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Apolipoprotein E (APOE) genotype has dissociable effects on memory and attentional–executive network function in Alzheimer’s disease

2010; National Academy of Sciences; Volume: 107; Issue: 22 Linguagem: Inglês

10.1073/pnas.1001412107

1091-6490

David A. Wolk, Bradford C. Dickerson, Michael D. Weiner, Marilyn Aiello, Paul Aisen, Marilyn Albert, Gene E. Alexander, Heather S. Anderson, Karen Anderson, Liana Apostolova, S. R. Arnold, Wes Ashford, Michele Assaly, Sanjay Asthana, Dan Bandy, Robert Bartha, Vernice Bates, Laurel Beckett, Karen L. Bell, Amanda L. Benincasa, Howard Bergman, Charles Bernick, Matt A. Bernstein, Sandra E. Black, Karen Blank, Michael Borrie, Connie Brand, James Brewer, Alice D. Brown, Jeffrey M. Burns, Nigel J. Cairns, Curtis Caldwell, Horacio Capote, Cynthia M. Carlsson, Owen Carmichael, Janet S. Cellar, Dzintra Celmins, Kewei Chen, Howard Chertkow, Munir Chowdhury, David A. Clark, Donald J. Connor, Stephen Correia, Karen Crawford, Anders M. Dale, Mony J. de Leon, Susan M De Santi, Charles DeCarli, Leyla deToledo‐Morrell, Michael D. Devous, Ramon Diaz‐Arrastia, Sara Dolen, Michael Donohue, Rachelle S. Doody, P. Murali Doraiswamy, Ranjan Duara, Jessica Englert, Martin Farlow, Howard Feldman, Joel P. Felmlee, Adam Fleisher, E. Fletcher, Tatiana Foroud, Norm Foster, Nick C. Fox, R.T. Frank, Anthony Gamst, Curtis A. Given, Neill R. Graff‐Radford, Robert C. Green, Randall Griffith, Hillel Grossman, Ann Marie Hake, Peter Hardy, Danielle Harvey, Judith L. Heidebrink, Barry Hendin, Scott Herring, Lawrence S. Honig, Chris Hosein, Ging‐Yuek Robin Hsiung, Leon Hudson, M. Saleem Ismail, Clifford R. Jack, Sandra A. Jacobson, William J. Jagust, Annapurni Jayam‐Trouth, Kris Johnson, Heather Johnson, Nancy Johnson, Kathleen Johnson, Keith A. Johnson, Sterling C. Johnson, Zaven Kachaturian, Jason Karlawish, Maria Kataki, Jeffrey Kaye, Andrew Kertesz, Ronald Killiany, Smita Kittur, Robert A. Koeppe, Magdalena Korecka, John Kornak, Nicholas Kozauer, James J. Lah, Mary M. Laubinger, Virginia M.‐Y. Lee, T.-Y. Lee, Alan J. Lerner, Allan I. Levey, Crystal Flynn Longmire, Oscar L. López, Joanne Lord, Po H. Lu, Martha G. MacAvoy, Paul Malloy, Daniel Marson, Kristen Martin-Cook, Walter Martínez, George Marzloff, Chester A. Mathis, Catherine Mc-Adams-Ortiz, Marsel Mesulam, Bruce L. Miller, Mark A. Mintun, Jacobo Mintzer, Susan Molchan, Tom Montine, John C. Morris, Ruth A. Mulnard, Donna Munic, Anil K. Nair, Scott Neu, Dana Nguyen, Alexander Norbash, MaryAnn Oakley, Thomas O. Obisesan, Paula Ogrocki, Brian R. Ott, Francine Parfitt, Sonia Pawluczyk, Godfrey D. Pearlson, Ronald Petersen, Jeffrey R. Petrella, Steven Potkin, William Z. Potter, Adrian Preda, Joseph Quinn, Michelle Rainka, Stephanie Reeder, Eric M. Reiman, Dorene M. Rentz, Brigid Reynolds, Jennifer Richard, Peggy Roberts, John Rogers, Allyson Rosen, Howard J. Rosen, Henry Rusinek, Marwan N. Sabbagh, Carl Sadowsky, Stephen Salloway, Robert B. Santulli, Andrew J. Saykin, Douglas W. Scharre, Lon S. Schneider, Stacy Schneider, Norbert Schuff, Raj C. Shah, Les Shaw, Li Shen, Daniel Silverman, Donna M. Simpson, Kaycee M. Sink, Charles D. Smith, Peter J. Snyder, Bryan M. Spann, Reisa A. Sperling, Kenneth Spicer, Bojana Stefanovic, Yaakov Stern, Edward G. Stopa, Cheuk Y. Tang, Pierre N. Tariot, Lisa Taylor‐Reinwald, Gaby Thai, Ronald G. Thomas, Paul M. Thompson, Jared Tinklenberg, Arthur W. Toga, Geoffrey Tremont, John Q. Trojanowki, Dick Trost, Raymond Scott Turner, Christopher H. van Dyck, Helen Vanderswag, Daniel Varón, Javier Villanueva‐Meyer, Teresa Villena, Sarah Walter, Paul J. Wang, Franklin Watkins, Michael D. Weiner, Jeff D. Williamson, David A. Wolk, Chuang‐Kuo Wu, Maria Zerrate, Earl A. Zimmerman.,

Memory and Neural Mechanisms

The ε4 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 ε4 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 ε4 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.