Association of Amyloid and Tau With Cognition in Preclinical Alzheimer Disease: A Longitudinal Study

Bernard J. Hanseeuw, Rebecca A. Betensky, Heidi I. L. Jacobs, Aaron P. Schultz, Jorge Sepulcre, J. Alex Becker, Danielle M. Orozco Cosio, Michelle Farrell, Yakeel T. Quiroz, Elizabeth C. Mormino, Rachel F. Buckley, Kathryn V. Papp, Rebecca A. Amariglio, Ilse Dewachter, Adrian Ivanoiu, Willem Huijbers, Trey Hedden, Gad A. Marshall, Jasmeer P. Chhatwal, Dorene M. RentzReisa A. Sperling, Keith Johnson*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Key PointsQuestionIs cognitive decline associated with amyloid-beta or tau tangles accumulation? FindingsIn this cohort study that included 60 normal older adults with repeated positron emission tomography measures, the rate of tau accumulation in the inferior temporal neocortex was associated with the rate of cognitive decline. Amyloid accumulation was associated with subsequent tau accumulation, and this sequence of successive amyloid and tau changes in neocortex was found to mediate the association of initial amyloid with final cognition, measured 7 years later. MeaningAmyloid positron emission tomography is useful to detect early Alzheimer pathology; repeated tau positron emission tomography is useful to track disease progression.

ImportancePositron emission tomography (PET) imaging now allows in vivo visualization of both neuropathologic hallmarks of Alzheimer disease (AD): amyloid-beta (A beta) plaques and tau neurofibrillary tangles. Observing their progressive accumulation in the brains of clinically normal older adults is critically important to understand the pathophysiologic cascade leading to AD and to inform the choice of outcome measures in prevention trials. ObjectiveTo assess the associations among A beta, tau, and cognition, measured during different observation periods for 7 years. Design, Setting, and ParticipantsProspective cohort study conducted between 2010 and 2017 at the Harvard Aging Brain Study, Boston, Massachusetts. The study enrolled 279 clinically normal participants. An additional 90 individuals were approached but declined the study or did not meet the inclusion criteria. In this report, we analyzed data from 60 participants who had multiple A beta and tau PET observations available on October 31, 2017. Main Outcomes and MeasuresA median of 3 Pittsburgh compound B-PET (A beta, 2010-2017) and 2 flortaucipir-PET (tau, 2013-2017) images were collected. We used initial PET and slope data, assessing the rates of change in A beta and tau, to measure cognitive changes. Cognition was evaluated annually using the Preclinical Alzheimer Cognitive Composite (2010-2017). Annual consensus meetings evaluated progression to mild cognitive impairment. ResultsOf the 60 participants, 35 were women (58%) and 25 were men (42%); median age at inclusion was 73 years (range, 65-85 years). Seventeen participants (28%) exhibited an initial high A beta burden. An antecedent rise in A beta was associated with subsequent changes in tau (1.07 flortaucipir standardized uptake value ratios [SUVr]/PiB-SUVr; 95% CI, 0.13-3.46; P=.02). Tau changes were associated with cognitive changes (-3.28 z scores/SUVR; 95% CI, -6.67 to -0.91; P=.001), covarying baseline A beta and tau. Tau changes were greater in the participants who progressed to mild cognitive impairment (n=6) than in those who did not (n=11; 0.05 SUVr per year; 95% CI, 0.03-0.07; P=.001). A serial mediation model demonstrated that the association between initial A beta and final cognition, measured 7 years later, was mediated by successive changes in A beta and tau. Conclusions and RelevanceWe identified sequential changes in normal older adults, from A beta to tau to cognition, after which the participants with high A beta with greater tau increase met clinical criteria for mild cognitive impairment. These findings highlight the importance of repeated tau-PET observations to track disease progression and the importance of repeated amyloid-PET observations to detect the earliest AD pathologic changes.

This cohort study assesses the associations among amyloid-beta, tau, and cognition, measured during different observation periods for 7 years.

Original languageEnglish
Pages (from-to)915-924
Number of pages10
JournalJAMA Neurology
Issue number8
Publication statusPublished - Aug 2019



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