Sex and APOE genotype specific brain regional vulnerability to Alzheimer's Disease

Alzheimer's disease (AD) disproportionately affects women and carriers of the apolipoprotein E ε4 allele (APOE4), yet little is known about how sex and APOE interact to influence white matter (WM) integrity during disease progression. We integrated diffusion MRI and matched blood transcriptomic data to investigate these interactions and their underlying biological mechanisms. WM microstructure was quantified using diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI), and regional vulnerability was assessed with a composite vulnerability score (CVS) derived from associations between diffusion features and AD severity across clinical traits in each of the four sex-APOE groups (female or male, with or without APOE4). Brain parcellation with the Eve atlas revealed regions consistently affected across sex-APOE groups (e.g., parahippocampal and superior temporal gyri) and regions specific to individual groups (e.g., the cingulum in females with APOE4 and the middle frontal gyrus in males without APOE4). Gene co-expression network analysis of the matched blood expression data identified gene subnetworks linked to group-specific regional vulnerability, including a muscle tissue morphogenesis module regulated by NEURL1B and HIST1H2BN associated with middle frontal gyrus vulnerability. These findings demonstrate that sex and APOE genotype jointly shape region-specific WM vulnerability and its molecular signatures in AD. Understanding these interactions provides novel mechanistic insights and may inform precision approaches to drug development, biomarker discovery, and clinical trial design for AD.

Authors

Institutions

Publication Details

Journal
GeroScience
Published
2026-02-18
DOI
https://doi.org/10.1007/s11357-025-02089-4
Primary Topic
Advanced Neuroimaging Techniques and Applications
Type
article
Field-Weighted Citation Impact
0.00
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Sex and APOE genotype specific brain regional vulnerability to Alzheimer's Disease

Robin Bean, Debra Ordor, Aaron Jacobson, Eboni N. Walker et al.
GeroScience
Advanced Neuroimaging Techniques and Applications
article

Sex and APOE genotype specific brain regional vulnerability to Alzheimer's Disease

