Apolipoprotein E (APOE) genotype has dissociable effects on memory and attentional-executive network function in Alzheimer's disease
David A Wolk, Bradford C Dickerson, Alzheimer's Disease Neuroimaging Initiative, Michael Weiner, Leon Thal, Ronald Petersen, Clifford R Jack, William Jagust, John Trojanowki, Arthur Toga, Laurel Beckett, Robert C Green, Anthony Gamst, William Z Potter, Tom Montine, Dale Anders, Matthew Bernstein, Joel Felmlee, Nick Fox, Paul Thompson, Norbert Schuff, Gene Alexander, Dan Bandy, Robert A Koeppe, Norm Foster, Eric M Reiman, Kewei Chen, John Trojanowki, Les Shaw, Virginia M -Y Lee, Magdalena Korecka, Arthur Toga, Karen Crawford, Scott Neu, Danielle Harvey, Anthony Gamst, John Kornak, Zaven Kachaturian, Richard Frank, Peter J Snyder, Susan Molchan, Jeffrey Kaye, Remi Vorobik, Joseph Quinn, Lon Schneider, Sonia Pawluczyk, Bryan Spann, Adam S Fleisher, Helen Vanderswag, Judith L Heidebrink, Joanne L Lord, Kris Johnson, Rachelle S Doody, Javier Villanueva-Meyer, Munir Chowdhury, Yaakov Stern, Lawrence S Honig, Karen L Bell, John C Morris, Mark A Mintun, Stacy Schneider, Daniel Marson, Randall Griffith, Beverly Badger, Hillel Grossman, Cheuk Tang, Jessica Stern, Leyla deToledo-Morrell, Raj C Shah, Julie Bach, Ranjan Duara, Richard Isaacson, Silvia Strauman, Marilyn Albert, Julia Pedroso, Jaimie Toroney, Henry Rusinek, Mony J de Leon, Susan M De Santi, P Murali Doraiswamy, Jeffrey R Petrella, Marilyn Aiello, Christopher Clark, Cassie Pham, Jessica Nunez, Charles D Smith, Curtis A Given 2nd, Peter Hardy, Steven T DeKosky, Mary Ann Oakley, Donna Simpson, M Saleem Ismail, Anton Porsteinsson, Colleen McCallum, Steven C Cramer, Ruth A Mulnard, Catherine McAdams-Ortiz, Ramon Diaz-Arrastia, Kristen Martin-Cook, Michael DeVous, Allan I Levey, James J Lah, Janet S Cellar, Jeffrey M Burns, Heather S Anderson, Mary M Laubinger, George Bartzokis, Daniel H S Silverman, Po H Lu, Rita Fletcher, Francine Parfitt, Heather Johnson, Martin Farlow, Scott Herring, Ann M Hake, Christopher H van Dyck, Martha G MacAvoy, Laurel A Bifano, Howard Chertkow, Howard Bergman, Chris Hosein, Sandra Black, Simon Graham, Curtis Caldwell, Howard Feldman, Michele Assaly, Ging-Yuek R Hsiung, Andrew Kertesz, John Rogers, Dick Trost, Charles Bernick, Darren Gitelman, Nancy Johnson, Marsel Mesulam, Carl Sadowsky, Teresa Villena, Scott Mesner, Paul S Aisen, Kathleen B Johnson, Kelly E Behan, Reisa A Sperling, Dorene M Rentz, Keith A Johnson, Allyson Rosen, Jared Tinklenberg, Wes Ashford, Marwan Sabbagh, Donald Connor, Sanja Obradov, Ron Killiany, Alex Norbash, Thomas O Obisesan, Annapurni Jayam-Trouth, Paul Wang, Alexander P Auchus, Juebin Huang, Robert P Friedland, Charles DeCarli, Evan Fletcher, Owen Carmichael, Smita Kittur, Seema Mirje, Sterling C Johnson, Michael Borrie, T -Y Lee, Sanjay Asthana, Cynthia M Carlsson, Steven G Potkin, Diane Highum, Adrian Preda, Dana Nguyen, Pierre N Tariot, Barry A Hendin, Douglas W Scharre, Maria Kataki, David Q Beversdorf, Earl A Zimmerman, Dzintra Celmins, Alice D Brown, Sam Gandy, Marjorie E Marenberg, Barry W Rovner, Godfrey Pearlson, Karen Blank, Karen Anderson, Andrew J Saykin, Robert B Santulli, Nadia Pare, Jeff D Williamson, Kaycee M Sink, Huntington Potter, B Ashok Raj, Amy Giordano, Brian R Ott, Wu Chuang-Kuo, Ronald Cohen, Kerri L Wilks, David A Wolk, Bradford C Dickerson, Alzheimer's Disease Neuroimaging Initiative, Michael Weiner, Leon Thal, Ronald Petersen, Clifford R Jack, William Jagust, John Trojanowki, Arthur Toga, Laurel Beckett, Robert C Green, Anthony Gamst, William Z Potter, Tom Montine, Dale Anders, Matthew Bernstein, Joel Felmlee, Nick Fox, Paul Thompson, Norbert Schuff, Gene Alexander, Dan Bandy, Robert A Koeppe, Norm Foster, Eric M Reiman, Kewei Chen, John Trojanowki, Les Shaw, Virginia M -Y Lee, Magdalena Korecka, Arthur Toga, Karen Crawford, Scott Neu, Danielle Harvey, Anthony Gamst, John Kornak, Zaven Kachaturian, Richard Frank, Peter J Snyder, Susan Molchan, Jeffrey Kaye, Remi Vorobik, Joseph Quinn, Lon Schneider, Sonia Pawluczyk, Bryan Spann, Adam S Fleisher, Helen Vanderswag, Judith L Heidebrink, Joanne L Lord, Kris Johnson, Rachelle S Doody, Javier Villanueva-Meyer, Munir Chowdhury, Yaakov Stern, Lawrence S Honig, Karen L