TY  - JOUR
AU  - Morenas-Rodríguez, Estrella
AU  - Li, Yan
AU  - Nuscher, Brigitte
AU  - Franzmeier, Nicolai
AU  - Xiong, Chengjie
AU  - Suarez-Calvet, Marc
AU  - Fagan, Anne M
AU  - Schultz, Stephanie
AU  - Gordon, Brian A
AU  - Benzinger, Tammie L S
AU  - Hassenstab, Jason
AU  - McDade, Eric
AU  - Feederle, Regina
AU  - Karch, Celeste M
AU  - Schlepckow, Kai
AU  - Morris, John C
AU  - Kleinberger, Gernot
AU  - Nellgard, Bengt
AU  - Vöglein, Jonathan
AU  - Blennow, Kaj
AU  - Zetterberg, Henrik
AU  - Ewers, Michael
AU  - Jucker, Mathias
AU  - Levin, Johannes
AU  - Bateman, Randall J
AU  - Haass, Christian
AU  - Adams, Sarah
AU  - Allegri, Ricardo
AU  - Araki, Aki
AU  - Barthelemy, Nicolas
AU  - Bechara, Jacob
AU  - Berman, Sarah
AU  - Bodge, Courtney
AU  - Brandon, Susan
AU  - Brooks, William Bill
AU  - Brosch, Jared
AU  - Buck, Jill
AU  - Buckles, Virginia
AU  - Carter, Kathleen
AU  - Cash, Lisa
AU  - Chen, Charlie
AU  - Chhatwal, Jasmeer
AU  - Chrem, Patricio
AU  - Chua, Jasmin
AU  - Chui, Helena
AU  - Cruchaga, Carlos
AU  - Day, Gregory S
AU  - De La Cruz, Chrismary
AU  - Denner, Darcy
AU  - Diffenbacher, Anna
AU  - Dincer, Aylin
AU  - Donahue, Tamara
AU  - Douglas, Jane
AU  - Duong, Duc
AU  - Egido, Noelia
AU  - Esposito, Bianca
AU  - Farlow, Marty
AU  - Feldman, Becca
AU  - Fitzpatrick, Colleen
AU  - Flores, Shaney
AU  - Fox, Nick
AU  - Franklin, Erin
AU  - Friedrichsen, Nelly
AU  - Fujii, Hisako
AU  - Gardener, Samantha
AU  - Ghetti, Bernardino
AU  - Goate, Alison
AU  - Goldberg, Sarah
AU  - Goldman, Jill
AU  - Gonzalez, Alyssa
AU  - Gräber-Sultan, Susanne
AU  - Graff-Radford, Neill
AU  - Graham, Morgan
AU  - Gray, Julia
AU  - Gremminger, Emily
AU  - Grilo, Miguel
AU  - Groves, Alex
AU  - Häsler, Lisa
AU  - Hellm, Cortaiga
AU  - Herries, Elizabeth
AU  - Hoechst-Swisher, Laura
AU  - Hofmann, Anna
AU  - Holtzman, David
AU  - Hornbeck, Russ
AU  - Igor, Yakushev
AU  - Ihara, Ryoko
AU  - Ikeuchi, Takeshi
AU  - Ikonomovic, Snezana
AU  - Ishii, Kenji
AU  - Jack, Clifford
AU  - Jerome, Gina
AU  - Johnson, Erik
AU  - Kaeser, Stephan
AU  - Kasuga, Kensaku
AU  - Keefe, Sarah
AU  - Klunk, William Bill
AU  - Koeppe, Robert
AU  - Koudelis, Deb
AU  - Kuder-Buletta, Elke
AU  - Laske, Christoph
AU  - Levey, Allan
AU  - Lopez, Oscar
AU  - Marsh, Jacob
AU  - Martinez, Rita
AU  - Martins, Ralph
AU  - Mason, Neal Scott
AU  - Masters, Colin
AU  - Mawuenyega, Kwasi
AU  - McCullough, Austin
AU  - Mejia, Arlene
AU  - MountzMD, James
AU  - Mummery, Cath
AU  - Nadkarni, Neelesh
AU  - Nagamatsu, Akemi
AU  - Neimeyer, Katie
AU  - Niimi, Yoshiki
AU  - Noble, James
AU  - Norton, Joanne
AU  - Nuscher, Brigitte
AU  - O'Connor, Antoinette
AU  - Obermüller, Ulricke
AU  - Patira, Riddhi
AU  - Perrin, Richard
AU  - Ping, Lingyan
AU  - Preische, Oliver
AU  - Renton, Alan
AU  - Ringman, John
AU  - Salloway, Stephen
AU  - Schofield, Peter
AU  - Senda, Michio
AU  - Seyfried, Nick
AU  - Shady, Kristine
AU  - Shimada, Hiroyuki
AU  - Sigurdson, Wendy
AU  - Smith, Jennifer
AU  - Smith, Lori
AU  - Snitz, Beth
AU  - Sohrabi, Hamid
AU  - Stephens, Sochenda
AU  - Taddei, Kevin
AU  - Thompson, Sarah
AU  - Wang, Peter
AU  - Wang, Qing
AU  - Weamer, Elise
AU  - Xu, Jinbin
AU  - Xu, Xiong
TI  - Soluble TREM2 in CSF and its association with other biomarkers and cognition in autosomal-dominant Alzheimer's disease: a longitudinal observational study.