Robin Bean, Debra Ordor, Aaron Jacobson, Eboni N. Walker, Choe Ma, Beverly Meacham, David J. Mossa, Jim J. Pekar, Michael Asbach, T. F. R. Hamm, K J Ayers, Ruchi Aggarwal, Amanda C. Glueck, Karen L. Blank, Serena Lowery, Courtney Dawson, Sheryl Lynch, Andrea Kippels, Cesar Chirinos, Corey Demsky, Béla M. Ajtai, Emmeline Lin, Maria Scanlan, Marissa Natelson-Love, Mingkai Chen, Daniel W. Bandy, Erming Wang, Rachael Penn, Bryan L. Smelser, F. E. Jones, N B Mathis, Payam H. Mahboubi, Claire Grill, Adaora Ngozi Nwosu, Cecily Jenkins, Lesley K. Rao, Laura Goins, Bradley Wallace, Heather Polson, Sunnie Kenowsky, Kayla Nichols, Soumya Bouchachi, Caila Ryan, Ara Ko, Romina A. Romero, Gary R. Cornell, Marjan Farshadi, Traci Aladeen, Carolyn English, Jessica M. Mallory, Abey Thomas, J Harp, K Lacy, L. P. Teodoro, Shaundra Hall, Xianxiao Zhou, Rawan Tarawneh, Alexandra Groome, Cyrus A. Raji, Martha R. Forloines, Kelly McCann, L T Quinlan, Grace Nelson, Cynthia Stover, Bonomi Robin, Kelly M. Durbin, Molchan Se, Connie Mayo, Veronika Solomon, Felmlee JP, M Nguyen Thao, Thomas C. Hawk, Regan Buckler, Leila Parand, Evan T. Schulze, S MCKINZIE, Tia C. Hall, Tahlee Marian, Richard H. Le, Joseph Boonsiri, Alexandra Dahlgren, Samantha Fikru, Maryam Beigi, Hamid Reza Okhravi, Anish Kapadia, Casie K Lyons, Kandise Chrestensen, Mariana Palou, Hitesh Patel, Iris Marion Young, Brendan Lynch, Lisa Laverne Barnes, Kelsey King, Connie Kreuger, Zach Bonacorsi, Xiomara Mendoza Apuango, Sheryl Detling, Barbara Rodzon, Emilie Geesey, Emily Petrocca, Ann Arlene Malia, Kimberly Nelsen, Skieff Acothley, Haley Hendrix, Bethanie Gamble, Morgan Yazell, Xanthia Saganis, Roxxanne Polleys, Emily Roglaski, John Moore-Weiss, Renee LaBarge, Victoria Rufo, Ivan Mares, Sarah Basadre, Heather Dooly, Katelynn Kreszyn, Aferdita Haviari, Nicole DaSilva, Shaniya Parkins, Brandi Barger, REMA RAMAN, Maushami Gurung, VJ Lowe, Carole Ho, Jacob Faircloth, Nathiel Pacini, Cammie Hellegers, Ezequiel Zamora, Charles J. Duffy, Sylvia White Salazar, Robert Hernandez, E. Schwartz, Akiva Mintz, Nicole Barcelos, Tascha Helland, Kelly Larkin, J. Plenge, Prabin Mandal, Stephen D’Ambrosio, Tiffani Fox, Tracey Moore, Jasmine Stewart, Chad Ward, Jessica Magnuson, Abbey Arnold, Nicole Gagliano, Tatianne Martinez, Patricia Place, Matalin Miller, Haley Tong, Amy Browning, Lorena Macias, Ina Hoti, Michael Asbach, Allison L Perrin, Charna Bates, Alex Groves, Juris Janavs, Warren W Barker, Robin Hsiung, Wendy Baker, Maribel Nunez, Alka Khera, Terence Wong, Cindy Parry, Mara Acevedo, Thao Rodriguez, Martin Ayres, Chelsea Reichert, Ricardo Salazar, Guy Harris, Christina Rosario, Amanda Jimenez, Laura Donnelly, Nadeen Elayan, Chuang-Kuo Wu, Hongzheng Zhang, Jennifer Bray, Lisa C Silbert, Nichol Ferng, Charles Windon, Sarah Munie, Tera Clay, Andrea Fidell, Diana Ferman, Scott Neu, Madiha Fairooz, Loren Brown Ashley, Adrienne Kormos, Taylor Clanton, Kristin Oleary, Tanya Harte, Gina Garcia-Camilo, John K Hsiao, Emily Largent, Blake Vogler, Kara Wever, Maria Kataki, Sheila Ogwang, Gregory Ikner, Regan Brooks, Jeff Gunter, Crystal Duncan, Traci Day, Carolyn Ward, Meagan Yong, Scott Herring, Morris Wishnia, Kevin Hopkins, Richard Zawislak, Carol Cline, Hadley Hustead, Sara Manning, Anne Arthur, Susan DeStefano, Brigit Lieb, Inara Jooma, Kathy King, Caroline Smith, Sarah Ash, Alexis DeMarco, Russell Kurvach, Emma Cooper, Alicia Jessup, Kerstin