Smith, Stephanie R.
Mayo Clinic
for the ADNI, ALFA, and PREVENT-AD Study Groups
Citations 2
Plasma Phosphorylated Tau 217 to Identify Preclinical Alzheimer Disease
Janelidze, Shorena, Bali, Divya , Dolado, Anna Orduña , Binette, Alexa Pichet , Rahmouni, Nesrine , Blennow, Kaj, Doré, Vincent , Feizpour, Azadeh , Rowe, Christopher C., Villeneuve, Sylvia , Petersen, Ronald C., Jack, Clifford R. , Groups, ADNI, ALFA, and PREVENT-AD Study, Adegoke, Olusegun, Hussen, Kedir Adem, Aisen, Paul, Ajayi, Adeyinka, Amaza, Hannatu, Apostolova, Liana G. , Ashford, Miriam T. , Ayo, Omobolanle, Bernard, Marie , Bernhardt, Haley, Boatwright, Virginia, Borowski, Bret, Brylska, Magdalena, Buckholtz, Neil, Cabrera, Yuliana, Cairns, Nigel J. , Carrillo, Maria, Choe, Mark, Clanton, Taylor, Conti, Cat, Craft, Hannah, Crawford, Karen , DeCarli, Charles , Benedetto, Joseph Di, Diaz, Adam , Drake, Erin, Faber, Kelley, Felmlee, Joel P. , Fidell, Andrea, Flenniken, Derek , Fockler, Juliet , Forghanian-Arani, Arvin, Frank, R.T., Franklin, Erin , Glittenberg, Matt, Gunter, Jeff, Guzmán, Vanessa , Harvey, Danielle, Hedberg, Caitie, Hergesheimer, Lindsey, Hoang, Isabella, Jackson, Jonathan , Jagust, William, Jahanshad, Neda , Jenkins, Cecily, Jiménez, Gustavo , Jin, Chengshi , Kachaturian, Zaven, Kaddurah-Daouk, Rima, Kantarci, Kejal, Karlawish, Jason , Khachaturian, Zaven S., Knaack, Alexander , Korecka, Magdalena , Kormos, Adrienne, Germano, Kaori Kubo, Kwang, Winnie, Lacy, Kaci, Landau, Susan, Lopresti, Brian J. , Magana, Fabiola, Mahboubi, Payam, Malone, Ian G., Masliah, Eliezer , Masterman, Donna, Matoush, Leonard, Miller, Melanie J. , Molchan, Susan, Montine, Tom, Moore-Weiss, John, Neu, Scott, Nosheny, Rachel L. , Ogwang, Sheila, Okonkwo, Ozioma, Parkins, Shaniya, Perrin, Richard J. , Petersen, Ronald, Pizzola, Jeremy, Potter, Zoë, Potter, William Z., Rafii, Michael, Raman, Rema , Reyes, Calvin, Reyes, Denise , Robison, Justin , Chen, Stephanie Rossi, Ryan, Laurie, Sachdev, Pallavi, Saito, Naomi , Salazar, Jennifer, Thao, Mai Seng, Shaffer, Elizabeth , Shaw, Leslie M. , Silverberg, Nina, Strong, Joe, Talavera, Sandra , Taylor‐Reinwald, Lisa, Thal, Leon J., Thomas, Lisa , Thompson, Paul , Tosun, Duygu , Trojanowki, John Q., Sacrey, Diana Truran, Villemagne, Victor L. , Walter, Sarah , Wan, Yang , Ward, Chad, Webb, Caitlin, Weiner, Michael W. , Weisensel, Trinity, Zimmerman, Caileigh, Poirier, Judes, Breitner, John C.S. , Badawy, Mohamed , Baril, Andrée‐Ann, Aguilar, Ricardo A, Gorriti, Annabella B, Gispert, Lidia C, Martinez, Alba C, Iglesias, Ruth D, Julian, Sherezade F, Serra, P, González‐Escalante, Armand , Penas, Laura H, Rodriguez, Gema H, Ninou, Jordi H, Gamaz, Laura Iglesias, Knezevic, Iva, Alvarez, Paula M, Diaz, Tania M, Palacios, Eva , Ballester, A, Mendez, Sandra P, Freixedes, Laura Ros, Vila, Aleix S, Harster, Lluis S, Prat, Anna S, Jaramillo, Marc V, Jack, Clifford R , Feizpour, Azadeh , Doré, Vincent , Pichet Binette, Alexa , Salvadó, Gemma , Janelidze, Shorena , Therriault, Joseph , Brum, Wagner Scheeren , Stomrud, Erik , Mattsson, Niklas , Palmqvist, Sebastian , Coomans, Emma M. , Teunissen, Charlotte E. , Flier, Wiesje M. van der , Benzinger, Tammie L.S. , Gispert, Juan Domingo , Blennow, Kaj , Alcolea, Daniel , Fortea, Juan , Johnson, Sterling C. , Rosa-Neto, Pedro , Schindler, Suzanne E. , Suárez‐Calvet, Marc , Ossenkoppele, Rik , Hansson, Oskar , Groups, ADNI, ALFA, and PREVENT-AD Study, Aisen, Paul , Barnes, Lisa L. , Beckett, Laurel , Das, Sandhitsu R. , Donohue, Michael , Drake, Erin, Erickson, Claire M. , Fletcher, Evan M. , Arani, Arvin , Foroud, Tatiana , Fox, Nick C. , Frank, Richard, González, Hector, Green, Robert C. , Grill, Joshua D. , Harkins, Kristin , Ho, Carole , Hsiao, John , Jo, Taeho, Kaddurah‐Daouk, Rima , Kantarci, Kejal , Koeppe, Robert A. , Largent, Emily A. , Lee, Edward B. , Lee, Virginia M.‐Y. , Morris, John C. , Nho, Kwangsik T. , Nir, Talia M. , Nudelman, Kelly , Okonkwo, Ozioma, Petersen, Ronald, Rabinovici, Gil D. , Rafii, Michael S. , Reid, Robert, Reyes, Denise, Risacher, Shannon L. , Mindt, Mónica Rivera , Sachdev, Pallavi, Saykin, Andrew J. , Schwarz, Christopher G. , Senjem, Matthew L. , Li, Shen , Smith, Stephanie R. , Snyder, Peter J. , Thomopoulos, Sophia I. , Toga, Arthur W. , Vemuri, Prashanthi , Yushkevich, Paul A. , Badawy, Mohamed, Baillet, Sylvain , Minguillón, Carolina , Brugulat‐Serrat, Anna , Cacciaglia, Raffaele , Campo, Marta del , Pascual, Maria, Rodríguez‐Fernández, Blanca , Vilor‐Tejedor, Natàlia
JAMA Neurology | September 15, 2025 | Volume: 82 | Issue: 11 | Pages: 1122
Importance Advances in Alzheimer disease (AD) have shifted research focus to earlier disease stages, necessitating more scalable approaches to identify cognitively unimpaired individuals with amyloid β (Aβ) pathology. Objective To assess the utility of plasma phosphorylated tau 217 (p-tau217) for classifying Aβ status in cognitively unimpaired individuals, both as a stand-alone test and in a 2-step approach where positive plasma results were confirmed using a second modality (Aβ positron emission tomography [PET] or cerebrospinal fluid [CSF]). Design, Setting, and Participants This cross-sectional cohort study used data collected between June 2009 and March 2024. We included 2916 cognitively unimpaired participants from 12 international independent observational cohorts in the US, Europe, Australia, and Canada with available plasma p-tau217 levels and CSF or PET Aβ biomarkers. Performance comparisons between mass spectrometry and immunoassay-based p-tau217 measurements were also performed (n = 964). Exposures Plasma p-tau217 levels measured by immunoassay. Main Outcome and Measures Aβ status, determined by CSF or Aβ PET biomarkers. Results Participants had a mean (SD) age of 66.9 (9.9) years; 971 (33.3%) were Aβ positive by either CSF or PET, 1667 (57.2%) were women, and 1108 (38.1%) carried at least 1 APOE ε4 allele. As a stand-alone test, plasma p-tau217 achieved a positive predictive value (PPV) of 79% (95% CI, 74-84) and an overall accuracy of 81% (95% CI, 80-82). In a 2-step workflow, the PPV and accuracy significantly increased to 91% (95% CI, 86-95). While this approach required screening of 677 individuals with plasma p-tau217 to identify 100 Aβ-positive individuals, compared to 536 participants when using PET alone, it reduced the need for PET testing to 124. Immunoassays demonstrated comparable PPVs to mass spectrometry (80% [95% CI, 74-86] vs 85% [95% CI, 81-90]; P = .12) but significantly lower overall accuracy (82% [95% CI, 79-84]% vs 88 [95% CI, 86-90]; P < .001) and true Aβ-positive detection rate (49% [95% CI, 43-55] vs 69% [95% CI, 64-75]; P < .001). Conclusions and Relevance The findings highlight the potential of plasma p-tau217 as a stand-alone test—or when used in a sequential 2-step approach alongside PET or CSF testing—as a cost-effective, scalable, and minimally burdensome strategy for identifying preclinical AD. Tailored screening workflows that incorporate p-tau217 can improve efficiency in participant selection for preclinical AD trials and, in the future, help guide access to disease-modifying treatments.
Etiology of White Matter Hyperintensities in Autosomal Dominant and Sporadic Alzheimer Disease
Shirzadi, Zahra , Schultz, Stephanie A. , Yau, Wai‐Ying Wendy , Fitzpatrick, Colleen , Levin, Raina, Kantarci, Kejal , Preboske, Gregory M., Jack, Clifford R. , Farlow, Martin R. , Hassenstab, Jason , Morris, John C. , Xiong, Chengjie , Levey, Allan I. , Gordon, Brian A. , Salloway, Stephen , Perrin, Richard J. , Xiong, Chengjie , Fox, Nick C. , Goate, Alison , Day, Gregory S. , Chui, Helena C., Berman, Sarah , Mori, Hiroshi , Ruthirakuhan, Myuri , Wu, Che‐Yuan , Sohrabi, Hamid R. , Martins, Ralph N. , Johnson, Keith A. , Greenberg, Steven M. , Chhatwal, Jasmeer P. , Initiative, Dominantly Inherited Alzheimer Network and the Alzheimer’s Disease Neuroimaging, Weiner, Michael W. , Aisen, Paul, Petersen, Ronald , Jack, Clifford R., Jagust, William J. , Trojanowki, John Q., Morris, John C., Shaw, Leslie M. , Khachaturian, Zaven S., Carrillo, Maria, Potter, William Z., Bernard, Marie , Jackson, Jonathan , Masliah, Eliezer , Masterman, Donna, Okonkwo, Ozioma C. , Ryan, Laurie, Silverberg, Nina, Fleisher, Adam , Sacrey, Diana Truran, Fockler, Juliet , Conti, Cat, Jin, Chengshi , Nosheny, Rachel L. , Ashford, Miriam T. , Flenniken, Derek , Kormos, Adrienne, Montine, Tom, Raman, Rema , Jiménez, Gustavo , Gessert, Devon, Salazar, Jennifer, Zimmerman, Caileigh, Cabrera, Yuliana, Walter, Sarah , Miller, Garrett, Coker, Godfrey, Clanton, Taylor, Hergesheimer, Lindsey, Adegoke, Olusegun, Mahboubi, Payam, Moore, Shelley, Pizzola, Jeremy, Shaffer, Elizabeth , Sloan, Brittany, Forghanian-Arani, Arvin, Borowski, Bret, Ward, Chad, Gunter, Jeff, Jahanshad, Neda , DeCarli, Charles, Knaack, Alexander , Chen, Stephanie Rossi, Choe, Mark, Crawford, Karen , Reiman, Eric M. , Mathis, Chet, Landau, Susan, Cairns, Nigel J., Householder, Erin, Franklin, Erin , Bernhardt, Haley, Taylor‐Reinwald, Lisa, Korecka, Magdalena , Figurski, Michael, Neu, Scott, Apostolova, Liana G. , Foroud, Tatiana M., Faber, Kelley, Wilmes, Kristi, Thal, Leon J., Lind, Betty, Crissey, Rachel, Carter, Raina, Dolen, Sara, Schneider, Lon S. , Pawluczyk, Sonia, Becerra, Mauricio, Teodoro, Liberty, Dagerman, Karen, Spann, Bryan M., Brewer, James B., Vanderswag, Helen, Ziolkowski, Jaimie, Heidebrink, Judith L. , Zbizek-Nulph, Lisa, Mason, Sara S., Albers, Colleen S., Johnson, Kris , Villaneuva-Meyer, Javier, Pavlik, Valory , Pacini, Nathaniel, Lamb, Ashley, Kass, Joseph S. , Doody, Rachelle S., Shibley, Victoria, Chowdhury, Munir , Rountree, Susan, Dang, Mimi, Mintz, Akiva , Winkfield, David, Carroll, Maria , Stobbs-Cucchi, Georgia , Oliver, Angela , Creech, Mary L., Mintun, Mark A., Schneider, Stacy, Geldmacher, David , Love, Marissa Natelson , Griffith, Randall, Clark, David, Brockington, John, Marson, Daniel , Grossman, Hillel, Goldstein, Martin , Mitsis, Effie, Samuels, Patricia, Duara, Ranjan , Greig‐Custo, Maria T., Rodriguez, Rosemarie, Albert, Marilyn, Onyike, Chiadi, Farrington, Leonie, Rudow, Scott, Brichko, Rottislav, Kielb, Stephanie , Smith, Amanda , Raj, Balebail Ashok, Fargher, Kristin, Shulman, Melanie , Faustin, Arline , Rao, Julia, Castro, Karen M. , Ulysse, Anaztasia, Chen, Shannon, Sheikh, Mohammed O., Singleton-Garvin, Jamika, Doraiswamy, P. Murali , Petrella, Jeffrey R. , James, Olga, Borges‐Neto, Salvador , Karlawish, Jason , Vaishnavi, Sanjeev , Clark, Christopher M. , Arnold, Steven E. , Smith, Charles D. , Khouli, Riham El , Raslau, Flavius D., Oakley, MaryAnn, Simpson, Donna M., Martin, Kim, Kowalski, Nancy, Keltz, Melanie, Goldstein, Bonnie S., Makino, Kelly M., Ismail, M. Saleem , Brand, Connie, Thai, Gaby , Pierce, Aimee, Witbracht, Megan , Mathews, Dana, Quiceno, Mary , Hajjar, Ihab , Cellar, Janet S., Swerdlow, Russell H. , Kremen, Sarah , Tingus, Kathleen, Lu, Po H. , Bartzokis, George, Woo, Ellen, Graff‐Radford, Neill R. , Parfitt, Francine, Poki-Walker, Kim, Hake, Ann Marie , Matthews, Brandy R., Herring, Scott, Dyck, Christopher H. van , Mecca, Adam P. , Good, Susan P., MacAvoy, Martha G., Carson, Richard E. , Varma, Pradeep, Chertkow, Howard , Vaitekunis, Susan, Hosein, Chris, Mudge, Benita, Assaly, Michele, Rachinsky, Irina, Kertesz, Andrew, Drost, Dick, Rogers, John, Grant, Ian , Muse, Brittanie, Rogalskı, Emily , Robson, Jordan, Mesulam, M.