Etiology of White Matter Hyperintensities in Autosomal Dominant and Sporadic Alzheimer Disease
Authors: Shirzadi Zahra , Schultz Stephanie A. , Yau Wai-Ying W. , Joseph-Mathurin Nelly , Fitzpatrick Colleen D. , Levin Raina , Kantarci Kejal , Preboske Gregory M. , Jack Clifford R. , Farlow Martin R. , Hassenstab Jason , Jucker Mathias , Morris John C. , Xiong Chengjie , Karch Celeste M. , Levey Allan I. , Gordon Brian A. , Schofield Peter R. , Salloway Stephen P. , Perrin Richard J. , McDade Eric , Levin Johannes , Cruchaga Carlos , Allegri Ricardo F. , Fox Nick C. , Goate Alison , Day Gregory S. , Koeppe Robert , Chui Helena C. , Berman Sarah , Mori Hiroshi , Sanchez-Valle Raquel , Lee Jae-Hong , Rosa-Neto Pedro , Ruthirakuhan Myuri , Wu Che-Yuan , Swardfager Walter , Benzinger Tammie L. S. , Sohrabi Hamid R. , Martins Ralph N. , Bateman Randall J. , Johnson Keith A. , Sperling Reisa A. , Greenberg Steven M. , Schultz Aaron P. , Chhatwal Jasmeer P. ,   Dominantly Inherited Alzheimer Network and the Alzheimer’s Disease Neuroimaging Initiative, Weiner Michael W. , Aisen Paul , Petersen Ronald , Jack Clifford R. , Jagust William , Trojanowki John Q. , Toga Arthur W. , Beckett Laurel , Green Robert C. , Saykin Andrew J. , Morris John C. , Perrin Richard J. , Shaw Leslie M. , Khachaturian Zaven , Carrillo Maria , Potter William , Barnes Lisa , Bernard Marie , González Hector , Ho Carole , Hsiao John K. , Jackson Jonathan , Masliah Eliezer , Masterman Donna , Okonkwo Ozioma , Ryan Laurie , Silverberg Nina , Fleisher Adam , Sacrey Diana Truran , Fockler Juliet , Conti Cat , Veitch Dallas , Neuhaus John , Jin Chengshi , Nosheny Rachel , Ashford Miriam , Flenniken Derek , Kormos Adrienne , Montine Tom , Rafii Michael , Raman Rema , Jimenez Gustavo , Donohue Michael , Gessert Devon , Salazar Jennifer , Zimmerman Caileigh , Cabrera Yuliana , Walter Sarah , Miller Garrett , Coker Godfrey , Clanton Taylor , Hergesheimer Lindsey , Smith Stephanie , Adegoke Olusegun , Mahboubi Payam , Moore Shelley , Pizzola Jeremy , Shaffer Elizabeth , Sloan Brittany , Harvey Danielle , Forghanian-Arani Arvin , Borowski Bret , Ward Chad , Schwarz Christopher , Jones David , Gunter Jeff , Kantarci Kejal , Senjem Matthew , Vemuri Prashanthi , Reid Robert , Fox Nick C. , Malone Ian , Thompson Paul , Thomopoulos Sophia I. , Nir Talia M. , Jahanshad Neda , DeCarli Charles , Knaack Alexander , Fletcher Evan , Tosun-Turgut Duygu , Chen Stephanie Rossi , Choe Mark , Crawford Karen , Yushkevich Paul A. , Das Sandhitsu , Koeppe Robert A. , Reiman Eric M. , Chen Kewei , Mathis Chet , Landau Susan , Cairns Nigel J. , Householder Erin , Franklin Erin , Bernhardt Haley , Taylor-Reinwald Lisa , Korecka Magdalena , Figurski Michael , Neu Scott , Nho Kwangsik , Risacher Shannon L. , Apostolova Liana G. , Shen Li , Foroud Tatiana M. , Nudelman Kelly , Faber Kelley , Wilmes Kristi , Thal Leon , Silbert Lisa C. , Lind Betty , Crissey Rachel , Kaye Jeffrey