Brain Imaging and Biomarker Research Group – PI: Michael Ewers
Our research focuses on the spreading of key pathologies in Alzheimer’s disease (AD) and the improvement of prediction tools. Specifically, we combine functional connectomics, myelin imaging and advanced molecular PET markers to model the spatiotemporal evolution of fibrillar tau and beta-amyloid. Our prediction models are tailored to enable precision-medicine guided patient-level prognosis of disease progression. Another research focus of our team centers on brain mechanisms underlying cognitive resilience in AD. Specifically, we examine the protective factors of the brain’s innate immune system along with functional network changes that alleviate cognitive decline.
Functional connectome & progression of tau pathology
Neurofibrillar tangles are the single most important drivers of neurodegeneration and cognitive decline in AD. The tau-bearing tangle deposits progress in spatiotemporally distinct patterns in the brain, but which factors shape that spatial distribution is unclear. Based on joined resting-state fMRI connectivity and tau PET analysis, we found that fibrillar tau accumulation progresses from initial epicenters of high tau to those brain areas that are most closely connected to the epicenter. Our approach allows to predict the progression of tau accumulation at the patient-level, thus providing an important step towards precision medicine.
Functional networks supporting cognitive resilience
Cognitive resilience designates the ability to show disproportional high levels of cognitive function despite substantial brain pathology. Cognitive resilience is an important factor slowing down the development of dementia in AD, but the underlying mechanism are not well understood. To address that question, we focus on the topological characteristics of the functional connectome of the brain that underly resilience. Using graph theoretical analyses, we identified hub connectivity in the fronto-parietal control network (Neitzel et al. 2019) as well as higher segregation of functional networks (Franzmeier et al. Brain, in press) as key neural substrates supporting cognitive resilience against pathologic tau.
The role of TREM2-related microglia activation in Alzheimer’s
Rare loss-of-function mutations in the gene encoding TREM2, i.e. a receptor molecular expressed by microglia, are associated with a dramatic increase in the risk of AD. Together with our collaborator Prof. Christian Haass (DZNE, Munich), we found changes in biofluid levels of soluble TREM2 protein occur up to 5 years before the onset of AD dementia (Suarez-Calvet, Science Trans Med, 2016), consistent with a microglia response triggered by AD pathology. Importantly, higher biomarker levels of sTREM2 at a given level of beta-amyloid and tau pathology were associated with slower subsequent cognitive decline (Ewers et al. Science Transl Medicine 2019), reduced detrimental effects of ApoE e3 genotype (Franzmeier et al. Mol Neurodeg. 2020) and slower rate of increase in amyloid PET (Ewers et al. EMBO Mol Med. 2020).
Publications by Michael Ewers
Neitzel J, Franzmeier N, Rubinski A, Dichgans M, Brendel M; Alzheimer’s Disease Neuroimaging Initiative (ADNI), Malik R, Ewers M. KL-VS heterozygosity is associated with lower amyloid-dependent tau accumulation and memory impairment in Alzheimer's disease. Nat Commun. 2021 Jun 22;12(1):3825. doi: 10.1038/s41467-021-23755-z. PMID: 34158479.
Franzmeier N, Ossenkoppele R, Brendel M, Rubinski A, Smith R, Kumar A, Mattsson-Carlgren N, Strandberg O, Duering M, Buerger K, Dichgans M, Hansson O, Ewers M; Alzheimer's Disease Neuroimaging Initiative (ADNI)* and the Swedish BioFINDER study. The BIN1 rs744373 Alzheimer's disease risk SNP is associated with faster Aβ-associated tau accumulation and cognitive decline. Alzheimers Dement. 2021 Jun 1. doi: 10.1002/alz.12371. Epub ahead of print.
Ewers M, Luan Y, Frontzkowski L, Neitzel J, Rubinski A, Dichgans M, Hassenstab J, Gordon BA, Chhatwal JP, Levin J, Schofield P, Benzinger TLS, Morris JC, Goate A, Karch CM, Fagan AM, McDade E, Allegri R, Berman S, Chui H, Cruchaga C, Farlow M, Graff-Radford N, Jucker M, Lee JH, Martins RN, Mori H, Perrin R, Xiong C, Rossor M, Fox NC, O'Connor A, Salloway S, Danek A, Buerger K, Bateman RJ, Habeck C, Stern Y, Franzmeier N; Alzheimer’s Disease Neuroimaging Initiative and the Dominantly Inherited Alzheimer Network. Segregation of functional networks is associated with cognitive resilience in Alzheimer's disease. Brain. 2021 Mar 16:awab112. doi: 10.1093/brain/awab112. Epub ahead of print.
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.
Franzmeier N, Koutsouleris N, Benzinger T, Goate A, Karch CM, Fagan AM, McDade E, Duering M, Dichgans M, Levin J, Gordon BA, Lim YY, Masters CL, Rossor M, Fox NC, O'Connor A, Chhatwal J, Salloway S, Danek A, Hassenstab J, Schofield PR, Morris JC, Bateman RJ; Alzheimer's disease neuroimaging initiative (ADNI); Dominantly Inherited Alzheimer Network (DIAN), Ewers M. Predicting sporadic Alzheimer's disease progression via inherited Alzheimer's disease-informed machine-learning. Alzheimers Dement. 2020 Feb 11. [Epub ahead of print]
Ewers M, Franzmeier N, Suárez-Calvet M, Morenas-Rodriguez E, Caballero MAA, 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).
