The BDNFVal66Met SNP modulates the association between beta-amyloid and hippocampal disconnection in Alzheimer’s disease
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 modulatin...
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| Veröffentlicht in: | Molecular psychiatry 2021-02, Vol.26 (2), p.614-628 |
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| creator | Franzmeier, Nicolai Ren, Jinyi Damm, Alexander Monté-Rubio, Gemma Boada, Mercè Ruiz, Agustín Ramirez, Alfredo Jessen, Frank Düzel, Emrah Rodríguez Gómez, Octavio Benzinger, Tammie Goate, Alison Karch, Celeste M. Fagan, Anne M. McDade, Eric Buerger, Katharina Levin, Johannes Duering, Marco Dichgans, Martin Suárez-Calvet, Marc Haass, Christian Gordon, Brian A. Lim, Yen Ying Masters, Colin L. Janowitz, Daniel Catak, Cihan Wolfsgruber, Steffen Wagner, Michael Milz, Esther Moreno-Grau, Sonia Teipel, Stefan Grothe, Michel J Kilimann, Ingo Rossor, Martin Fox, Nick Laske, Christoph Chhatwal, Jasmeer Falkai, Peter Perneczky, Robert Lee, Jae-Hong Spottke, Annika Boecker, Henning Brosseron, Frederic Fliessbach, Klaus Heneka, Michael T. Nestor, Peter Peters, Oliver Fuentes, Manuel Menne, Felix Priller, Josef Spruth, Eike J. Franke, Christiana Schneider, Anja Westerteicher, Christine Speck, Oliver Wiltfang, Jens Bartels, Claudia Araque Caballero, Miguel Ángel Metzger, Coraline Bittner, Daniel Salloway, Stephen Danek, Adrian Hassenstab, Jason Yakushev, Igor Schofield, Peter R. Morris, John C. Bateman, Randall J. Ewers, Michael |
| description | 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. |
| doi_str_mv | 10.1038/s41380-019-0404-6 |
| format | Article |
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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.</description><identifier>ISSN: 1359-4184</identifier><identifier>EISSN: 1476-5578</identifier><identifier>DOI: 10.1038/s41380-019-0404-6</identifier><identifier>PMID: 30899092</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>59/36 ; 59/57 ; 631/208 ; 631/378 ; Alzheimer's disease ; Behavioral Sciences ; Biological Psychology ; Brain mapping ; Brain-derived neurotrophic factor ; Cognitive ability ; Dementia disorders ; Functional magnetic resonance imaging ; Gene polymorphism ; Hippocampus ; Medicine ; Medicine & Public Health ; Neural networks ; Neurodegeneration ; Neurodegenerative diseases ; Neurosciences ; Pharmacotherapy ; Positron emission tomography ; Psychiatry ; Single-nucleotide polymorphism ; β-Amyloid</subject><ispartof>Molecular psychiatry, 2021-02, Vol.26 (2), p.614-628</ispartof><rights>Springer Nature Limited 2019</rights><rights>Springer Nature Limited 2019.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c513t-d191d7b9e08b55c21a9f36d8dee6671285d0bc23e53ff6e57f82dd14ba1b1333</citedby><cites>FETCH-LOGICAL-c513t-d191d7b9e08b55c21a9f36d8dee6671285d0bc23e53ff6e57f82dd14ba1b1333</cites><orcidid>0000-0003-2109-2955 ; 0000-0003-1981-7435 ; 0000-0003-1492-5330 ; 0000-0001-9736-2283 ; 0000-0002-4869-1627 ; 0000-0002-6854-5547 ; 0000-0001-8857-5383 ; 0000-0003-2600-9022 ; 0000-0003-2967-9662 ; 0000-0003-4996-1630 ; 0000-0002-0576-2472 ; 0000-0002-2631-0942 ; 0000-0003-4991-763X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids></links><search><creatorcontrib>Franzmeier, Nicolai</creatorcontrib><creatorcontrib>Ren, Jinyi</creatorcontrib><creatorcontrib>Damm, Alexander</creatorcontrib><creatorcontrib>Monté-Rubio, Gemma</creatorcontrib><creatorcontrib>Boada, Mercè</creatorcontrib><creatorcontrib>Ruiz, Agustín</creatorcontrib><creatorcontrib>Ramirez, Alfredo</creatorcontrib><creatorcontrib>Jessen, Frank</creatorcontrib><creatorcontrib>Düzel, Emrah</creatorcontrib><creatorcontrib>Rodríguez Gómez, Octavio</creatorcontrib><creatorcontrib>Benzinger, Tammie</creatorcontrib><creatorcontrib>Goate, Alison</creatorcontrib><creatorcontrib>Karch, Celeste M.