Doyon, Jelena Pejic, Diego Mejia, Bennett Myers, Pamela Friedman, Erin Yurko, Steven Presto, Gaby Thai, Ella Wright, Elaine Most, Aparna Bhan, Lisa Rankin, Neetha Basheer, Glen Nyborg, Kylee York, Yair Avila, Adam Mecca, Faye Sheppard, Yanis Cavrel, Vita Pomara, Sarah Jefferson, Elisa Hidalgo, Melissa Hamski, Kirsten Glennon, Bevan Hoover, Ellen Hartman, Laura Ashe, Steven Lenio, Stacy Pot, Triana Rudd, Ruby Endre, Ijeoma Mba, Tuba Ahmed, Emma Brennan, Paula Nunes, Chris Figueroa, Steven Tam, Anna Mattle, Ariana Moss, Dick Trost, Isabell Mwaura, Alayne Nieto, Julia Waszak, Violet Wenner, Scott Warren, Terry Camarro, Donna Munic, Amy Boegel, Margaret Bassett, Leena Lukose, Alyssa Ton, Sari Pham, Chad Ward, Tolulope Alo, Ala Abusalim, Chris Hosein, Anton Thomas, Cyndy Toso, Dr Rob Bartha, Ali Raja, Abby Brown, Helena Colvee, Ronald Bailey, Megan King, Ridiane Denis, Ryan Townley, Juliet Fockler, Samira Yeboah, Sarah Bohlman, Joshua Knaack, Linda Watts, Alisa Adhikari, Audrey Ruan, Amy Saklad, Dylan Wint, Campbell Long, Kenneth Spicer, Stefka Lyron, Ifreke Udodong, Jade Uffelman, Ycar Devis, Walter Martinez, Kevin Epperson, Terra Burney, Todd Peehler, Kyliah Hughes, Latasha Chapman, Hannah McCoubrey, Olga James, Sonia Olgin, Molly Goddard, Nadira Trncic, Richard Isip, Susan Henkle, Cary Zik, Arlene Richards, Mary Locke, Rebecca Logan, Martin Pomper, Lena Moretz, Gillian Gabriel, Edgardo Rivera, Asa Widman, Angelica Garcia, Maya Farchi, Tuan Luu, Jeanine May, Marie Amoyaw, Sarab Singh, Linda Fenice, Jaila Coleman, Ljubica Zotovic, Deb Thompson, Allison Acree, Eugene Yau, Erin Drake, Mona Lauture, Rachel Rovere, Meghan Sinn, Sylvia Grant, Dorothy Ross, Della Carter, Daryn Slazyk, Audrie Swain, David Bissig, Maurylette Gui, Andrew Stone, Lynn Nguyen, Meghan Donahue, Amy Rangel, Erin Fransen, Karen Gagnon, Paige C. Tacey, Mikell White, Cynthia Munoz, Hannatu Amaza, James Lah, Jeffrey Petrella, Leonie Farrington, Alexa Puleio, Winnie Kwang, Maria Chaudhary, Carlota Conant, Veronica Briglall, Debra Silberberg Kovac, Lisa Taylor-Reinwald, Erawadi Singh, Anaztasia Ulysse, Caitlin Webb, Richard King, Paula Ogrocki, Beatriz Vides, Rebecca Long, Ronald C Petersen, Costin Tanase, Meghan Mitchell, Kailey Basham, Eliezer Masliah, Benjamin Wagner, Steven Smith, Dzintra Celmins, Anthony Daley, Duygu Tosun, Nick C. Fox, Roberta Calzavara, Peter J. Snyder, Benjamin Lam, T-Y Lee, Jessica Lam, Susan Landau, Edward B. Lee, James Bateman, Brigid Reynolds, Elizabeth Cheatham, Charles DeCarli, Elaheh Salardini, Neda Jahanshad, Chengshi Jin, Karen Anderson, Amelia Troutman, Sophia I. Thomopoulos, Jennifer Frascino, Christine Dittrich, Michael Borrie, Jessica Swiniarski, Zoë Potter, Tara Villinger, Candy Monarrez, William Potter, Agathe Vrillon, Sydni Jenee Hill, Karen Nolan, Hugo Botha, Jennifer Davis, Michael Rafii, Kathryn Turner, Kelly Nudelman, Sudha Seshadri, Renaud La Joie, Joanna Gonzalez, Sarah Malakauskas, Lisa Thomas, Erin Westerhold, Kimberly Martin, Bruce L. Miller, Fabiola Magana, Jonathan Cordona, Socorro Trujillo, Colleen Albers, Raymundo Hernando, Howard Bergman, Derek Flenniken, Leonard Matoush, Esmeralda Morales, Sonia Garrison, Adeyinka Ajayi, Chi Kim, Kristin Harkins, Marie Bernard, Bridget Holvey, Danielle Goldfarb, Valory Pavlik, Sochenda Stephens, Gregory S. Day, Katlynn Patterson, Natalie Martinez, Katie Vo, Stephen Salloway, Wendy Stewart, Cierra McCurry, Kathleen