Bell, John C Morris, Mark A Mintun, Stacy Schneider, Daniel Marson, Randall Griffith, Beverly Badger, Hillel Grossman, Cheuk Tang, Jessica Stern, Leyla deToledo-Morrell, Raj C Shah, Julie Bach, Ranjan Duara, Richard Isaacson, Silvia Strauman, Marilyn Albert, Julia Pedroso, Jaimie Toroney, Henry Rusinek, Mony J de Leon, Susan M De Santi, P Murali Doraiswamy, Jeffrey R Petrella, Marilyn Aiello, Christopher Clark, Cassie Pham, Jessica Nunez, Charles D Smith, Curtis A Given 2nd, Peter Hardy, Steven T DeKosky, Mary Ann Oakley, Donna Simpson, M Saleem Ismail, Anton Porsteinsson, Colleen McCallum, Steven C Cramer, Ruth A Mulnard, Catherine McAdams-Ortiz, Ramon Diaz-Arrastia, Kristen Martin-Cook, Michael DeVous, Allan I Levey, James J Lah, Janet S Cellar, Jeffrey M Burns, Heather S Anderson, Mary M Laubinger, George Bartzokis, Daniel H S Silverman, Po H Lu, Rita Fletcher, Francine Parfitt, Heather Johnson, Martin Farlow, Scott Herring, Ann M Hake, Christopher H van Dyck, Martha G MacAvoy, Laurel A Bifano, Howard Chertkow, Howard Bergman, Chris Hosein, Sandra Black, Simon Graham, Curtis Caldwell, Howard Feldman, Michele Assaly, Ging-Yuek R Hsiung, Andrew Kertesz, John Rogers, Dick Trost, Charles Bernick, Darren Gitelman, Nancy Johnson, Marsel Mesulam, Carl Sadowsky, Teresa Villena, Scott Mesner, Paul S Aisen, Kathleen B Johnson, Kelly E Behan, Reisa A Sperling, Dorene M Rentz, Keith A Johnson, Allyson Rosen, Jared Tinklenberg, Wes Ashford, Marwan Sabbagh, Donald Connor, Sanja Obradov, Ron Killiany, Alex Norbash, Thomas O Obisesan, Annapurni Jayam-Trouth, Paul Wang, Alexander P Auchus, Juebin Huang, Robert P Friedland, Charles DeCarli, Evan Fletcher, Owen Carmichael, Smita Kittur, Seema Mirje, Sterling C Johnson, Michael Borrie, T -Y Lee, Sanjay Asthana, Cynthia M Carlsson, Steven G Potkin, Diane Highum, Adrian Preda, Dana Nguyen, Pierre N Tariot, Barry A Hendin, Douglas W Scharre, Maria Kataki, David Q Beversdorf, Earl A Zimmerman, Dzintra Celmins, Alice D Brown, Sam Gandy, Marjorie E Marenberg, Barry W Rovner, Godfrey Pearlson, Karen Blank, Karen Anderson, Andrew J Saykin, Robert B Santulli, Nadia Pare, Jeff D Williamson, Kaycee M Sink, Huntington Potter, B Ashok Raj, Amy Giordano, Brian R Ott, Wu Chuang-Kuo, Ronald Cohen, Kerri L Wilks
Abstract
The epsilon4 allele of the apolipoprotein E (APOE) gene is the major genetic risk factor for Alzheimer's disease (AD), but limited work has suggested that APOE genotype may modulate disease phenotype. Carriers of the epsilon4 allele have been reported to have greater medial temporal lobe (MTL) pathology and poorer memory than noncarriers. Less attention has focused on whether there are domains of cognition and neuroanatomical regions more affected in noncarriers. Further, a major potential confound of prior in vivo studies is the possibility of different rates of clinical misdiagnosis for carriers vs. noncarriers. We compared phenotypic differences in cognition and topography of regional cortical atrophy of epsilon4 carriers (n = 67) vs. noncarriers (n = 24) with mild AD from the Alzheimer's Disease Neuroimaging Initiative, restricted to those with a cerebrospinal fluid (CSF) molecular profile consistent with AD. Between-group comparisons were made for psychometric tests and morphometric measures of cortical thickness and hippocampal volume. Carriers displayed significantly greater impairment on measures of memory retention, whereas noncarriers were more impaired on tests of working memory, executive control, and lexical access. Consistent with this cognitive dissociation, carriers exhibited greater MTL atrophy, whereas noncarriers had greater frontoparietal atrophy. Performance deficits in particular cognitive domains were associated with disproportionate regional brain atrophy within nodes of cortical networks thought to subserve these cognitive processes. These convergent cognitive and neuroanatomic findings in individuals with a CSF molecular profile consistent with AD support the hypothesis that APOE genotype modulates the clinical phenotype of AD through influence on specific large-scale brain networks.
Conflict of interest statement
The authors declare no conflict of interest.
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Source: PubMed