The BDNFVal66Met SNP modulates the association between beta-amyloid and hippocampal disconnection in Alzheimer’s disease

Nicolai Franzmeier; Jinyi Ren; Alexander Damm; Gemma Monté-Rubio; Mercè Boada; Agustín Ruiz; Alfredo Ramirez; Frank Jessen; Emrah Düzel; Octavio Rodríguez Gómez; Tammie Benzinger; Alison Goate; Celeste M. Karch; Anne M. Fagan; Eric McDade; Katharina Buerger; Johannes Levin; Marco Duering; Martin Dichgans; Marc Suárez-Calvet; Christian Haass; Brian A. Gordon; Yen Ying Lim; Colin L. Masters; Daniel Janowitz; Cihan Catak; Steffen Wolfsgruber; Michael Wagner; Esther Milz; Sonia Moreno-Grau; Stefan Teipel; Michel J. Grothe; Ingo Kilimann; Martin Rossor; Nick Fox; Christoph Laske; Jasmeer Chhatwal; Peter Falkai; Robert Perneczky; Jae Hong Lee; Annika Spottke; Henning Boecker; Frederic Brosseron; Klaus Fliessbach; Michael T. Heneka; Peter Nestor; Oliver Peters; Manuel Fuentes; Felix Menne; Josef Priller; Eike J. Spruth; Christiana Franke; Anja Schneider; Christine Westerteicher; Oliver Speck; Jens Wiltfang; Claudia Bartels; Miguel Ángel Araque Caballero; Coraline Metzger; Daniel Bittner; Stephen Salloway; Adrian Danek; Jason Hassenstab; Igor Yakushev; Peter R. Schofield; John C. Morris; Randall J. Bateman; Michael Ewers

doi:10.1038/s41380-019-0404-6

The BDNF_Val66Met SNP modulates the association between beta-amyloid and hippocampal disconnection in Alzheimer’s disease

Nicolai Franzmeier, Jinyi Ren, Alexander Damm, Gemma Monté-Rubio, Mercè Boada, Agustín Ruiz, Alfredo Ramirez, Frank Jessen, Emrah Düzel, Octavio Rodríguez Gómez, Tammie Benzinger, Alison Goate, Celeste M. Karch, Anne M. Fagan, Eric McDade, Katharina Buerger, Johannes Levin, Marco Duering, Martin Dichgans, Marc Suárez-CalvetChristian Haass, Brian A. Gordon, Yen Ying Lim, Colin L. Masters, Daniel Janowitz, Cihan Catak, Steffen Wolfsgruber, Michael Wagner, Esther Milz, Sonia Moreno-Grau, Stefan Teipel, Michel J. Grothe, Ingo Kilimann, Martin Rossor, Nick Fox, Christoph Laske, Jasmeer Chhatwal, Peter Falkai, Robert Perneczky, Jae Hong Lee, Annika Spottke, Henning Boecker, Frederic Brosseron, Klaus Fliessbach, Michael T. Heneka, Peter Nestor, Oliver Peters, Manuel Fuentes, Felix Menne, Josef Priller, Eike J. Spruth, Christiana Franke, Anja Schneider, Christine Westerteicher, Oliver Speck, Jens Wiltfang, Claudia Bartels, Miguel Ángel Araque Caballero, Coraline Metzger, Daniel Bittner, Stephen Salloway, Adrian Danek, Jason Hassenstab, Igor Yakushev, Peter R. Schofield, John C. Morris, Randall J. Bateman, Michael Ewers