A. , Carter Raina , Dolen Sara , Quinn Joseph , Schneider Lon S. , Pawluczyk Sonia , Becerra Mauricio , Teodoro Liberty , Dagerman Karen , Spann Bryan M. , Brewer James , Vanderswag Helen , Ziolkowski Jaimie , Heidebrink Judith L. , Zbizek-Nulph Lisa , Lord Joanne L. , Mason Sara S. , Albers Colleen S. , Knopman David , 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 , Stern Yaakov , Honig Lawrence S. , Mintz Akiva , Ances Beau , 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 A. , Greenberg Jonathan , Mitsis Effie , Shah Raj C. , Lamar Melissa , 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 , Sadowski Martin , Wisniewski Thomas , 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 , Wong Terence Z. , Borges-Neto Salvador , Karlawish Jason H. , Wolk David A. , Vaishnavi Sanjeev , Clark Christopher M. , Arnold Steven E. , Smith Charles D. , Jicha Gregory A. , El Khouli Riham , Raslau Flavius D. , Lopez Oscar L. , Oakley MaryAnn , Simpson Donna M. , Porsteinsson Anton P. , Martin Kim , Kowalski Nancy , Keltz Melanie , Goldstein Bonnie S. , Makino Kelly M. , Ismail M. Saleem , Brand Connie , Thai Gaby , Pierce Aimee , Yanez Beatriz , Sosa Elizabeth , Witbracht Megan , Kelley Brendan , Nguyen Trung , Womack Kyle , Mathews Dana , Quiceno Mary , Levey Allan I. , Lah James J. , Hajjar Ihab , Cellar Janet S. , Burns Jeffrey M. , Swerdlow Russell H. , Brooks William M. , Silverman Daniel H.S. , Kremen Sarah , Tingus Kathleen , Lu Po H. , Bartzokis George , Woo Ellen , Teng Edmond , Graff-Radford Neill R. , Parfitt Francine , Poki-Walker Kim , Farlow Martin R. , Hake Ann Marie , Matthews Brandy R. , Brosch Jared R. , Herring Scott , van Dyck Christopher H. , Mecca Adam P. , Good Susan P. , MacAvoy Martha G. , Carson Richard E. , Varma Pradeep , Chertkow Howard , Vaitekunis Susan , Hosein Chris , Black Sandra , Stefanovic Bojana , Heyn Chris (Chinthaka) , Hsiung Ging-Yuek Robin , Kim Ellen , Mudge Benita , Sossi Vesna , Feldman Howard , Assaly Michele , Finger Elizabeth , Pasternak Stephen , Rachinsky Irina , Kertesz Andrew , Drost Dick , Rogers John , Grant Ian , Muse Brittanie , Rogalski Emily , Robson Jordan , Mesulam M.-Marsel , Kerwin Diana , Wu Chuang-Kuo , Johnson Nancy , Lipowski Kristine , Weintraub Sandra , Bonakdarpour Borna , Pomara Nunzio , Hernando Raymundo , Sarrael Antero , Rosen Howard J. , Miller Bruce L. , Perry David , Turner Raymond Scott , Johnson Kathleen , Reynolds Brigid , MCCann Kelly , Poe Jessica , Sperling Reisa A. , Johnson Keith A. , Marshall Gad A. , Yesavage Jerome , Taylor Joy L. , Chao Steven , Coleman Jaila , White Jessica D. , Lane Barton , Rosen Allyson , Tinklenberg Jared , Belden Christine M. , Atri Alireza , Clark Kelly A. , Zamrini Edward , Sabbagh Marwan , Killiany Ronald , Stern Robert , Mez Jesse , Kowall Neil , Budson Andrew E. , Obisesan Thomas O. , Ntekim Oyonumo E. , Wolday Saba , Khan Javed I. , Nwulia Evaristus , Nadarajah Sheeba , Lerner Alan , Ogrocki