JO  - The lancet  / Neurology
VL  - 21
IS  - 4
SN  - 1474-4422
CY  - London
PB  - Lancet Publ. Group
M1  - DZNE-2022-00472
SP  - 329 - 341
PY  - 2022
N1  - (CC BY-NC-ND)
AB  - Therapeutic modulation of TREM2-dependent microglial function might provide an additional strategy to slow the progression of Alzheimer's disease. Although studies in animal models suggest that TREM2 is protective against Alzheimer's pathology, its effect on tau pathology and its potential beneficial role in people with Alzheimer's disease is still unclear. Our aim was to study associations between the dynamics of soluble TREM2, as a biomarker of TREM2 signalling, and amyloid β (Aβ) deposition, tau-related pathology, neuroimaging markers, and cognitive decline, during the progression of autosomal dominant Alzheimer's disease.We did a longitudinal analysis of data from the Dominantly Inherited Alzheimer Network (DIAN) observational study, which includes families with a history of autosomal dominant Alzheimer's disease. Participants aged over 18 years who were enrolled in DIAN between Jan 1, 2009, and July 31, 2019, were categorised as either carriers of pathogenic variants in PSEN1, PSEN2, and APP genes (n=155) or non-carriers (n=93). We measured amounts of cleaved soluble TREM2 using a novel immunoassay in CSF samples obtained every 2 years from participants who were asymptomatic (Clinical Dementia Rating [CDR]=0) and annually for those who were symptomatic (CDR>0). CSF concentrations of Aβ40, Aβ42, total tau (t-tau), and tau phosphorylated on threonine 181 (p-tau) were measured by validated immunoassays. Predefined neuroimaging measurements were total cortical uptake of Pittsburgh compound B PET (PiB-PET), cortical thickness in the precuneus ascertained by MRI, and hippocampal volume determined by MRI. Cognition was measured using a validated cognitive composite (including DIAN word list test, logical memory delayed recall, digit symbol coding test [total score], and minimental status examination). We based our statistical analysis on univariate and bivariate linear mixed effects models.In carriers of pathogenic variants, a high amyloid burden at baseline, represented by low CSF Aβ42 (β=-4·28 × 10-2 [SE 0·013], p=0·0012), but not high cortical uptake in PiB-PET (β=-5·51 × 10-3 [0·011], p=0·63), was the only predictor of an augmented annual rate of subsequent increase in soluble TREM2. Augmented annual rates of increase in soluble TREM2 were associated with a diminished rate of decrease in amyloid deposition, as measured by Aβ42 in CSF (r=0·56 [0·22], p=0·011), in presymptomatic carriers of pathogenic variants, and with diminished annual rate of increase in PiB-PET (r=-0·67 [0·25], p=0·0060) in symptomatic carriers of pathogenic variants. Presymptomatic carriers of pathogenic variants with annual rates of increase in soluble TREM2 lower than the median showed a correlation between enhanced annual rates of increase in p-tau in CSF and augmented annual rates of increase in PiB-PET signal (r=0·45 [0·21], p=0·035), that was not observed in those with rates of increase in soluble TREM2 higher than the median. Furthermore, presymptomatic carriers of pathogenic variants with rates of increase in soluble TREM2 above or below the median had opposite associations between Aβ42 in CSF and PiB-PET uptake when assessed longitudinally. Augmented annual rates of increase in soluble TREM2 in presymptomatic carriers of pathogenic variants correlated with decreased cortical shrinkage in the precuneus (r=0·46 [0·22]), p=0·040) and diminished cognitive decline (r=0·67 [0·22], p=0·0020).Our findings in autosomal dominant Alzheimer's disease position the TREM2 response within the amyloid cascade immediately after the first pathological changes in Aβ aggregation and further support the role of TREM2 on Aβ plaque deposition and compaction. Furthermore, these findings underpin a beneficial effect of TREM2 on Aβ deposition, Aβ-dependent tau pathology, cortical shrinkage, and cognitive decline. Soluble TREM2 could, therefore, be a key marker for clinical trial design and interpretation. Efforts to develop TREM2-boosting therapies are ongoing.German Research Foundation, US National Institutes of Health.
KW  - Adult
KW  - Alzheimer Disease: diagnostic imaging
KW  - Alzheimer Disease: genetics
KW  - Amyloid beta-Peptides
KW  - Biomarkers
KW  - Cognition: physiology
KW  - Cognitive Dysfunction: diagnostic imaging
KW  - Cognitive Dysfunction: genetics
KW  - Humans
KW  - Membrane Glycoproteins: cerebrospinal fluid
KW  - Membrane Glycoproteins: genetics
KW  - Middle Aged
KW  - Receptors, Immunologic: genetics
KW  - United States
KW  - Amyloid beta-Peptides (NLM Chemicals)
KW  - Biomarkers (NLM Chemicals)
KW  - Membrane Glycoproteins (NLM Chemicals)
KW  - Receptors, Immunologic (NLM Chemicals)
KW  - TREM2 protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:35305339
C2  - pmc:PMC8926925
DO  - DOI:10.1016/S1474-4422(22)00027-8
UR  - https://pub.dzne.de/record/163733
ER  -