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 Rentz & 2 others Reisa A Sperling, Keith Johnson

Research output: Contribution to journalArticleScientificpeer-review

Abstract

Importance: Positron emission tomography (PET) imaging now allows in vivo visualization of both neuropathologic hallmarks of Alzheimer disease (AD): amyloid-β (Aβ) 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.

Objective: To assess the associations among Aβ, tau, and cognition, measured during different observation periods for 7 years.

Design, Setting, and Participants: Prospective 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 Aβ and tau PET observations available on October 31, 2017.

Main Outcomes and Measures: A median of 3 Pittsburgh compound B-PET (Aβ, 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 Aβ 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.

Results: Of 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 Aβ burden. An antecedent rise in Aβ 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 Aβ 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 Aβ and final cognition, measured 7 years later, was mediated by successive changes in Aβ and tau.

Conclusions and Relevance: We identified sequential changes in normal older adults, from Aβ to tau to cognition, after which the participants with high Aβ 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.

Original languageEnglish
JournalJAMA neurology
DOIs
Publication statusE-pub ahead of print - 3 Jun 2019

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Alzheimer Disease
Neurofibrillary Tangles
Consensus
Observation
Cognitive Dysfunction

Cite this

Hanseeuw, B. J., Betensky, R. A., Jacobs, H. I. L., Schultz, A. P., Sepulcre, J., Becker, J. A., ... Johnson, K. (2019). Association of Amyloid and Tau With Cognition in Preclinical Alzheimer Disease: A Longitudinal Study. JAMA neurology. https://doi.org/10.1001/jamaneurol.2019.1424
Hanseeuw, Bernard J ; Betensky, Rebecca A ; Jacobs, Heidi I L ; Schultz, Aaron P ; Sepulcre, Jorge ; Becker, J Alex ; Cosio, Danielle M Orozco ; Farrell, Michelle ; Quiroz, Yakeel T ; Mormino, Elizabeth C ; Buckley, Rachel F ; Papp, Kathryn V ; Amariglio, Rebecca A ; Dewachter, Ilse ; Ivanoiu, Adrian ; Huijbers, Willem ; Hedden, Trey ; Marshall, Gad A ; Chhatwal, Jasmeer P ; Rentz, Dorene M ; Sperling, Reisa A ; Johnson, Keith. / Association of Amyloid and Tau With Cognition in Preclinical Alzheimer Disease : A Longitudinal Study. In: JAMA neurology. 2019.
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title = "Association of Amyloid and Tau With Cognition in Preclinical Alzheimer Disease: A Longitudinal Study",
abstract = "Importance: Positron emission tomography (PET) imaging now allows in vivo visualization of both neuropathologic hallmarks of Alzheimer disease (AD): amyloid-β (Aβ) 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.Objective: To assess the associations among Aβ, tau, and cognition, measured during different observation periods for 7 years.Design, Setting, and Participants: Prospective 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 Aβ and tau PET observations available on October 31, 2017.Main Outcomes and Measures: A median of 3 Pittsburgh compound B-PET (Aβ, 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 Aβ 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.Results: Of 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 Aβ burden. An antecedent rise in Aβ 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 Aβ 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 Aβ and final cognition, measured 7 years later, was mediated by successive changes in Aβ and tau.Conclusions and Relevance: We identified sequential changes in normal older adults, from Aβ to tau to cognition, after which the participants with high Aβ 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.",
author = "Hanseeuw, {Bernard J} and Betensky, {Rebecca A} and Jacobs, {Heidi I L} and Schultz, {Aaron P} and Jorge Sepulcre and Becker, {J Alex} and Cosio, {Danielle M Orozco} and Michelle Farrell and Quiroz, {Yakeel T} and Mormino, {Elizabeth C} and Buckley, {Rachel F} and Papp, {Kathryn V} and Amariglio, {Rebecca A} and Ilse Dewachter and Adrian Ivanoiu and Willem Huijbers and Trey Hedden and Marshall, {Gad A} and Chhatwal, {Jasmeer P} and Rentz, {Dorene M} and Sperling, {Reisa A} and Keith Johnson",
year = "2019",
month = "6",
day = "3",
doi = "10.1001/jamaneurol.2019.1424",
language = "English",
journal = "JAMA neurology",
issn = "2168-6149",
publisher = "American Medical Association",