Paula , Tatsuoka Curtis , Fatica Parianne , Maillard Pauline , Olichney John , Carmichael Owen , Bates Vernice , Capote Horacio , Rainka Michelle , Borrie Michael , Lee T-Y , Bartha Rob , Johnson Sterling , Asthana Sanjay , Carlsson Cynthia M. , Perrin Allison , Burke Anna , Scharre Douglas W. , Kataki Maria , Tarawneh Rawan , Hart David , Zimmerman Earl A. , Celmins Dzintra , Miller Delwyn D. , Boles Ponto Laura L. , Smith Karen Ekstam , Koleva Hristina , Shim Hyungsub , Nam Ki Won , Schtulz Susan K. , Williamson Jeff D. , Craft Suzanne , Cleveland Jo , Yang Mia , Sink Kaycee M. , 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 , Shi Jiong , Garcia Angelica , Newhouse Paul , Potkin Steven , Salloway Steven , Malloy Paul , Correia Stephen , Kittur Smita , Pearlson Godfrey D. , 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 , Arfanakis Konstantinos , Varon Daniel , Greig Maria T. , Goldstein Bonnie , Martin Kimberly S. , Reist Christopher , Sadowsky Carl , Martinez Walter , Villena Teresa , Rosen Howard , Marshall Gad , Peskind Elaine R. , Petrie Eric C. , Li Gail , Noble James M. , Voglein Jonathan , Chrem Mendez Patricio , Surace Ezequiel , Ikonomovic Snezana , Nadkarni Neelesh K. , Lopera Francisco , Ramirez Laura , Aguillon David , Leon Yudy , Ramos Claudia , Alzate Diana , Baena Ana , Londono Natalia , Moreno Sonia , Laske Christoph , Kuder-Buletta Elke , Graber-Sultan Susanne , Preische Oliver , Hofmann Anna , Ikeuchi Takeshi , Kasuga Kensaku , Niimi Yoshiki , Ishii Kenji , Senda Michio , Cash Dave , Roh Jee Hoon , Riddle Meghan C. , Menard William , Bodge Courtney , Surti Mustafa , Takada Leonel Tadao , Farlow Martin , Sanchez-Gonzalez VJ , Orozco-Barajas Maribel , Renton Alan E. , Esposito Bianca T. , Karch Celeste M. , Marsh Jacob , Fernanadez Victoria , Jerome Gina , Herries Elizabeth , Llibre-Guerra Jorge , Johnson Erik C.B. , Seyfried Nicholas T. , Brooks William S. , Bechara Jacob A , Franklin Erin E. , Chen Allison , Chen Charles , Flores Shaney , Hantler Nancy , Hornbeck Russ , Jarman Steve , Keefe Sarah , Koudelis Deborah , Massoumzadeh Parinaz , McCullough Austin , McKay Nicole , Nicklaus Joyce , Pulizos Christine , Wang Qing , Mishall Sheetal , Sabaredzovic Edita , Deng Emily , Candela Madison , Smith Hunter , Hobbs Diana , Scott Jalen , Xiong Chengjie , Wang Peter , Xu Xiong , Li Yan , Gremminger Emily , Ma Yinjiao , Bui Ryan , Lu Ruijin , Martins Ralph , Sosa Ortiz Ana Luisa , Daniels Alisha , Courtney Laura , Mori Hiroshi , Supnet-Bell, PhD (CSB) Charlene , Xu Jinbin , Ringman John , Barthelemy Nicolas , Smith Jennifer 
Published: October 2023

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 &amp;lt; .001]; HABS: t = −2.2 [P = .03]), greater in older individuals (DIAN: t = 6.8 [P &amp;lt; .001]; ADNI: t = 9.1 [P &amp;lt; .001]; HABS: t = 5.4 [P &amp;lt; .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 &amp;lt; .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.