Keith A Josephs1, Stephen D Weigand1, Jennifer L Whitwell1. 1. From the Departments of Neurology (K.A.J.), Health Sciences Research (Division of Biomedical Informatics and Statistics) (S.D.W.), and Radiology (J.W.), Mayo Clinic, Rochester, MN.
Abstract
BACKGROUND AND OBJECTIVE: Individuals with biomarker evidence of β-amyloid (Aβ) deposition are increasingly being enrolled in clinical treatment trials but there is a need to identify markers to predict which of these individuals will also develop tau deposition. We aimed to determine whether Aβ-positive individuals can remain tau-negative for at least 5 years and identify characteristics that could distinguish between these individuals and those who develop high tau within this period. METHODS: Tau PET positivity was defined using a Gaussian mixture model with log-transformed standard uptake value ratio values from 7 temporal and medial parietal regions using all participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) with flortaucipir PET. Tau PET scans were classified as normal if the posterior probability of elevated tau was less than 1%. Aβ PET positivity was defined based on ADNI cutpoints. We identified all Aβ-positive individuals from ADNI who had normal tau PET more than 5 years after their first abnormal Aβ PET (amyloid with low tau [ALT] group) and all Aβ-positive individuals with abnormal tau PET within 5 years (biomarker AD). In a case-control design, logistic regression was used to model the odds of biomarker AD vs ALT accounting for sex, age, APOE ε4 carriership, Aβ Centiloid, and hippocampal volume. RESULTS: We identified 45 individuals meeting criteria for ALT and 157 meeting criteria for biomarker AD. The ALT group had a lower proportion of APOE ε4 carriers, lower Aβ Centiloid, larger hippocampal volumes, and more preserved cognition, and were less likely to develop dementia, than the biomarker AD group. APOE ε4, higher Aβ Centiloid, and hippocampal atrophy were independently associated with increased odds of abnormal tau within 5 years. A Centiloid value of 50 effectively discriminated biomarker AD and ALT with 80% sensitivity and specificity. The majority of the ALT participants did not develop dementia throughout the 5-year interval. DISCUSSION: Aβ-positive individuals can remain tau-negative for at least 5 years. Baseline characteristics can help identify these ALT individuals who are less likely to develop dementia. Conservative Aβ cutpoints should be utilized for clinical trials to better capture individuals with high risk of developing biomarker AD.
BACKGROUND AND OBJECTIVE: Individuals with biomarker evidence of β-amyloid (Aβ) deposition are increasingly being enrolled in clinical treatment trials but there is a need to identify markers to predict which of these individuals will also develop tau deposition. We aimed to determine whether Aβ-positive individuals can remain tau-negative for at least 5 years and identify characteristics that could distinguish between these individuals and those who develop high tau within this period. METHODS: Tau PET positivity was defined using a Gaussian mixture model with log-transformed standard uptake value ratio values from 7 temporal and medial parietal regions using all participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) with flortaucipir PET. Tau PET scans were classified as normal if the posterior probability of elevated tau was less than 1%. Aβ PET positivity was defined based on ADNI cutpoints. We identified all Aβ-positive individuals from ADNI who had normal tau PET more than 5 years after their first abnormal Aβ PET (amyloid with low tau [ALT] group) and all Aβ-positive individuals with abnormal tau PET within 5 years (biomarker AD). In a case-control design, logistic regression was used to model the odds of biomarker AD vs ALT accounting for sex, age, APOE ε4 carriership, Aβ Centiloid, and hippocampal volume. RESULTS: We identified 45 individuals meeting criteria for ALT and 157 meeting criteria for biomarker AD. The ALT group had a lower proportion of APOE ε4 carriers, lower Aβ Centiloid, larger hippocampal volumes, and more preserved cognition, and were less likely to develop dementia, than the biomarker AD group. APOE ε4, higher Aβ Centiloid, and hippocampal atrophy were independently associated with increased odds of abnormal tau within 5 years. A Centiloid value of 50 effectively discriminated biomarker AD and ALT with 80% sensitivity and specificity. The majority of the ALT participants did not develop dementia throughout the 5-year interval. DISCUSSION: Aβ-positive individuals can remain tau-negative for at least 5 years. Baseline characteristics can help identify these ALT individuals who are less likely to develop dementia. Conservative Aβ cutpoints should be utilized for clinical trials to better capture individuals with high risk of developing biomarker AD.