‐Marsel, Kerwin, Diana , Wu, Chuang‐Kuo, Johnson, Nancy E., Lipowski, Kristine, Weıntraub, Sandra , Bonakdarpour, Borna , Hernando, Raymundo, Sarrael, Antero, Rosen, Howard J., Johnson, Kathleen, Reynolds, Brigid, Poe, Jessica, Sperling, Reisa A., Marshall, Gad A. , Yesavage, Jerome A. , Taylor, Joy L. , Chao, Steven, Coleman, Jaila, White, Jessica D. , Lane, Barton , Rosen, Allyson , Tinklenberg, Jared, Belden, Christine M. , Clark, Kelly, Zamrini, Edward , Sabbagh, Marwan, Kowall, Neil W. , Budson, Andrew E. , Ntekim, Oyonumo, Wolday, Saba, Khan, Javed , Nwulia, Evaristus , Nadarajah, Sheeba , Lerner, Alan J. , Ogrocki, Paula, Tatsuoka, Curtis , Fatica, Parianne, Olichney, John , Bates, Vernice, Capote, Horacio, Rainka, Michelle, Borrie, Michael, Lee, T‐Y, Asthana, Sanjay , Carlsson, Cynthia M., Perrin, Allison, Burke, Anna , Kataki, Maria , Hart, David , Zimmerman, Earl A. , Celmins, Dzintra, Smith, Karen Ekstam, Shim, Hyungsub , Nam, Ki Won , Schtulz, Susan K., Williamson, Jeff D. , Craft, Suzanne , Cleveland, Jo, Ott, Brian R. , Drake, Jonathan, Tremont, Geoffrey , Daiello, Lori A. , Ritter, Aaron, Bernick, Charles , Munic, Donna, O’Connell, Abigail, Mintzer, Jacobo , Wiliams, Arthur, Masdeu, Joseph C. , Shi, Jiong , Garcia, Angelica, Newhouse, Paul , Salloway, Steven, Malloy, Paul, Correia, Stephen , Kittur, Smita, Blank, Karen, Anderson, Karen, Flashman, Laura A. , Seltzer, Marc, Hynes, Mary L. , Santulli, Robert B. , Relkin, Norman , Chiang, Gloria, Lee, Athena, Lin, Michael, Ravdin, Lisa , Sood, Ajay, Blanchard, Kimberly S., Fleischman, Debra , Varon, Daniel, Greig, Maria T., Martin, Kimberly S., Reist, Christopher , Sadowsky, Carl, Villena, Teresa, Rosen, Howard, Peskind, Elaine R. , Li, Gail, Vöglein, Jonathan , Méndez, Patricio Chrem, Ikonomović, Snežana, Nadkarni, Neelesh K. , Ramírez, Laura, Leon, Yudy Milena, Ramos, Cláudia , Alzate, Diana, Baena, Ana , Londono, Natalia, Laske, Christoph , Kuder-Buletta, Elke, Gräber‐Sultan, Susanne, Preische, Oliver, Hofmann, Anna, Ishii, Kenji , Senda, Michio , Riddle, Meghan C., Menard, William, Bodge, Courtney, Surti, Mustafa, Sanchez-Gonzalez, VJ, Orozco-Barajas, Maribel, Esposito, Bianca, Fernanadez, Victoria, Jerome, Gina, Herries, Elizabeth, Seyfried, Nicholas T. , Bechara, Jacob , Chen, Allison , Hantler, Nancy, Hornbeck, Russ C. , Jarman, Steve, Keefe, Sarah , Koudelis, Deborah, Massoumzadeh, Parinaz , Nicklaus, Joyce , Pulizos, Christine, Mishall, Sheetal, Sabaredzovic, Edita, Deng, Emily , Candela, Madison, Smith, Hunter , Scott, Jalen , Gremminger, Emily, Ma, Yinjiao , Bui, Ryan , Lu, Ruijin , Daniels, Alisha , Courtney, Laura, Supnet, Charlene , Xu, Jinbin , Ringman, John M. , Barthélemy, Nicolas R. , Jack, Clifford R , Gordon, Brian A , Kantarci, Kejal , Day, Gregory S , Vöglein, Jonathan , Xiong, Chengjie , Fox, Nick C , Hassenstab, Jason , Morris, John C , Goate, Alison M , Supnet-Bell, Charlene , Berman, Sarah , Levey, Allan I , Kremen, Sarah , Joseph‐Mathurin, Nelly , Jucker, Mathias , Xiong, Chengjie , Karch, Celeste M. , Schofield, Peter