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Hanseeuw, BJ, Betensky, RA, Jacobs, HIL, Schultz, AP, Sepulcre, J, Becker, JA, Cosio, DMO, Farrell, M, Quiroz, YT, Mormino, EC, Buckley, RF, Papp, KV, Amariglio, RA, Dewachter, I, Ivanoiu, A, Huijbers, W, Hedden, T, Marshall, GA, Chhatwal, JP, Rentz, DM, Sperling, RA & Johnson, K 2019, 'Association of Amyloid and Tau With Cognition in Preclinical Alzheimer Disease: A Longitudinal Study' JAMA neurology. https://doi.org/10.1001/jamaneurol.2019.1424

Association of Amyloid and Tau With Cognition in Preclinical Alzheimer Disease : A Longitudinal Study. / Hanseeuw, Bernard J; Betensky, Rebecca A; Jacobs, Heidi I L; Schultz, Aaron P; Sepulcre, Jorge; Becker, J Alex; Cosio, Danielle M Orozco; Farrell, Michelle; Quiroz, Yakeel T; Mormino, Elizabeth C; Buckley, Rachel F; Papp, Kathryn V; Amariglio, Rebecca A; Dewachter, Ilse; Ivanoiu, Adrian; Huijbers, Willem; Hedden, Trey; Marshall, Gad A; Chhatwal, Jasmeer P; Rentz, Dorene M; Sperling, Reisa A; Johnson, Keith.

In: JAMA neurology, 03.06.2019.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Association of Amyloid and Tau With Cognition in Preclinical Alzheimer Disease

T2 - A Longitudinal Study

AU - Hanseeuw, Bernard J

AU - Betensky, Rebecca A

AU - Jacobs, Heidi I L

AU - Schultz, Aaron P

AU - Sepulcre, Jorge

AU - Becker, J Alex

AU - Cosio, Danielle M Orozco

AU - Farrell, Michelle

AU - Quiroz, Yakeel T

AU - Mormino, Elizabeth C

AU - Buckley, Rachel F

AU - Papp, Kathryn V

AU - Amariglio, Rebecca A

AU - Dewachter, Ilse

AU - Ivanoiu, Adrian

AU - Huijbers, Willem

AU - Hedden, Trey

AU - Marshall, Gad A

AU - Chhatwal, Jasmeer P

AU - Rentz, Dorene M

AU - Sperling, Reisa A

AU - Johnson, Keith

PY - 2019/6/3

Y1 - 2019/6/3

N2 - Importance: Positron emission tomography (PET) imaging now allows in vivo visualization of both neuropathologic hallmarks of Alzheimer disease (AD): amyloid-β (Aβ) 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.Objective: To assess the associations among Aβ, tau, and cognition, measured during different observation periods for 7 years.Design, Setting, and Participants: Prospective 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 Aβ and tau PET observations available on October 31, 2017.Main Outcomes and Measures: A median of 3 Pittsburgh compound B-PET (Aβ, 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 Aβ 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.Results: Of 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 Aβ burden. An antecedent rise in Aβ 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 Aβ 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 Aβ and final cognition, measured 7 years later, was mediated by successive changes in Aβ and tau.Conclusions and Relevance: We identified sequential changes in normal older adults, from Aβ to tau to cognition, after which the participants with high Aβ 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.

AB - Importance: Positron emission tomography (PET) imaging now allows in vivo visualization of both neuropathologic hallmarks of Alzheimer disease (AD): amyloid-β (Aβ) 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.Objective: To assess the associations among Aβ, tau, and cognition, measured during different observation periods for 7 years.Design, Setting, and Participants: Prospective 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 Aβ and tau PET observations available on October 31, 2017.Main Outcomes and Measures: A median of 3 Pittsburgh compound B-PET (Aβ, 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 Aβ 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.Results: Of 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 Aβ burden. An antecedent rise in Aβ 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 Aβ 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 Aβ and final cognition, measured 7 years later, was mediated by successive changes in Aβ and tau.Conclusions and Relevance: We identified sequential changes in normal older adults, from Aβ to tau to cognition, after which the participants with high Aβ 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.

U2 - 10.1001/jamaneurol.2019.1424

DO - 10.1001/jamaneurol.2019.1424

M3 - Article

JO - JAMA neurology

JF - JAMA neurology

SN - 2168-6149

ER -