 2017. Progranulin: a new avenue to- itations include the relatively small sample size, which may have wards the understanding and treatment of neurodegenerative disease. Brain 140 affected statistical power to detect group differences. Furthermore, (12), 3081–3104. the MMSE score might not be an optimal measure of disease sever- Ewers, M., Biechele, G., Suárez-Calvet, M., Sacher, C., Blume, T., Morenas-Ro- driguez, E., Deming, Y., Piccio, L., Cruchaga, C., Kleinberger, G., Shaw, L., Tro- ity in FTD, however it is a highly standardized instrument which janowski, J.Q., Herms, J., Dichgans, M.Alzheimer’s Disease Neuroimaging, 2020. we feel provides a suitable cognitive screening for this multicen- Higher CSF sTREM2 and microglia activation are associated with slower rates of ter study. Finally, we cannot rule out that some subjects may have beta-amyloid accumulation. EMBO Mol Med 12 (9), e12308. Ewers, M., Franzmeier, N., Suárez-Calvet, M., Morenas-Rodriguez, E., Ca- carried rare genetic variants in TREM2, which are known to affect ballero, M.A.A., Kleinberger, G., Piccio, L., Cruchaga, C., Deming, Y., Dichgans, M., sTREM2 levels (Kleinberger et al., 2014; Suárez-Calvet et al., 2019). Trojanowski, J.Q., Shaw, L.M., Weiner, M.W., Haass, C.Alzheimer’s Disease Neu- In conclusion, while sTREM2 is of limited diagnostic utility in roimaging, I, 2019. Increased soluble TREM2 in cerebrospinal fluid is associated with reduced cognitive and clinical decline in Alzheimer’s disease. Sci Transl FTD-GRN, its further study might help to elucidate the role of neu- Med 11 (507). roinflammation in FTD pathogenesis. It would be interesting to fur- Franzmeier, N., Suárez-Calvet, M., Frontzkowski, L., Moore, A., Hohman, T.J., More- ther characterize the small number of GRN mutation carriers with nas-Rodriguez, E., Nuscher, B., Shaw, L., Trojanowski, J.Q., Dichgans, M., Klein- berger, G., Haass, C., Ewers, M.Alzheimer’s Disease Neuroimaging, I, 2020. very high sTREM2 levels and to investigate sTREM2 dynamics over Higher CSF sTREM2 attenuates ApoE4-related risk for cognitive decline and neu- the course of disease through longitudinal measurements. rodegeneration. Mol Neurodegener 15 (1), 57. Gorno-Tempini, M.L., Hillis, A.E., Weintraub, S., Kertesz, A., Mendez, M., Cappa, S.F., Ogar, J.M., Rohrer, J.D., Black, S., Boeve, B.F., Manes, F., Dronkers, N.F., Vanden- Disclosure statement berghe, R., Rascovsky, K., Patterson, K., Miller, B.L., Knopman, D.S., Hodges, J.R., Mesulam, M.M., Grossman, M., 2011. Classification of primary progressive apha- sia and its variants. Neurology 76 (11), 1006–1014. C.H. collaborates with Denali Therapeutics, participated in one Götzl, J.K., Brendel, M., Werner, G., Parhizkar, S., Sebastian Monasor, L., Klein- advisory board meeting of Biogen and received a speaker hono- berger, G., Colombo, A.V., Deussing, M., Wagner, M., Winkelmann, J., Diehl- Schmid, J., Levin, J., Fellerer, K., Reifschneider, A., Bultmann, S., Bartenstein, P., rarium from Novartis and Roche. C.H. is chief advisor of ISAR Bio- Rominger, A., Tahirovic, S., Smith, S.T., Madore, C., Butovsky, O., Capell, A., science. The remaining authors declare no conflicts of interest. Haass, C., 2019. Opposite microglial activation stages upon loss of PGRN or TREM2 result in reduced cerebral glucose metabolism. EMBO Mol Med 11 (6), e9711. doi:10.15252/emmm.201809711. Acknowledgements Hamelin, L., Lagarde, J., Dorothée, G., Potier, M.C., Corlier, F., Kuhnast, B., Caillé, F., Dubois, B., Fillon, L., Chupin, M., Bottlaender, M., Sarazin, M., 2018. Distinct dynamic profiles of microglial activation are associated with progression of This work was supported by 2 Memorabel grants from Delta- Alzheimer’s disease. Brain 141 (6), 1855–1870. plan Dementie (The Netherlands Organisation for Health Re- Heneka, M.T., Kummer, M.P., Latz, E., 2014. Innate immune activation in neurode- generative disease. Nat Rev Immunol 14 (7), 463–477. search and Development and Alzheimer Nederland; grant num- Heslegrave, A., Heywood, W., Paterson, R., Magdalinou, N., Svensson, J., Johansson, P., bers 7330550813 and 733050103); The Bluefield Project to Cure Ohrfelt, A., Blennow, K., Hardy, J., Schott, J., Mills, K., Zetterberg, H., 2016. In- Frontotemporal Dementia; the Dioraphte Foundation (grant num- creased cerebrospinal fluid soluble TREM2 concentration in Alzheimer’s disease. Mol Neurodegener 11, 3. ber 1402 1300); the European Joint Programme – Neurodegen- Keren-Shaul, H., Spinrad, A., Weiner, A., Matcovitch-Natan, O., Dvir-Szternfeld, R., erative Disease Research (JPND, PreFrontALS); NIH (grant num- Ulland, T.K., David, E., Baruch, K., Lara-Astaiso, D., Toth, B., Itzkovitz, S., ber AG017586); the Wyncote Foundation; Arking Family Fund; Colonna, M., Schwartz, M., Amit, I., 2017. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169 (7), 1276–1290 Invetissements d’avenir (grant number ANR-11-INBS-0011); the e17. Schörling Foundation - Swedish FTD Initiative, Swedish Research Kleinberger, G., Brendel, M., Mracsko, E., Wefers, B., Groeneweg, L., Xiang, X., Council (2015-02926, 2018-02754, and 2019-02248: JPND GENFI- Focke, C., Deußing, M., Suárez-Calvet, M., Mazaheri, F., Parhizkar, S., Pettkus, N., PROX), Swedish Alzheimer’s Foundation, Brain Foundation, De- Wurst, W., Feederle, R., Bartenstein, P., Mueggler, T., Arzberger, T., Knuesel, I., Rominger, A., Haass, C., 2017. The FTD-like syndrome causing TREM2 T66M mensfonden, Stiftelsen för Gamla Tjänarinnor, Stohnes foundation, mutation impairs microglia function, brain perfusion, and glucose metabolism. and Region Stockholm (ALF project). Embo J 36 (13), 1837–1853. 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