Savage, Kathleen Johnson, Heather Rose, Aaliyah Korkoyah, Samantha Rogers, Peng Xu, Stephanie Rossi Chen, Zaven Khachaturian, Caitlin Chiado, Rachel Henson, Allan Levey, Julien Lagarde, Maria Corona, Lauren Mariotti, Ajay Sood, Bin Zhang, Katie Seidenberg, Jennifer Ramirez, Andrea Williams, Saurabh Sharma, Vanessa Clayton, Barbara Hackenmiller, Olusegun Adegoke, Dongming Cai, Maria Toth, Mary Sano, Jennifer L Johns, Martin Sadowski, Jaimie Ziolkowski, Jessica Harkins, Minghui Wang, Sarah Binder, Michael Erkkinen, Jared Brosch, Paul Newhouse, Martin Farlow, Zoe Lin, Madeline Paczynski, Thomas Obisesan, Allison Ardolino, Heather Nicole Elmore, James O’Connor, Carl Sadowsky, Morgan Blackburn, Anna Middleton, Haley Bernhardt, Elizabeth Robinson, Marwan Sabbagh, Steven MacDonald, Daniel Clark, J. Q. Trojanowki, Pallavi Sachdev, Maria Carrillo, Lindsey Booth Robbins, Arjun Masurkar, Stephen Smilowitz, Karen Dagerman, Kimberly Jackson, Teresa Kalowsky, Elizeva Ellie Phillips, Arvin Forghanian-Arani, Marianne Sanders, Stephen Correia, Phyllis Vaughn, Sanjay Asthana, Hector A. Gonzalez, Abhay Moghekar, Brandon Anderson, Mario Masellis, Skylar Wilson, Tom Montine, Samantha Sullivan, Amber Khan, Mauricio Becerra, Jessica Morales, Judith Neugroschl, Michael Alosco, Jeffrey Kaye, Jason Karlawish, Aimee Pierce, Sonia Pawluczyk, Bradley Boeve, Pauline Wu, Delaney Fragale, Olga Brawman-Mintzer, Kimberly Blanchard, P. Murali Doraiswamy, Heather Klemp, Judith Heidebrink, Phyllis Switzer, Omobolanle Ayo, Gad Marshall, Nicole Robert, Katherine Berner, Jennifer Rowell, Raymond Scott Turner, Robert Bryant, Stephanie de Santiago, Minal Vasanawala, William Hu, Katherine Stapleton, Kejal Kantarci, Abigail O’Connell, Seth Gale, James Webster, Oscar Lopez, Naomi Saito, Miriam Ashford, Richard J. Perrin, David T. Jones, Melanie Tallakson, Jennifer Mahaffey, Steven Chao, Robert Swarm, Julia Boudreau, Zhala Taghi-Zada, Evan Fletcher, Clifford R. Jack, Amanda Brennan, William Jagust, Josalen Gondrez, Hannah Craft, Isabella Hoang, Katherine Britt, Elizabeth Shaffer, Matthew Senjem, Nunzio Pomara, Heather Russell, Jennifer Ryan, Brendan Kelley, Jason Weller, Nina Silverberg, Rachel Nosheny, Chadwick M. Hales, Kelly Wallace, Emily McKinley, Sterling C Johnson, Gillian Devereux, Paul Eigenberger, Kerry Crawley, Regina M. Silver, Stacey Winterton, Ozioma Okonkwo, Jeffrey Maneval, Nathaniel Houghtaling, Jeff Williamson, Anton Porsteinsson, Kayley Lawrence, Lon Schneider, Joanne Lim, Mauro Veras Acosta, Paul A. Yushkevich, Immaculata Okonkwo, Donna Masterman, Robert A. Koeppe, Melissa Yu, Emily Little, Victor Villemagne, Jennifer Salazar, Justin Long, Jenny Echevarria, Jesse Mez, Stephanie Smith, David Knopman, Meghan Riddle, Leon Thal, Randall Barker, Aidyn Rose Hills, Jessica Nath, Virginia Rogers, Nasrin Ghesani, Rebecca Devine, Dana Mathews, Brittney Luong, Jennifer Wong, Abigail Mathewson, Lawrence S. Honig, Jane Mwicigi, Andrew Ellison, Harold Matthew Cooper, Shannon L. Risacher, Jennifer Horenkamp, Jahmila Al-Amin, Kirsten Hendrickson, Adam Fleisher, Duygu Tosun-Turgut, Katherin Martin, Andrew Kertesz, Elizabeth Trejo, Karen L. Crawford, Mayer Joshua Hasbani, Konstantinos Chiotis, Laurel Beckett, Rebecca Taylor, Trung Nguyen, David Geldmacher, Jeffrey Bishop, Gilberto Perez, Sarah Bowser, Douglas W. Scharre, Ilya Nasrallah, Sandra Calderon, Arun Ramamurthy, Ava Stipanovich, Lora Gallagher, Paul