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Abstract

In Alzheimer’s disease (AD), a single-nucleotide polymorphism in the gene encoding brain-derived neurotrophic factor (BDNF_Val66Met) is associated with worse impact of primary AD pathology (beta-amyloid, Aβ) on neurodegeneration and cognitive decline, rendering BDNF_Val66Met an important modulating factor of cognitive impairment in AD. However, the effect of BDNF_Val66Met on functional networks that may underlie cognitive impairment in AD is poorly understood. Using a cross-validation approach, we first explored in subjects with autosomal dominant AD (ADAD) from the Dominantly Inherited Alzheimer Network (DIAN) the effect of BDNF_Val66Met on resting-state fMRI assessed functional networks. In seed-based connectivity analysis of six major large-scale networks, we found a stronger decrease of hippocampus (seed) to medial-frontal connectivity in the BDNF_Val66Met carriers compared to BDNF_Val homozogytes. BDNF_Val66Met was not associated with connectivity in any other networks. Next, we tested whether the finding of more pronounced decrease in hippocampal-medial-frontal connectivity in BDNF_Val66Met could be also found in elderly subjects with sporadically occurring Aβ, including a group with subjective cognitive decline (N = 149, FACEHBI study) and a group ranging from preclinical to AD dementia (N = 114, DELCODE study). In both of these independently recruited groups, BDNF_Val66Met was associated with a stronger effect of more abnormal Aβ-levels (assessed by biofluid-assay or amyloid-PET) on hippocampal-medial-frontal connectivity decreases, controlled for hippocampus volume and other confounds. Lower hippocampal-medial-frontal connectivity was associated with lower global cognitive performance in the DIAN and DELCODE studies. Together these results suggest that BDNF_Val66Met is selectively associated with a higher vulnerability of hippocampus-frontal connectivity to primary AD pathology, resulting in greater AD-related cognitive impairment.

Original language	English
Pages (from-to)	614-628
Number of pages	15
Journal	Molecular Psychiatry
Volume	26
Issue number	2
DOIs	https://doi.org/10.1038/s41380-019-0404-6
State	Published - Feb 2021

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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, C. M., Fagan, A. M., McDade, E., Buerger, K., Levin, J., Duering, M., Dichgans, M., ... Ewers, M. (2021). The BDNF_Val66Met SNP modulates the association between beta-amyloid and hippocampal disconnection in Alzheimer’s disease. Molecular Psychiatry, 26(2), 614-628. https://doi.org/10.1038/s41380-019-0404-6

@article{5b5878643fca4eeaa590ce77cc8989b1,

title = "The BDNFVal66Met SNP modulates the association between beta-amyloid and hippocampal disconnection in Alzheimer{\textquoteright}s disease",

abstract = "In Alzheimer{\textquoteright}s disease (AD), a single-nucleotide polymorphism in the gene encoding brain-derived neurotrophic factor (BDNFVal66Met) is associated with worse impact of primary AD pathology (beta-amyloid, Aβ) on neurodegeneration and cognitive decline, rendering BDNFVal66Met an important modulating factor of cognitive impairment in AD. However, the effect of BDNFVal66Met on functional networks that may underlie cognitive impairment in AD is poorly understood. Using a cross-validation approach, we first explored in subjects with autosomal dominant AD (ADAD) from the Dominantly Inherited Alzheimer Network (DIAN) the effect of BDNFVal66Met on resting-state fMRI assessed functional networks. In seed-based connectivity analysis of six major large-scale networks, we found a stronger decrease of hippocampus (seed) to medial-frontal connectivity in the BDNFVal66Met carriers compared to BDNFVal homozogytes. BDNFVal66Met was not associated with connectivity in any other networks. Next, we tested whether the finding of more pronounced decrease in hippocampal-medial-frontal connectivity in BDNFVal66Met could be also found in elderly subjects with sporadically occurring Aβ, including a group with subjective cognitive decline (N = 149, FACEHBI study) and a group ranging from preclinical to AD dementia (N = 114, DELCODE study). In both of these independently recruited groups, BDNFVal66Met was associated with a stronger effect of more abnormal Aβ-levels (assessed by biofluid-assay or amyloid-PET) on hippocampal-medial-frontal connectivity decreases, controlled for hippocampus volume and other confounds. Lower hippocampal-medial-frontal connectivity was associated with lower global cognitive performance in the DIAN and DELCODE studies. Together these results suggest that BDNFVal66Met is selectively associated with a higher vulnerability of hippocampus-frontal connectivity to primary AD pathology, resulting in greater AD-related cognitive impairment.",