</creatorcontrib><creatorcontrib>Fagan, Anne M.</creatorcontrib><creatorcontrib>McDade, Eric</creatorcontrib><creatorcontrib>Buerger, Katharina</creatorcontrib><creatorcontrib>Levin, Johannes</creatorcontrib><creatorcontrib>Duering, Marco</creatorcontrib><creatorcontrib>Dichgans, Martin</creatorcontrib><creatorcontrib>Suárez-Calvet, Marc</creatorcontrib><creatorcontrib>Haass, Christian</creatorcontrib><creatorcontrib>Gordon, Brian A.</creatorcontrib><creatorcontrib>Lim, Yen Ying</creatorcontrib><creatorcontrib>Masters, Colin L.</creatorcontrib><creatorcontrib>Janowitz, Daniel</creatorcontrib><creatorcontrib>Catak, Cihan</creatorcontrib><creatorcontrib>Wolfsgruber, Steffen</creatorcontrib><creatorcontrib>Wagner, Michael</creatorcontrib><creatorcontrib>Milz, Esther</creatorcontrib><creatorcontrib>Moreno-Grau, Sonia</creatorcontrib><creatorcontrib>Teipel, Stefan</creatorcontrib><creatorcontrib>Grothe, Michel J</creatorcontrib><creatorcontrib>Kilimann, Ingo</creatorcontrib><creatorcontrib>Rossor, Martin</creatorcontrib><creatorcontrib>Fox, Nick</creatorcontrib><creatorcontrib>Laske, Christoph</creatorcontrib><creatorcontrib>Chhatwal, Jasmeer</creatorcontrib><creatorcontrib>Falkai, Peter</creatorcontrib><creatorcontrib>Perneczky, Robert</creatorcontrib><creatorcontrib>Lee, Jae-Hong</creatorcontrib><creatorcontrib>Spottke, Annika</creatorcontrib><creatorcontrib>Boecker, Henning</creatorcontrib><creatorcontrib>Brosseron, Frederic</creatorcontrib><creatorcontrib>Fliessbach, Klaus</creatorcontrib><creatorcontrib>Heneka, Michael T.</creatorcontrib><creatorcontrib>Nestor, Peter</creatorcontrib><creatorcontrib>Peters, Oliver</creatorcontrib><creatorcontrib>Fuentes, Manuel</creatorcontrib><creatorcontrib>Menne, Felix</creatorcontrib><creatorcontrib>Priller, Josef</creatorcontrib><creatorcontrib>Spruth, Eike J.</creatorcontrib><creatorcontrib>Franke, Christiana</creatorcontrib><creatorcontrib>Schneider, Anja</creatorcontrib><creatorcontrib>Westerteicher, Christine</creatorcontrib><creatorcontrib>Speck, Oliver</creatorcontrib><creatorcontrib>Wiltfang, Jens</creatorcontrib><creatorcontrib>Bartels, Claudia</creatorcontrib><creatorcontrib>Araque Caballero, Miguel Ángel</creatorcontrib><creatorcontrib>Metzger, Coraline</creatorcontrib><creatorcontrib>Bittner, Daniel</creatorcontrib><creatorcontrib>Salloway, Stephen</creatorcontrib><creatorcontrib>Danek, Adrian</creatorcontrib><creatorcontrib>Hassenstab, Jason</creatorcontrib><creatorcontrib>Yakushev, Igor</creatorcontrib><creatorcontrib>Schofield, Peter R.</creatorcontrib><creatorcontrib>Morris, John C.</creatorcontrib><creatorcontrib>Bateman, Randall J.</creatorcontrib><creatorcontrib>Ewers, Michael</creatorcontrib><title>The BDNFVal66Met SNP modulates the association between beta-amyloid and hippocampal disconnection in Alzheimer’s disease</title><title>Molecular psychiatry</title><addtitle>Mol Psychiatry</addtitle><description>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.