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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.
Safety and tolerability of lumbar puncture for the evaluation of Alzheimer's disease
Baldaranov, Dobri , García, Victoria , Miller, Garrett, Donohue, Michael , Shaw, Leslie M. , Weiner, Mike, Petersen, Ronald C. , Aisen, Paul , Raman, Rema , Donohue, Michael C , Garcia, Victoria, Rafii, Michael S.
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring | April 19, 2023 | Volume: 15 | Issue: 2 | Pages: No page available
AbstractIntroductionLumbar puncture (LP) to collect and examine cerebrospinal fluid (CSF) is an important option for the evaluation of Alzheimer's disease (AD) biomarkers but it is not routinely performed due to its invasiveness and link to adverse effects (AE).MethodsWe include all participants who received at least one LP in the Alzheimer's Disease Neuroimaging Initiative (ADNI) Study. For comparison between groups, two‐sample t‐tests for continuous, and Pearson's chi‐square test for categorical variables were performed.ResultsTwo hundred twenty‐seven LP‐related AEs were reported by 172 participants after 1702 LPs (13.3%). The mean age of participants who reported at least one AE was 69.79 (standard deviation (SD) 6.3) versus none 72.44 (7.17) years (p < 0.001) with female predominance (115/172 = 67.4% vs 435/913 = 48%), and had greater entorhinal cortical thickness and hippocampal volume (3.903 (0.782) vs 3.684 (0.775) mm, p = 0.002; 7.38 (1.06) vs 7.05 (1.15) mm3, p < 0.001), respectively.DiscussionWe found that younger age, female sex, and greater thickness of the entorhinal cortex were associated with a higher rate of LP‐related AE reports.
Improving generalizability and study design of Alzheimer's disease cohort studies in the United States by including under‐represented populations
Okonkwo, Ozioma C. , Weiner, Michael W. , Aisen, Paul , Ashford, Miriam T. , Coker, Godfrey, Donohue, Michael , Langa, Kenneth M. , Miller, Garrett, Petersen, Ronald C. , Raman, Rema , Nosheny, Rachel L. , Donohue, Michael C , Mindt, Mónica Rivera , Veitch, Dallas P.
Alzheimer's & Dementia | November 14, 2022 | Volume: 19 | Issue: 4 | Pages: 1549-1557
AbstractThe poor generalizability of clinical research data due to the enrollment of highly educated, non‐Latinx White participants hampers the development of therapies for Alzheimer's disease (AD). Black and Latinx older adults have a greater risk for dementia, yet it is unclear how health‐care disparities and sociocultural factors influence potential AD therapies and prognosis. Low enrollment of under‐represented populations may be attributable to several factors including greater exclusion due to higher rates of comorbidities, lower access to AD clinics, and the legacy of unethical treatment in medical research. This perspective outlines solutions tested in the Brain Health Registry (BHR) and the Alzheimer's Disease Neuroimaging Initiative (ADNI), including culturally‐informed digital research methods, community‐engaged research strategies, leadership from under‐represented communities, and the reduction of exclusion criteria based on comorbidities. Our successes demonstrate that it is possible to increase the inclusion and engagement of under‐represented populations into US‐based clinical studies, thereby increasing the generalizability of their results.
Screening and enrollment of underrepresented ethnocultural and educational populations in the Alzheimer's Disease Neuroimaging Initiative (ADNI)
Ashford, Miriam T. , Raman, Rema , Miller, Garrett, Donohue, Michael , Okonkwo, Ozioma C. , Nosheny, Rachel L. , Coker, Godfrey, Petersen, Ronald C. , Aisen, Paul , Weiner, Michael W. , Initiative, the Alzheimer's Disease Neuroimaging, Donohue, Michael C , Mindt, Mónica Rivera , Initiative, the Alzheimer's Disease Neuroimaging
Alzheimer's & Dementia | February 25, 2022 | Volume: 18 | Issue: 12 | Pages: 2603-2613
AbstractIntroductionAn analysis of the ethnocultural and socioeconomic composition of Alzheimer's Disease Neuroimaging Initiative (ADNI) participants is needed to assess the generalizability of ADNI data to diverse populations.MethodsADNI data collected between October 2004 and November 2020 were used to determine ethnocultural and educational composition of the sample and differences in the following metrics: screening, screen fails, enrollment, biomarkers.ResultsOf 3739 screened individuals, 11% identified as being from ethnoculturally underrepresented populations (e.g., Black, Latinx) and 16% had <12 years of education. Of 2286 enrolled participants, 11% identified as ethnoculturally underrepresented individuals and 15% had <12 years of education. This participation is considerably lower than US Census data for adults 60+ (ethnoculturally underrepresented populations: 25%; <12 years of education: 4%). Individuals with <12 years of education failed screening at a higher rate.DiscussionOur findings suggest that ADNI results may not be entirely generalizable to ethnoculturally diverse and low education populations.
The screening and enrollment of underrepresented ethnoracial and educational populations in the Alzheimer's Disease Neuroimaging Initiative
Ashford, Miriam T. , Miller, Garrett, Raman, Rema , Okonkwo, Ozioma C. , Nosheny, Rachel L. , Petersen, Ronald C. , Aisen, Paul , Weiner, Mike, Donohue, Michael , Mindt, Mónica Rivera
Alzheimer's & Dementia | December 31, 2021 | Volume: 17 | Issue: S10 | Pages: No page available
AbstractBackgroundAn analysis of the ethnoracial and educational composition of Alzheimer's Disease Neuroimaging Initiative (ADNI) participants, and the relationship between ethnoracial/education and screening, enrollment, dropout, and biomarkers is needed to assess the generalizability of ADNI data to diverse populations, and to inform efforts to increase diversity.MethodData from all 4 ADNI phases were used to determine ethnoracial and educational breakdown and differences of the following ADNI participation metrics: screening, screen fails, enrollment, as well as drop‐out within and between ADNI phases. Multivariable logistic regression was used to analyze the association between ethnoracial and educational group and either amyloid positivity or ApoE e4 status, adjusting for age, gender, and diagnostic group.ResultAcross the 4 ADNI phases (screened: n=3,739; enrolled: n=2,286), 11% of screened and enrolled participants identified as Latinx, non‐Latinx Black, or non‐Latinx‐Asian and 16% of the screened and 15% of the enrolled participants reported having =<12 years of education. In contrast, the 2019 US Census American Community Survey for adults 60+ reports 25% non‐White, and 44 % =< 12 years of education. There were no observed differences between participants from historically underrepresented ethnoracial groups and NLW participants in screen fail and dropout rates. We found that individuals with =<12 years of education failed screening at a significantly higher rate (p=.01) and rolled‐over significantly less to subsequent ADNI phases (p<.001) compared to individuals with an education >12 years. Identifying as non‐Latinx Asian was associated with lower odds of being amyloid positive (OR=0.36; p=.014) and an ApoE4 carrier (OR=0.36; p=.008) compared to NLW. Identifying as Latinx was associated with being less likely to be amyloid positive than NLW participants (OR=0.54; p=.031).ConclusionCompared to the US Census, ADNI underrepresents enrollment of Latinx, non‐Latinx Black, and non‐Latinx Asian participants and those with low educational attainment. Hence, ADNI reflects the on‐going challenges with recruiting and enrolling underrepresented populations into most AD research. Our findings highlight the need for ADNI to increase enrollment and engagement of underrepresented ethnoracial and educational populations. ADNI is actively undertaking steps to implement improved recruitment approaches aimed at increasing ethnoracial and socioeconomical representation in multi‐center cohort studies.