R. , McDade, Eric , Cruchaga, Carlos , Allegri, Ricardo , Koeppe, Robert A. , Chui, Helena C. , Sánchez‐Valle, Raquel , Lee, Jae‐Hong , Rosa-Neto, Pedro , Swardfager, Walter , Benzinger, Tammie L.S. , Bateman, Randall J. , Sperling, Reisa Anne , Schultz, Aaron P. , Initiative, Dominantly Inherited Alzheimer Network and the Alzheimer’s Disease Neuroimaging, Jack, Clifford R., Toga, Arthur W. , Beckett, Laurel , Green, Robert C. , Saykin, Andrew J. , Morris, John C., Barnes, Lisa L. , González, Hector, Ho, Carole , Hsiao, John , Veitch, Dallas P. , Neuhaus, John M , Rafii, Michael S. , Donohue, Michael , Smith, Stephanie R. , Harvey, Danielle , Arani, Arvin , Schwarz, Christopher G. , Jones, David T. , Senjem, Matthew L. , Vemuri, Prashanthi , Reid, Robert I. , Malone, Ian B. , Thompson, Paul M. , Thomopoulos, Sophia I. , Nir, Talia M. , Fletcher, Evan M. , Tosun, Duygu , Yushkevich, Paul A. , Das, Sandhitsu R. , Chen, Kewei , Mathis, Chet, Nho, Kwangsik T. , Risacher, Shannon L. , Shen, Li , Nudelman, Kelly , Silbert, Lisa C. , Kaye, Jeffrey , Carter, Raina, Quinn, Joseph F. , Lord, Joanne L. , Knopman, David S. , Stern, Yaakov , Honig, Lawrence S. , Ances, Beau M. , Goldstein, Martin A., Greenberg, Jonathan, Shah, Raj C. , Lamar, Melissa , Duara, Ranjan , Sadowski, Martin , Wısnıewskı, Thomas , Wong, Terence Z. , Wolk, David A. , Jicha, Gregory A. , López, Oscar L. , Porsteinsson, Anton P. , Yanez, Beatriz, Sosa, Elizabeth M. , Kelley, Brendan , Nguyen, Trung Dung , Womack, Kyle , Lah, James J. , Burns, Jeffrey M. , Brooks, William Miles , Silverman, Daniel H.S. , Teng, Edmond , Brosch, Jared R. , Black, Sandra E. , Stefanovic, Bojana , Heyn, Chris , Hsiung, Ging‐Yuek Robin , Kim, Ellen , Sossi, Vesna , Feldman, Howard , Finger, Elizabeth C. , Pasternak, Stephen , Miller, Bruce L. , Perry, David C. , Turner, Raymond Scott , MCCann, Kelly, Sperling, Reisa A., Atri, Alireza , Killiany, Ronald , Stern, Robert A. , Mez, Jesse , Obisesan, Thomas O. , Maillard, Pauline , Carmichael, Owen , Bartha, Robert , Johnson, Sterling C. , Carlsson, Cynthia M. , Scharre, Douglas W. , Tarawneh, Rawan M. , Miller, Del D. , Ponto, Laura L. Boles , Koleva, Hristina , Yang, Mia , Sink, Kaycee M. , Masdeu, Joseph C , Potkin, Steven G. , Salloway, Steve , Pearlson, Godfrey D. , Sood, Ajay, Arfanakis, Konstantinos , Varón, Daniel , Martínez, Walter Fabián , Petrie, Eric C. , Noble, James M. , Surace, Ezequiel , Lopera, Francisco Javier , Aguillon, David , Londono, Natalia, Moreno, Sonia, Ikeuchi, Takeshi , Kasuga, Kensaku , Niimi, Yoshiki , Cash, David M. , Roh, Jee Hoon , Takada, Leonel Tadao , Renton, Alan , Marsh, Jacob A. , Llibre‐Guerra, Jorge J. , Johnson, Erik C. B. , Brooks, William S. , Chen, Charles , Flores, Shaney , McCullough, Austin , McKay, Nicole S. , Wáng, Qīng , Candela, Madison, Hobbs, Diana A. , Wang, Peter , Xu, Xiong, Li, Yan , Sosa, Ana Luisa , Smith, Jennifer A.
