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Frequency and Clinical Outcomes Associated With Tau Positron Emission Tomography Positivity
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Eunice Farah, Verfaillie, Sander C.J. , Farzin, Sarah , Salaciak, Alyssa , Tullo, Stéphanie , Daoust, Leslie‐Ann, Köbe, Theresa , McSweeney, Melissa, Nilsson, Nathalie , Pishnamazi, Morteza, Bedetti, Christophe , Hudon, Louise, Greco, Claudia, Chapleau, Marianne , St‐Onge, Frédéric , Boutin, Sophie , Geddes, Maiya R. , Ducharme, Simon , Jean, Gabriel, Sylvain, Elisabeth, Élie, Marie‐Josee, Leblond‐Baccichet, Gloria, Soucy, Jean‐Paul , Ozlen, Hazal , Bailly, Julie, Mohammediyan, Béry, Chen, Yalin , Remz, Jordana, Rentz, Dorene M., Amariglio, Rebecca E. , Blacker, Deborah , Chhatwal, Jasmeer P. , Dickerson, Brad C., Donovan, Nancy J. , Farrell, Michelle E. , Gómez, Cristina Lois, Marshall, Gad A. , Oaoo, Kate, Price, Julie, Prokopiou, Prokopis C. , Reynolds, Gretchen , Skylar-Scott, Irina A., Vila‐Castelar, Clara , Yang, Hyun‐Sik , Trojanowki, John Q., Green, Robert C, Perrin, Richard J. , Shaw, Leslie M. , Potter, William Z. , Bernard, Marie , Jackson, Jonathan, Masliah, Eliezer , 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JAMA | June 16, 2025 | Volume: 334 | Issue: 3 | Pages: 229
Importance Tau positron emission tomography (PET) allows in vivo detection of neurofibrillary tangles, a core neuropathologic feature of Alzheimer disease (AD). Objective To provide estimates of the frequency of tau PET positivity and its associated risk of clinical outcomes. Design, Setting, and Participants Longitudinal study using data pooled from 21 cohorts, comprising a convenience sample of 6514 participants from 13 countries, collected between January 2013 and June 2024. Cognitively unimpaired individuals and patients with a clinical diagnosis of mild cognitive impairment (MCI), AD dementia, or other neurodegenerative disorders were included. Exposures Tau PET with flortaucipir F 18, amyloid-β (Aβ) PET, and clinical examinations. Tau PET scans were visually rated as positive according to a US Food and Drug Administration– and European Medicines Agency–approved method, designed to indicate the presence of advanced neurofibrillary tangle pathology (Braak stages V-VI). Main Outcomes and Measures Frequency of tau PET positivity and absolute risk of clinical progression (eg, progression to MCI or dementia). Results Among the 6514 participants (mean age, 69.5 years; 50.5% female), median follow-up time ranged from 1.5 to 4.0 years. Of 3487 cognitively unimpaired participants, 349 (9.8%) were tau PET positive; the estimated frequency of tau PET positivity was less than 1% in those aged younger than 50 years, and increased from 3% (95% CI, 2%-4%) at 60 years to 19% (95% CI, 16%-24%) at 90 years. Tau PET positivity frequency estimates increased across MCI and AD dementia clinical diagnoses (43% [95% CI, 41%-46%] and 79% [95% CI, 77%-82%] at 75 years, respectively). Most tau PET–positive individuals (92%) were also Aβ PET positive. Cognitively unimpaired participants who were positive for both Aβ PET and tau PET had a higher absolute risk of progression to MCI or dementia over the following 5 years (57% [95% CI, 45%-71%]) compared with both Aβ PET–positive/tau PET–negative (17% [95% CI, 13%-22%]) and Aβ PET–negative/tau PET–negative (6% [95% CI, 5%-8%]) individuals. Among participants with MCI at the time of the tau PET scan, an Aβ PET–positive/tau PET–positive profile was associated with a 5-year absolute risk of progression to dementia of 70% (95% CI, 59%-81%). Conclusions and Relevance In a large convenience sample, a positive tau PET scan occurred at a nonnegligible rate among cognitively unimpaired individuals, and the combination of Aβ PET positivity and tau PET positivity was associated with a high risk of clinical progression in both preclinical and symptomatic stages of AD. These findings underscore the potential of tau PET as a biomarker for staging AD pathology.
Culturally‐informed Community‐engaged Efforts to Improve Inclusion and Engagement of Underrepresented Ethnocultural Populations in the Alzheimer’s Disease Neuroimaging Initiative 3 Study: The ADNI Diversity Task Force
Okonkwo, Ozioma C. , Ashford, Miriam T. , Conti, Catherine , Strong, Jospeh, Raman, Rema , Miller, Garrett, Nosheny, Rachel L. , Coker, Godfrey, Miller, Melanie J. , Petersen, Ronald C. , Aisen, Paul S. S, Mindt, Mónica Rivera , Donohue, Michael , Aisen, Paul , Barkhof, Frederik
Alzheimer's & Dementia | December 25, 2023 | Volume: 19 | Issue: S22 | Pages: No page available
AbstractBackgroundEthnoculturally diverse individuals from underrepresented populations (URPs), including but not limited to Black/African American and Hispanic/Latinx adults, are disproportionally affected by Alzheimer’s disease (AD) compared to non‐Hispanic/Latinx white (NLW) adults. However, URPs have historically been under‐included in AD studies. The objective of this study is to describe efforts, and the results of those efforts, to increase enrollment and engagement of ethnoculturally diverse individuals from URPs in the Alzheimer’s Disease Neuroimaging Initiative 3 (ADNI3).MethodsEfforts undertaken by ADNI to increase enrollment and engagement of URPs included (1) launching of a Diversity Taskforce (DVTF) lead by two health disparities experts in July 2020, charged with overseeing ADNI’s mission in this space. Specific DVTF activities included: (2) the establishment, funding, and instrumental support (e.g., training, consultation, resources) of diversity at 13 ADNI3 sites; (3) changing ADNI protocol to facilitate research participation of URPs (e.g., optional lumbar puncture and sharing of amyloid PET results); (4) hiring a marketing agency to launch culturally‐informed digital/social media campaigns for the 13 DVTF Sites, with local websites; (5) development of a database to capture performance metrics of inclusion efforts at the 13 DVTF Sites; and (6) formation of a six‐member External Advisory Board, comprised of leaders in health disparities research, to guide DVTF efforts.ResultURP enrollment at these 13 DVTF sites improved from 1.1 URPs per month previously to >4 URPs per month, a 264% increase. Across all 59 ADNI sites, overall enrollment of ethnoculturally diverse individuals from URPs went from 89 (16.8%) to 126 (21.1%), representing a 25% increase in enrollment between May 2020 and September 2021. Moreover, since February 1st, 2021, ADNI enrolled 43 new participants of which 33 (77%) were from URPs.ConclusionIt is possible to improve the enrollment and retention of URPs in AD research using a multi‐pronged community engaged approach that also provides human capital, infrastructure, and financial resources. The success of the DVTF has led to the formation of a new Engagement Core in ADNI4, tasked with implementing a scaled‐up culturally‐informed, community‐engaged research approach to URP inclusion and retention across all 59 ADNI sites.
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. 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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.