</description><subject>59/36</subject><subject>59/57</subject><subject>631/208</subject><subject>631/378</subject><subject>Alzheimer's disease</subject><subject>Behavioral Sciences</subject><subject>Biological Psychology</subject><subject>Brain mapping</subject><subject>Brain-derived neurotrophic factor</subject><subject>Cognitive ability</subject><subject>Dementia disorders</subject><subject>Functional magnetic resonance imaging</subject><subject>Gene polymorphism</subject><subject>Hippocampus</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Neural networks</subject><subject>Neurodegeneration</subject><subject>Neurodegenerative diseases</subject><subject>Neurosciences</subject><subject>Pharmacotherapy</subject><subject>Positron emission tomography</subject><subject>Psychiatry</subject><subject>Single-nucleotide 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BDNFVal66Met SNP modulates the association between beta-amyloid and hippocampal disconnection in Alzheimer’s disease</title><author>Franzmeier, Nicolai ; Ren, Jinyi ; Damm, Alexander ; Monté-Rubio, Gemma ; Boada, Mercè ; Ruiz, Agustín ; Ramirez, Alfredo ; Jessen, Frank ; Düzel, Emrah ; Rodríguez Gómez, Octavio ; Benzinger, Tammie ; Goate, Alison ; Karch, Celeste M. ; Fagan, Anne M. ; McDade, Eric ; Buerger, Katharina ; Levin, Johannes ; Duering, Marco ; Dichgans, Martin ; Suárez-Calvet, Marc ; Haass, Christian ; Gordon, Brian A. ; Lim, Yen Ying ; Masters, Colin L. ; Janowitz, Daniel ; Catak, Cihan ; Wolfsgruber, Steffen ; Wagner, Michael ; Milz, Esther ; Moreno-Grau, Sonia ; Teipel, Stefan ; Grothe, Michel J ; Kilimann, Ingo ; Rossor, Martin ; Fox, Nick ; Laske, Christoph ; Chhatwal, Jasmeer ; Falkai, Peter ; Perneczky, Robert ; Lee, Jae-Hong ; Spottke, Annika ; Boecker, Henning ; Brosseron, Frederic ; Fliessbach, Klaus ; Heneka, Michael T. ; Nestor, Peter ; Peters, Oliver ; Fuentes, Manuel ; Menne, Felix ; Priller, Josef ; Spruth, Eike J. ; Franke, Christiana ; Schneider, Anja ; Westerteicher, Christine ; Speck, Oliver ; Wiltfang, Jens ; Bartels, Claudia ; Araque Caballero, Miguel Ángel ; Metzger, Coraline ; Bittner, Daniel ; Salloway, Stephen ; Danek, Adrian ; Hassenstab, Jason ; Yakushev, Igor ; Schofield, Peter R. ; Morris, John C. ; Bateman, Randall J. ; Ewers, Michael</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c513t-d191d7b9e08b55c21a9f36d8dee6671285d0bc23e53ff6e57f82dd14ba1b1333</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>59/36</topic><topic>59/57</topic><topic>631/208</topic><topic>631/378</topic><topic>Alzheimer's disease</topic><topic>Behavioral Sciences</topic><topic>Biological Psychology</topic><topic>Brain mapping</topic><topic>Brain-derived neurotrophic factor</topic><topic>Cognitive ability</topic><topic>Dementia disorders</topic><topic>Functional magnetic resonance imaging</topic><topic>Gene polymorphism</topic><topic>Hippocampus</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Neural networks</topic><topic>Neurodegeneration</topic><topic>Neurodegenerative diseases</topic><topic>Neurosciences</topic><topic>Pharmacotherapy</topic><topic>Positron emission tomography</topic><topic>Psychiatry</topic><topic>Single-nucleotide polymorphism</topic><topic>β-Amyloid</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Franzmeier, Nicolai</creatorcontrib><creatorcontrib>Ren, Jinyi</creatorcontrib><creatorcontrib>Damm, Alexander</creatorcontrib><creatorcontrib>Monté-Rubio, Gemma</creatorcontrib><creatorcontrib>Boada, Mercè</creatorcontrib><creatorcontrib>Ruiz, Agustín</creatorcontrib><creatorcontrib>Ramirez, Alfredo</creatorcontrib><creatorcontrib>Jessen, Frank</creatorcontrib><creatorcontrib>Düzel, Emrah</creatorcontrib><creatorcontrib>Rodríguez Gómez, Octavio</creatorcontrib><creatorcontrib>Benzinger, Tammie</creatorcontrib><creatorcontrib>Goate, Alison</creatorcontrib><creatorcontrib>Karch, Celeste M.