JAMA Neurology | October 16, 2023 | Volume: 80 | Issue: 12 | Pages: 1353
ImportanceIncreased white matter hyperintensity (WMH) volume is a common magnetic resonance imaging (MRI) finding in both autosomal dominant Alzheimer disease (ADAD) and late-onset Alzheimer disease (LOAD), but it remains unclear whether increased WMH along the AD continuum is reflective of AD-intrinsic processes or secondary to elevated systemic vascular risk factors.ObjectiveTo estimate the associations of neurodegeneration and parenchymal and vessel amyloidosis with WMH accumulation and investigate whether systemic vascular risk is associated with WMH beyond these AD-intrinsic processes.Design, Setting, and ParticipantsThis cohort study used data from 3 longitudinal cohort studies conducted in tertiary and community-based medical centers—the Dominantly Inherited Alzheimer Network (DIAN; February 2010 to March 2020), the Alzheimer’s Disease Neuroimaging Initiative (ADNI; July 2007 to September 2021), and the Harvard Aging Brain Study (HABS; September 2010 to December 2019).Main Outcome and MeasuresThe main outcomes were the independent associations of neurodegeneration (decreases in gray matter volume), parenchymal amyloidosis (assessed by amyloid positron emission tomography), and vessel amyloidosis (evidenced by cerebral microbleeds [CMBs]) with cross-sectional and longitudinal WMH.ResultsData from 3960 MRI sessions among 1141 participants were included: 252 pathogenic variant carriers from DIAN (mean [SD] age, 38.4 [11.2] years; 137 [54%] female), 571 older adults from ADNI (mean [SD] age, 72.8 [7.3] years; 274 [48%] female), and 318 older adults from HABS (mean [SD] age, 72.4 [7.6] years; 194 [61%] female). Longitudinal increases in WMH volume were greater in individuals with CMBs compared with those without (DIAN: t = 3.2 [P = .001]; ADNI: t = 2.7 [P = .008]), associated with longitudinal decreases in gray matter volume (DIAN: t = −3.1 [P = .002]; ADNI: t = −5.6 [P < .001]; HABS: t = −2.2 [P = .03]), greater in older individuals (DIAN: t = 6.8 [P < .001]; ADNI: t = 9.1 [P < .001]; HABS: t = 5.4 [P < .001]), and not associated with systemic vascular risk (DIAN: t = 0.7 [P = .40]; ADNI: t = 0.6 [P = .50]; HABS: t = 1.8 [P = .06]) in individuals with ADAD and LOAD after accounting for age, gray matter volume, CMB presence, and amyloid burden. In older adults without CMBs at baseline, greater WMH volume was associated with CMB development during longitudinal follow-up (Cox proportional hazards regression model hazard ratio, 2.63; 95% CI, 1.72-4.03; P < .001).Conclusions and RelevanceThe findings suggest that increased WMH volume in AD is associated with neurodegeneration and parenchymal and vessel amyloidosis but not with elevated systemic vascular risk. Additionally, increased WMH volume may represent an early sign of vessel amyloidosis preceding the emergence of CMBs.