Citations 2
Alzheimer Disease as a Clinical-Biological Construct—An International Working Group Recommendation
Dubois, Bruno , Villain, Nicolas , Schneider, Lon S. , Galasko, Douglas, Kivipelto, Miia , Jessen, Frank , Boada, Merçé , Barkhof, Frederik , Frederiksen, Kristian Steen , Planche, Vincent , Bejanin, Alexandre , Ibáñez, Agustín , Blennow, Kaj , Agronin, Marc , Lopera, Francisco, Delano‐Wood, Lisa , Bombois, Stéphanie , Lévy, Richard, Thambisetty, Madhav , Swantek, Sandra, Newhouse, Paul , Feldman, Howard , Frisoni, Giovanni B. , Bejanin, Alexandre , Barkhof, Frederik , Ibañez, Agustín , Boada, Merce , Feldman, Howard H , Fox, Nick C. , Campbell, Noll L. , Hanseeuw, Bernard , Nordberg, Agneta , Froelich, Lutz , Waldemar, Gunhild , Padovani, Alessandro , Rowe, Christopher Cleon , Cappa, Stefano F. , Caramelli, Paulo , Nitríni, Ricardo , Allegri, Ricardo , Slachevsky, Andrea , Souza, Leonardo Cruz de , Bozoki, Andrea C , Widera, Eric , Ritchie, Craig , Lopera, Francisco, Georges, Jean , Jones, David T. , Lavretsky, Helen , Schott, Jonathan M. , Gatchel, Jennifer R.
JAMA Neurology | November 1, 2024 | Volume: 81 | Issue: 12 | Pages: 1304
Importance Since 2018, a movement has emerged to define Alzheimer disease (AD) as a purely biological entity based on biomarker findings. The recent revision of the Alzheimer’s Association (AA) criteria for AD furthers this direction. However, concerns about a purely biological definition of AD being applied clinically, the understanding of AD by society at large, and the translation of blood-based biomarkers into clinical practice prompt these International Working Group (IWG) updated recommendations. Objective To consider the revised AA criteria and to offer an alternative definitional view of AD as a clinical-biological construct for clinical use. The recommendations of the 2021 IWG diagnostic criteria are updated for further elaborating at-risk and presymptomatic states. Evidence Review PubMed was searched for articles published between July 1, 2020, and March 1, 2024, using the terms “biomarker” OR “amyloid” OR “tau” OR “neurodegeneration” OR “preclinical” OR “CSF” OR “PET” OR “plasma” AND “Alzheimer’s disease.” The references of relevant articles were also searched. Findings In the new AA diagnostic criteria, AD can be defined clinically as encompassing cognitively normal people having a core 1 AD biomarker. However, recent literature shows that the majority of biomarker-positive cognitively normal individuals will not become symptomatic along a proximate timeline. In the clinical setting, disclosing a diagnosis of AD to cognitively normal people with only core 1 AD biomarkers represents the most problematic implication of a purely biological definition of the disease. Conclusions and Relevance The ultimate aim of the field was to foster effective AD treatments, including preventing symptoms and dementia. The approach of diagnosing AD without a clinical and biological construct would be unwarranted and potentially concerning without a clear knowledge of when or whether symptoms will ever develop. It is recommended that those who are amyloid-positive only and, more generally, most biomarker-positive cognitively normal individuals, should not be labeled as having AD. Rather, they should be considered as being at risk for AD. The expansion of presymptomatic AD is viewed as a better diagnostic construct for those with a specific pattern of biomarkers, indicating that they are proximate to the expression of symptoms in the near future.
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. , 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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 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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.