Franzmeier N, Ren J, Damm A, Monté-Rubio G, Boada M, Ruiz A, Ramirez A, Jessen F, Düzel E, Rodríguez Gómez O, Benzinger T, Goate A, Karch CM, Fagan AM, McDade E, Buerger K, Levin J, Duering M, Dichgans M, Suárez-Calvet M, Haass C, Gordon BA, Lim YY, Masters CL, Janowitz D, Catak C, Wolfsgruber S, Wagner M, Milz E, Moreno-Grau S, Teipel S, Grothe MJ, Kilimann I, Rossor M, Fox N, Laske C, Chhatwal J, Falkai P, Perneczky R, Lee JH, Spottke A, Boecker H, Brosseron F, Fliessbach K, Heneka MT, Nestor P, Peters O, Fuentes M, Menne F, Priller J, Spruth EJ, Franke C, Schneider A, Westerteicher C, Speck O, Wiltfang J, Bartels C, Araque Caballero MÁ, Metzger C, Bittner D, Salloway S, Danek A, Hassenstab J, Yakushev I, Schofield PR, Morris JC, Bateman RJ, Ewers M. The BDNFVal66Met SNP modulates the association between beta-amyloid and hippocampal disconnection in Alzheimer's disease. Mol Psychiatry. 2019 Mar 21.
Perneczky R, Kempermann G, Korczyn AD, Matthews FE, Ikram MA, Scarmeas N, Chetelat G, Stern Y, Ewers M. Translational research on reserve against neurodegenerative disease: consensus report of the International Conference on Cognitive Reserve in the Dementias and the Alzheimer's Association Reserve, Resilience and Protective Factors Professional Interest Area working groups. BMC Med. 2019 Feb 27;17(1):47.
Araque Caballero MÁ, Suárez-Calvet M, Duering M, Franzmeier N, Benzinger T, Fagan AM, Bateman RJ, Jack CR, Levin J, Dichgans M, Jucker M, Karch C, Masters CL, Morris JC, Weiner M, Rossor M, Fox NC, Lee JH, Salloway S, Danek A, Goate A, Yakushev I, Hassenstab J, Schofield PR, Haass C, Ewers M. White matter diffusion alterations precede symptom onset in autosomal dominant Alzheimer's disease. Brain. 2018 Oct 1;141(10):3065-3080.
Stern Y, Arenaza-Urquijo EM, Bartrés-Faz D, Belleville S, Cantilon M, Chetelat G, Ewers M, Franzmeier N, Kempermann G, Kremen WS, Okonkwo O, Scarmeas N, Soldan A, Udeh-Momoh C, Valenzuela M, Vemuri P, Vuoksimaa E; Reserve, Resilience and Protective Factors PIA Empirical Definitions and Conceptual Frameworks Workgroup. Whitepaper: Defining and investigating cognitive reserve, brain reserve, and brain maintenance. Alzheimers Dement. 2018 Sep 14.
Franzmeier N, Düzel E, Jessen F, Buerger K, Levin J, Duering M, Dichgans M, Haass C, Suárez-Calvet M, Fagan AM, Paumier K, Benzinger T, Masters CL, Morris JC, Perneczky R, Janowitz D, Catak C, Wolfsgruber S, Wagner M, Teipel S, Kilimann I, Ramirez A, Rossor M, Jucker M, Chhatwal J, Spottke A, Boecker H, Brosseron F, Falkai P, Fliessbach K, Heneka MT, Laske C, Nestor P, Peters O, Fuentes M, Menne F, Priller J, Spruth EJ, Franke C, Schneider A, Kofler B, Westerteicher C, Speck O, Wiltfang J, Bartels C, Araque Caballero MÁ, Metzger C, Bittner D, Weiner M, Lee JH, Salloway S, Danek A, Goate A, Schofield PR, Bateman RJ, Ewers M. Left frontal hub connectivity delays cognitive impairment in autosomal-dominant and sporadic Alzheimer's disease. Brain. 2018 Apr 1;141(4):1186-1200.
Franzmeier N, Hartmann J, Taylor ANW, Araque-Caballero MÁ, Simon-Vermot L, Kambeitz-Ilankovic L, Bürger K, Catak C, Janowitz D, Müller C, Ertl-Wagner B, Stahl R, Dichgans M, Duering M, Ewers M. The left frontal cortex supports reserve in aging by enhancing functional network efficiency. Alzheimers Res Ther. 2018 Mar 6;10(1):28.
Ewers, Michael, Prof. Dr. / PI
Franzmeier, Nicolai, Dr. / Postdoc
Neitzel, Julia, Dr. / Postdoc
Habash, Susan / radiographer (MTRA)
Hübner, Mathias / research assistant
Frontzkowski, Lukas / PhD student
Ren, Jinyi / PhD student
Rubinski, Anna / PhD student
Pietsch, Hedwig / Team assistant