Malloy, Parichita Choudhury, Michaela Johnson, Nigel J. Cairns, Richard Frank, Sandra Black, Maria Gallegos, Robert Reid, Susan Good, Members of the Alzheimers Disease Neuroimaging Initiative, Patricia O’Donnell, Jonathan P Jackson, Vanessa Guzman, Nicole Johnson, Yuliana Cabrera, Brittany Marti, Michelle Villar, John Rogers, Sandra Talavera, Amanda Smith, Yang Wan, Michael Glass, Paul S Aisen, Isabella Levesque, James Ruszkiewicz, Elizabeth McCorkle, Amber Watkins, Catherine Munro, Joseph Bottoms, Godfrey D. Pearlson, Doris Chen, Maureen McMillan, Scott McGinnis, Laszlo Mechtler, Michael W. Weiner, Stephanie Reeder, W. Toga, Esteban Figueroa, Gil D Rabinovici, Sanjeev Vaishnavi, James Brewer, Lindsey Hergesheimer, Alyssa Miller, Joe Strong, Neill Graff-Radford, Ellen Kim, Virginia Boatwright, Tatiana M. Foroud, Li Shen, Victoria Sanborn, Danielle Harvey, Alison Pietras, Sarah Berman, Monica Rivera-Mindt, Antonio Gama, Genesis Burgos-Rivera, Mercedes Madison, Brian LoPresti, William Harrison, Christopher Schwarz, Pierre Tariot, Sylvia Vincent, Hillel Grossman, Joseph C. Masdeu, Mary Imhansiemhonehi, Christopher van Dyck, Micah Ellis Slaughter, Horacio Capote, Lauren Jennings, Trinity Weisensel, Stephanie O’Malley, Sandhitsu Das, Luter Lui, Courtney Williams, Arthur W. Toga, Queennie Majorie S. Kahulugan, Charles Bernick, Ronald Killiany, Melanie J. Miller, Rebecca Hunt, Justin Robison, Ian M. Grant, Mary Nguyen, Magdalena Korecka, Erin Franklin, Prashanthi Vemuri, Gregory Pontone, Catherine Cat Conti, Loreece Haddad, Jonathan Graff-Radford, Zaven Kachaturian, Eric Steinberg, Danielle Raynes-Goldfinger, Michael Shannon, Gladiliz Rivera-Delpin, Laurie Ryan, Joseph Di Benedetto, Kedir Adem Hussen, Nguyen DeCapo, Patricia Wiesenauer, Robert C. Green, Maria Cereijo, Parianne Fatica, Princess Carter, Sarah Walter, Qi Zeng, Michael Holt, Robert B. Santulli, Siddharth Khasnavis, Kathryn Moorlach, Erin Murphy, Michele Gutierrez, Alexandria Montero, Maison Abu Raya, Amy Thomas, Laili Soleimani, Roderick McColl, Daniel A. Schwartz, Yaakov Stern, Lorena Monserratt, Laura Barlow, Lisa Schoolcraft, Stephen Hegedus, Leslie M. Shaw, Mike Nguyen, Howard J. Rosen, Yaneicy Gonazalez Rojas, Serena Cepeda, Donna Veronelli, John Morris, María Katherine Salom Gutiérrez, Allison Lapins, Jesse Stanhope, Vijay Ramanan, Ian Malone, David Soleimani-Meigooni, Cynthia M. Carlsson, Jillian Turner, Gustavo Jimenez, Christopher Scott, Kirsten Evans, Michelle McDonnell, Vahram Haroutunian, Michael Callan, Amy Perkins, Liana G. Apostolova, Caileigh Zimmerman, Maria Greig-Custo, Anjana Mandal, Fatima S. Amtashar, Oshoze Kadiri, Adam Diaz, Ranjan Duara, Javed Khan, Wendy Qiu, Catherine McAdams-Ortiz, Matt Glittenberg, Kwangsik Nho, Yanan Shang, Rima Kaddurah-Daouk, Sallie Carpentier, Jennifer Olgin, Freda Crawford, Tatiana Jimenez-Knight, Andrew J. Saykin, A‘llana Marolt, Ashton Ellison, Allison Emborsky, Giuseppe Esposito, Michelle Hernandez, Denise Reyes, Alexander Alex Frolov, Arthur Williams, Olivia Schultz, Martha Combs, Dariya Malyarenko, Marilyn Albert, Paul Thompson, Carolyn Liebsack, Ryan O‘Dell, Kelley Faber, Alireza Atri, Crystal Flynn Longmire, Kelly Clark, Francisco Rivera, V. Sotelo, Talia M. Nir, Howard Chertkow, Diana Truran Sacrey, Kaori Kubo Germano, Matthew R. Jones, Raj Shah, Lauren Garcia, Taeho Jo, Emily Clark, Michael Donohue, YuQuan ″Oliver″ Lu, Jeffrey Burns
article en