</creatorcontrib><creatorcontrib>Fagan, Anne M.</creatorcontrib><creatorcontrib>McDade, Eric</creatorcontrib><creatorcontrib>Buerger, Katharina</creatorcontrib><creatorcontrib>Levin, Johannes</creatorcontrib><creatorcontrib>Duering, Marco</creatorcontrib><creatorcontrib>Dichgans, Martin</creatorcontrib><creatorcontrib>Suárez-Calvet, Marc</creatorcontrib><creatorcontrib>Haass, Christian</creatorcontrib><creatorcontrib>Gordon, Brian A.</creatorcontrib><creatorcontrib>Lim, Yen Ying</creatorcontrib><creatorcontrib>Masters, Colin L.</creatorcontrib><creatorcontrib>Janowitz, Daniel</creatorcontrib><creatorcontrib>Catak, Cihan</creatorcontrib><creatorcontrib>Wolfsgruber, Steffen</creatorcontrib><creatorcontrib>Wagner, Michael</creatorcontrib><creatorcontrib>Milz, Esther</creatorcontrib><creatorcontrib>Moreno-Grau, Sonia</creatorcontrib><creatorcontrib>Teipel, Stefan</creatorcontrib><creatorcontrib>Grothe, Michel J</creatorcontrib><creatorcontrib>Kilimann, Ingo</creatorcontrib><creatorcontrib>Rossor, Martin</creatorcontrib><creatorcontrib>Fox, Nick</creatorcontrib><creatorcontrib>Laske, Christoph</creatorcontrib><creatorcontrib>Chhatwal, Jasmeer</creatorcontrib><creatorcontrib>Falkai, Peter</creatorcontrib><creatorcontrib>Perneczky, Robert</creatorcontrib><creatorcontrib>Lee, Jae-Hong</creatorcontrib><creatorcontrib>Spottke, Annika</creatorcontrib><creatorcontrib>Boecker, Henning</creatorcontrib><creatorcontrib>Brosseron, Frederic</creatorcontrib><creatorcontrib>Fliessbach, Klaus</creatorcontrib><creatorcontrib>Heneka, Michael T.</creatorcontrib><creatorcontrib>Nestor, Peter</creatorcontrib><creatorcontrib>Peters, Oliver</creatorcontrib><creatorcontrib>Fuentes, Manuel</creatorcontrib><creatorcontrib>Menne, Felix</creatorcontrib><creatorcontrib>Priller, Josef</creatorcontrib><creatorcontrib>Spruth, Eike J.</creatorcontrib><creatorcontrib>Franke, Christiana</creatorcontrib><creatorcontrib>Schneider, Anja</creatorcontrib><creatorcontrib>Westerteicher, Christine</creatorcontrib><creatorcontrib>Speck, Oliver</creatorcontrib><creatorcontrib>Wiltfang, Jens</creatorcontrib><creatorcontrib>Bartels, Claudia</creatorcontrib><creatorcontrib>Araque Caballero, Miguel Ángel</creatorcontrib><creatorcontrib>Metzger, Coraline</creatorcontrib><creatorcontrib>Bittner, Daniel</creatorcontrib><creatorcontrib>Salloway, Stephen</creatorcontrib><creatorcontrib>Danek, Adrian</creatorcontrib><creatorcontrib>Hassenstab, Jason</creatorcontrib><creatorcontrib>Yakushev, Igor</creatorcontrib><creatorcontrib>Schofield, Peter R.</creatorcontrib><creatorcontrib>Morris, John C.</creatorcontrib><creatorcontrib>Bateman, Randall J.</creatorcontrib><creatorcontrib>Ewers, Michael</creatorcontrib><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Neurosciences Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Psychology Database (Alumni)</collection><collection>ProQuest Pharma Collection</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest 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Psychology</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular psychiatry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Franzmeier, Nicolai</au><au>Ren, Jinyi</au><au>Damm, Alexander</au><au>Monté-Rubio, Gemma</au><au>Boada, Mercè</au><au>Ruiz, Agustín</au><au>Ramirez, Alfredo</au><au>Jessen, Frank</au><au>Düzel, Emrah</au><au>Rodríguez Gómez, Octavio</au><au>Benzinger, Tammie</au><au>Goate, Alison</au><au>Karch, Celeste M.</au><au>Fagan, Anne M.