author = "Nicolai Franzmeier and Jinyi Ren and Alexander Damm and Gemma Mont{\'e}-Rubio and Merc{\`e} Boada and Agust{\'i}n Ruiz and Alfredo Ramirez and Frank Jessen and Emrah D{\"u}zel and {Rodr{\'i}guez G{\'o}mez}, Octavio and Tammie Benzinger and Alison Goate and Karch, {Celeste M.} and Fagan, {Anne M.} and Eric McDade and Katharina Buerger and Johannes Levin and Marco Duering and Martin Dichgans and Marc Su{\'a}rez-Calvet and Christian Haass and Gordon, {Brian A.} and Lim, {Yen Ying} and Masters, {Colin L.} and Daniel Janowitz and Cihan Catak and Steffen Wolfsgruber and Michael Wagner and Esther Milz and Sonia Moreno-Grau and Stefan Teipel and Grothe, {Michel J.} and Ingo Kilimann and Martin Rossor and Nick Fox and Christoph Laske and Jasmeer Chhatwal and Peter Falkai and Robert Perneczky and Lee, {Jae Hong} and Annika Spottke and Henning Boecker and Frederic Brosseron and Klaus Fliessbach and Heneka, {Michael T.} and Peter Nestor and Oliver Peters and Manuel Fuentes and Felix Menne and Josef Priller and Spruth, {Eike J.} and Christiana Franke and Anja Schneider and Christine Westerteicher and Oliver Speck and Jens Wiltfang and Claudia Bartels and {Araque Caballero}, {Miguel {\'A}ngel} and Coraline Metzger and Daniel Bittner and Stephen Salloway and Adrian Danek and Jason Hassenstab and Igor Yakushev and Schofield, {Peter R.} and Morris, {John C.} and Bateman, {Randall J.} and Michael Ewers",

note = "Publisher Copyright: {\textcopyright} 2019, Springer Nature Limited.",

year = "2021",

month = feb,

doi = "10.1038/s41380-019-0404-6",

language = "English",

volume = "26",

pages = "614--628",

journal = "Molecular Psychiatry",

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number = "2",

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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 2021, 'The BDNF_Val66Met SNP modulates the association between beta-amyloid and hippocampal disconnection in Alzheimer’s disease', Molecular Psychiatry, vol. 26, no. 2, pp. 614-628. https://doi.org/10.1038/s41380-019-0404-6

TY - JOUR

T1 - The BDNFVal66Met SNP modulates the association between beta-amyloid and hippocampal disconnection in Alzheimer’s disease

AU - Franzmeier, Nicolai

AU - Ren, Jinyi

AU - Damm, Alexander

AU - Monté-Rubio, Gemma

AU - Boada, Mercè

AU - Ruiz, Agustín

AU - Ramirez, Alfredo

AU - Jessen, Frank

AU - Düzel, Emrah

AU - Rodríguez Gómez, Octavio

AU - Benzinger, Tammie

AU - Goate, Alison

AU - Karch, Celeste M.

AU - Fagan, Anne M.

AU - McDade, Eric

AU - Buerger, Katharina

AU - Levin, Johannes

AU - Duering, Marco

AU - Dichgans, Martin

AU - Suárez-Calvet, Marc

AU - Haass, Christian

AU - Gordon, Brian A.

AU - Lim, Yen Ying

AU - Masters, Colin L.

AU - Janowitz, Daniel

AU - Catak, Cihan

AU - Wolfsgruber, Steffen

AU - Wagner, Michael

AU - Milz, Esther

AU - Moreno-Grau, Sonia

AU - Teipel, Stefan

AU - Grothe, Michel J.

AU - Kilimann, Ingo

AU - Rossor, Martin

AU - Fox, Nick

AU - Laske, Christoph

AU - Chhatwal, Jasmeer

AU - Falkai, Peter

AU - Perneczky, Robert

AU - Lee, Jae Hong

AU - Spottke, Annika

AU - Boecker, Henning

AU - Brosseron, Frederic

AU - Fliessbach, Klaus

AU - Heneka, Michael T.

AU - Nestor, Peter

AU - Peters, Oliver

AU - Fuentes, Manuel

AU - Menne, Felix

AU - Priller, Josef

AU - Spruth, Eike J.

AU - Franke, Christiana

AU - Schneider, Anja

AU - Westerteicher, Christine

AU - Speck, Oliver

AU - Wiltfang, Jens

AU - Bartels, Claudia

AU - Araque Caballero, Miguel Ángel

AU - Metzger, Coraline

AU - Bittner, Daniel

AU - Salloway, Stephen

AU - Danek, Adrian

AU - Hassenstab, Jason

AU - Yakushev, Igor

AU - Schofield, Peter R.

AU - Morris, John C.