Authors: Alexandra M Wennberg; Jennifer L Whitwell; Nirubol Tosakulwong; Stephen D Weigand; Melissa E Murray; Mary M Machulda; Leonard Petrucelli; Michelle M Mielke; Clifford R Jack; David S Knopman; Joseph E Parisi; Ronald C Petersen; Dennis W Dickson; Keith A Josephs Journal: Neurobiol Aging Date: 2019-01-21 Impact factor: 4.673
Authors: Shruti Mishra; Brian A Gordon; Yi Su; Jon Christensen; Karl Friedrichsen; Kelley Jackson; Russ Hornbeck; David A Balota; Nigel J Cairns; John C Morris; Beau M Ances; Tammie L S Benzinger Journal: Neuroimage Date: 2017-07-26 Impact factor: 6.556
Authors: Helena C Chui; Chris Zarow; Wendy J Mack; William G Ellis; Ling Zheng; William J Jagust; Dan Mungas; Bruce R Reed; Joel H Kramer; Charles C Decarli; Michael W Weiner; Harry V Vinters Journal: Ann Neurol Date: 2006-12 Impact factor: 10.422
Authors: Susan M Landau; Allison Fero; Suzanne L Baker; Robert Koeppe; Mark Mintun; Kewei Chen; Eric M Reiman; William J Jagust Journal: J Nucl Med Date: 2015-03-05 Impact factor: 10.057
Authors: Adam S Fleisher; Michael J Pontecorvo; Michael D Devous; Ming Lu; Anupa K Arora; Stephen P Truocchio; Patricia Aldea; Matthew Flitter; Tricia Locascio; Marybeth Devine; Andrew Siderowf; Thomas G Beach; Thomas J Montine; Geidy E Serrano; Craig Curtis; Allison Perrin; Stephen Salloway; Misty Daniel; Charles Wellman; Abhinay D Joshi; David J Irwin; Val J Lowe; William W Seeley; Milos D Ikonomovic; Joseph C Masdeu; Ian Kennedy; Thomas Harris; Michael Navitsky; Sudeepti Southekal; Mark A Mintun Journal: JAMA Neurol Date: 2020-07-01 Impact factor: 18.302
Authors: David N Soleimani-Meigooni; Leonardo Iaccarino; Renaud La Joie; Suzanne Baker; Viktoriya Bourakova; Adam L Boxer; Lauren Edwards; Rana Eser; Maria-Luisa Gorno-Tempini; William J Jagust; Mustafa Janabi; Joel H Kramer; Orit H Lesman-Segev; Taylor Mellinger; Bruce L Miller; Julie Pham; Howard J Rosen; Salvatore Spina; William W Seeley; Amelia Strom; Lea T Grinberg; Gil D Rabinovici Journal: Brain Date: 2020-12-05 Impact factor: 13.501
Authors: Michelle E Farrell; Shu Jiang; Aaron P Schultz; Michael J Properzi; Julie C Price; J Alex Becker; Heidi I L Jacobs; Bernard J Hanseeuw; Dorene M Rentz; Victor L Villemagne; Kathryn V Papp; Elizabeth C Mormino; Rebecca A Betensky; Keith A Johnson; Reisa A Sperling; Rachel F Buckley Journal: Neurology Date: 2020-11-16 Impact factor: 9.910
Authors: Clifford R Jack; Heather J Wiste; Stephen D Weigand; Terry M Therneau; Val J Lowe; David S Knopman; Hugo Botha; Jonathan Graff-Radford; David T Jones; Tanis J Ferman; Bradley F Boeve; Kejal Kantarci; Prashanthi Vemuri; Michelle M Mielke; Jennifer Whitwell; Keith Josephs; Christopher G Schwarz; Matthew L Senjem; Jeffrey L Gunter; Ronald C Petersen Journal: Brain Date: 2020-10-01 Impact factor: 13.501