</au><au>McDade, Eric</au><au>Buerger, Katharina</au><au>Levin, Johannes</au><au>Duering, Marco</au><au>Dichgans, Martin</au><au>Suárez-Calvet, Marc</au><au>Haass, Christian</au><au>Gordon, Brian A.</au><au>Lim, Yen Ying</au><au>Masters, Colin L.</au><au>Janowitz, Daniel</au><au>Catak, Cihan</au><au>Wolfsgruber, Steffen</au><au>Wagner, Michael</au><au>Milz, Esther</au><au>Moreno-Grau, Sonia</au><au>Teipel, Stefan</au><au>Grothe, Michel J</au><au>Kilimann, Ingo</au><au>Rossor, Martin</au><au>Fox, Nick</au><au>Laske, Christoph</au><au>Chhatwal, Jasmeer</au><au>Falkai, Peter</au><au>Perneczky, Robert</au><au>Lee, Jae-Hong</au><au>Spottke, Annika</au><au>Boecker, Henning</au><au>Brosseron, Frederic</au><au>Fliessbach, Klaus</au><au>Heneka, Michael T.</au><au>Nestor, Peter</au><au>Peters, Oliver</au><au>Fuentes, Manuel</au><au>Menne, Felix</au><au>Priller, Josef</au><au>Spruth, Eike J.</au><au>Franke, Christiana</au><au>Schneider, Anja</au><au>Westerteicher, Christine</au><au>Speck, Oliver</au><au>Wiltfang, Jens</au><au>Bartels, Claudia</au><au>Araque Caballero, Miguel Ángel</au><au>Metzger, Coraline</au><au>Bittner, Daniel</au><au>Salloway, Stephen</au><au>Danek, Adrian</au><au>Hassenstab, Jason</au><au>Yakushev, Igor</au><au>Schofield, Peter R.</au><au>Morris, John C.</au><au>Bateman, Randall J.</au><au>Ewers, Michael</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The BDNFVal66Met SNP modulates the association between beta-amyloid and hippocampal disconnection in Alzheimer’s disease</atitle><jtitle>Molecular psychiatry</jtitle><stitle>Mol Psychiatry</stitle><date>2021-02-01</date><risdate>2021</risdate><volume>26</volume><issue>2</issue><spage>614</spage><epage>628</epage><pages>614-628</pages><issn>1359-4184</issn><eissn>1476-5578</eissn><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.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>30899092</pmid><doi>10.1038/s41380-019-0404-6</doi><tpages>15</tpages><orcidid>https://orcid.org/0000-0003-2109-2955</orcidid><orcidid>https://orcid.org/0000-0003-1981-7435</orcidid><orcidid>https://orcid.org/0000-0003-1492-5330</orcidid><orcidid>https://orcid.org/0000-0001-9736-2283</orcidid><orcidid>https://orcid.org/0000-0002-4869-1627</orcidid><orcidid>https://orcid.org/0000-0002-6854-5547</orcidid><orcidid>https://orcid.org/0000-0001-8857-5383</orcidid><orcidid>https://orcid.org/0000-0003-2600-9022</orcidid><orcidid>https://orcid.org/0000-0003-2967-9662</orcidid><orcidid>https://orcid.org/0000-0003-4996-1630</orcidid><orcidid>https://orcid.org/0000-0002-0576-2472</orcidid><orcidid>https://orcid.org/0000-0002-2631-0942</orcidid><orcidid>https://orcid.org/0000-0003-4991-763X</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1359-4184 |
| ispartof | Molecular psychiatry, 2021-02, Vol.26 (2), p.614-628 |
| issn | 1359-4184 1476-5578 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6754794 |
| source | Alma/SFX Local Collection |
| subjects | 59/36 59/57 631/208 631/378 Alzheimer's disease Behavioral Sciences Biological Psychology Brain mapping Brain-derived neurotrophic factor Cognitive ability Dementia disorders Functional magnetic resonance imaging Gene polymorphism Hippocampus Medicine Medicine & Public Health Neural networks Neurodegeneration Neurodegenerative diseases Neurosciences Pharmacotherapy Positron emission tomography Psychiatry Single-nucleotide polymorphism β-Amyloid |
| title | The BDNFVal66Met SNP modulates the association between beta-amyloid and hippocampal disconnection in Alzheimer’s disease |
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