AU - Bateman, Randall J.

AU - Ewers, Michael

PY - 2021/2

Y1 - 2021/2

N2 - In Alzheimer’s disease (AD), a single-nucleotide polymorphism in the gene encoding brain-derived neurotrophic factor (BDNFVal66Met) is associated with worse impact of primary AD pathology (beta-amyloid, Aβ) on neurodegeneration and cognitive decline, rendering BDNFVal66Met an important modulating factor of cognitive impairment in AD. However, the effect of BDNFVal66Met on functional networks that may underlie cognitive impairment in AD is poorly understood. Using a cross-validation approach, we first explored in subjects with autosomal dominant AD (ADAD) from the Dominantly Inherited Alzheimer Network (DIAN) the effect of BDNFVal66Met on resting-state fMRI assessed functional networks. In seed-based connectivity analysis of six major large-scale networks, we found a stronger decrease of hippocampus (seed) to medial-frontal connectivity in the BDNFVal66Met carriers compared to BDNFVal homozogytes. BDNFVal66Met was not associated with connectivity in any other networks. Next, we tested whether the finding of more pronounced decrease in hippocampal-medial-frontal connectivity in BDNFVal66Met could be also found in elderly subjects with sporadically occurring Aβ, including a group with subjective cognitive decline (N = 149, FACEHBI study) and a group ranging from preclinical to AD dementia (N = 114, DELCODE study). In both of these independently recruited groups, BDNFVal66Met was associated with a stronger effect of more abnormal Aβ-levels (assessed by biofluid-assay or amyloid-PET) on hippocampal-medial-frontal connectivity decreases, controlled for hippocampus volume and other confounds. Lower hippocampal-medial-frontal connectivity was associated with lower global cognitive performance in the DIAN and DELCODE studies. Together these results suggest that BDNFVal66Met is selectively associated with a higher vulnerability of hippocampus-frontal connectivity to primary AD pathology, resulting in greater AD-related cognitive impairment.

AB - In Alzheimer’s disease (AD), a single-nucleotide polymorphism in the gene encoding brain-derived neurotrophic factor (BDNFVal66Met) is associated with worse impact of primary AD pathology (beta-amyloid, Aβ) on neurodegeneration and cognitive decline, rendering BDNFVal66Met an important modulating factor of cognitive impairment in AD. However, the effect of BDNFVal66Met on functional networks that may underlie cognitive impairment in AD is poorly understood. Using a cross-validation approach, we first explored in subjects with autosomal dominant AD (ADAD) from the Dominantly Inherited Alzheimer Network (DIAN) the effect of BDNFVal66Met on resting-state fMRI assessed functional networks. In seed-based connectivity analysis of six major large-scale networks, we found a stronger decrease of hippocampus (seed) to medial-frontal connectivity in the BDNFVal66Met carriers compared to BDNFVal homozogytes. BDNFVal66Met was not associated with connectivity in any other networks. Next, we tested whether the finding of more pronounced decrease in hippocampal-medial-frontal connectivity in BDNFVal66Met could be also found in elderly subjects with sporadically occurring Aβ, including a group with subjective cognitive decline (N = 149, FACEHBI study) and a group ranging from preclinical to AD dementia (N = 114, DELCODE study). In both of these independently recruited groups, BDNFVal66Met was associated with a stronger effect of more abnormal Aβ-levels (assessed by biofluid-assay or amyloid-PET) on hippocampal-medial-frontal connectivity decreases, controlled for hippocampus volume and other confounds. Lower hippocampal-medial-frontal connectivity was associated with lower global cognitive performance in the DIAN and DELCODE studies. Together these results suggest that BDNFVal66Met is selectively associated with a higher vulnerability of hippocampus-frontal connectivity to primary AD pathology, resulting in greater AD-related cognitive impairment.

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U2 - 10.1038/s41380-019-0404-6

DO - 10.1038/s41380-019-0404-6

M3 - Article

C2 - 30899092

AN - SCOPUS:85063195379

SN - 1359-4184

VL - 26

SP - 614

EP - 628

JO - Molecular Psychiatry

JF - Molecular Psychiatry

IS - 2

ER -

The BDNF_Val66Met SNP modulates the association between beta-amyloid and hippocampal disconnection in Alzheimer’s disease

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