Abstract

Alzheimer's disease (AD) disproportionately affects women and carriers of the apolipoprotein E ε4 allele (APOE4), yet little is known about how sex and APOE interact to influence white matter (WM) integrity during disease progression. We integrated diffusion MRI and matched blood transcriptomic data to investigate these interactions and their underlying biological mechanisms. WM microstructure was quantified using diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI), and regional vulnerability was assessed with a composite vulnerability score (CVS) derived from associations between diffusion features and AD severity across clinical traits in each of the four sex-APOE groups (female or male, with or without APOE4). Brain parcellation with the Eve atlas revealed regions consistently affected across sex-APOE groups (e.g., parahippocampal and superior temporal gyri) and regions specific to individual groups (e.g., the cingulum in females with APOE4 and the middle frontal gyrus in males without APOE4). Gene co-expression network analysis of the matched blood expression data identified gene subnetworks linked to group-specific regional vulnerability, including a muscle tissue morphogenesis module regulated by NEURL1B and HIST1H2BN associated with middle frontal gyrus vulnerability. These findings demonstrate that sex and APOE genotype jointly shape region-specific WM vulnerability and its molecular signatures in AD. Understanding these interactions provides novel mechanistic insights and may inform precision approaches to drug development, biomarker discovery, and clinical trial design for AD.

GeroScience
University of Minnesota (US), The King's College (US), Geriatric Research Education and Clinical Center (US), James J. Peters VA Medical Center (US), Minneapolis VA Health Care System (US), Icahn School of Medicine at Mount Sinai (US)
Gender equality
Openalex Percentile: Top 52%
Advanced Neuroimaging Techniques and Applications
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.