Association of Amyloid and Tau With Cognition in Preclinical Alzheimer Disease: A Longitudinal Study
Open accessAbstract
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.
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At the asymptomatic amyloid-positive stage, vascular and AD pathology independently contribute to cognition, with amyloid effects potentially mediated by tau.
“These findings suggest that, at this asymptomatic amyloid‐positive stage, vascular and AD pathology independently contribute to cognition, with amyloid effects potentially mediated by tau. 33”
From White matter hyperintensity modulates the amyloid‐tau‐cognition association and anti‐amyloid treatment efficacy in asymptomatic older adults (2025) · cites this paper as [33]
The Discussion reports a delayed, indirect, tau-mediated association between amyloid and cognition in preclinical AD, including changes shortly after amyloid positivity. It does not report that vascular pathology independently contributes to cognition; the cited paper examines amyloid, tau, and cognition, not that vascular contribution. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn individuals with low baseline WMH, the strong correlation between Aβ accumulation and p-Tau217 change suggests a rapid pathogenetic cross-talk and a temporal sequence of successive amyloid and tau phosphorylation in early pre-clinical stage.
“Individuals with low baseline WMH exhibited a strong correlation between Aβ accumulation and p‐Tau217 change, consistent with previous findings, 33 , 36 , 37 suggesting a rapid pathogenetic cross‐talk and a temporal sequence of successive amyloid and tau phosphorylation in this early pre‐clinical stage.”
From White matter hyperintensity modulates the amyloid‐tau‐cognition association and anti‐amyloid treatment efficacy in asymptomatic older adults (2025) · cites this paper as [33]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredAD begins several decades before the clinical onset of dementia with progressive amyloid accumulation preceding significant tau pathology and neurodegeneration.
“Alzheimer’s disease (AD) begins several decades before the clinical onset of dementia with progressive amyloid accumulation preceding significant tau pathology and neurodegeneration.10,11”
From Machine learning reveals prominent spontaneous behavioral changes and treatment efficacy in humanized and transgenic Alzheimer's disease models (2024) · cites this paper as [10]
The Discussion reports that amyloid accumulation preceded changes in inferior temporal tau and cites prior evidence that amyloid positivity occurs many years before dementia onset. It does not establish a several-decade interval, and the Limitations section says the sequence of neurodegenerative changes relative to amyloid and tau remains to be determined. (LLM, conf=0.88)
Experimental — accuracy not yet measuredRecent positron emission tomography imaging of tau indicates a stronger correlation of tau changes with cognitive impairment and transition to mild cognitive impairment.
“Older studies of 11C-Pittsburgh compound B imaging suggested that only 13% of cognitively normal individuals that are positive for Aβ will transition to mild cognitive impairment (MCI) or AD (Rowe et al., 2013), whereas recent positron emission tomography (PET) imaging of tau indicates a stronger correlation of tau changes with cognitive impairment and transition to MCI (Hanseeuw et al., 2019).”
From Dendritic Spine Remodeling and Synaptic Tau Levels in PS19 Tauopathy Mice (2021) · cites this paper as Hanseeuw et al., 2019
CSF and PET longitudinal studies support a model in which amyloidosis promotes or permits tau pathology spreading that likely drives clinical evolution.
“However, CSF and positron emission tomography longitudinal studies support the hypothetical pathophysiological model of AD for which amyloidosis proceeds, either promoting or being permissive to the spreading of tau pathology that is likely to drive disease clinical evolution (104–107).”
From The β-Secretase BACE1 in Alzheimer’s Disease (2021) · cites this paper as [105]
Robust evidence indicates that cerebral Aβ accumulation is one of the earliest mechanistic alterations in AD pathophysiology.
“robust evidence indicates that cerebral Aβ accumulation is one of the earliest mechanistic alterations of the whole pathophysiological dynamic of AD (104–107).”
From The β-Secretase BACE1 in Alzheimer’s Disease (2021) · cites this paper as [105]
Genetic and multimodal biomarker studies indicate that an imbalance between Aβ production and clearance plays a critical and early role in AD pathogenesis.
“Several genetic data studies (306 autosomal dominant mutations plus the APP gene duplication and trisomy 21) and multimodal biomarker studies indicate that an imbalance between Aβ production and clearance plays a critical and early role in AD pathogenesis (104–106,113,114).”
From The β-Secretase BACE1 in Alzheimer’s Disease (2021) · cites this paper as [105]
A large amount of evidence supports the hypothesis that cerebral Aβ deposition begins decades before AD clinical onset and before cortical tau spreading.
“A large amount of evidence also supports the hypothesis that cerebral Aβ deposition begins decades before AD clinical onset and prior to cortical spreading of tau pathology.”
From The β-Secretase BACE1 in Alzheimer’s Disease (2021) · cites this paper as [105]
The AD preclinical phase is characterized by a sequence of early Aβ deposition in the precuneus and default mode network, followed by regional cortical hypometabolism, tau accumulation, hippocampal volume loss, and cognitive impairment.
“characterized by early deposition of Aβ in the precuneus and other cortical regions comprising the default mode network, followed sequentially by regional cortical hypometabolism, accumulation of tau pathology, hippocampal volume loss, and onset of symptomatic cognitive impairment”
From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Hanseeuw et al., 2019
Longitudinal amyloid and tau PET suggests that the rate of amyloid accumulation predicts onset of tau accumulation, whereas the rate of tau accumulation predicts onset of cognitive impairment.
“Longitudinal assessment of amyloid and tau PET imaging suggests that rate of amyloid accumulation predicts onset of tau accumulation whereas rate of tau accumulation predicts onset of cognitive impairment”
From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Hanseeuw et al., 2019
Aβ deposition may be required for progression of tau pathology in AD.
“Several lines of evidence suggest Aβ deposition may be required for progression of tau pathology in AD”
From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Hanseeuw et al., 2019
Tau levels correlate much more strongly to cognitive symptoms than amyloid burden, suggesting a more direct link to disease progression.
“Compared to amyloid burden, tau levels correlate much more strongly to cognitive symptoms, suggesting a more direct link to disease progression [46].”
From Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau (2021) · cites this paper as [46]
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Biomarker-Based Prediction of Longitudinal Tau Positron Emission Tomography in Alzheimer Disease
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Multicellular communities are perturbed in the aging human brain and Alzheimer’s disease
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When Does Alzheimer′s Disease Really Start? The Role of Biomarkers
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PET Neuroimaging of Alzheimer's Disease: Radiotracers and Their Utility in Clinical Research
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Current trends in blood biomarker detection and imaging for Alzheimer’s disease
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Can exercise training teach us how to treat Alzheimer's disease?
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APOE effects on regional tau in preclinical Alzheimer’s disease
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Amyloid-β: A double agent in Alzheimer's disease?
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ApoE4 attenuates autophagy via FoxO3a repression in the brain
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Multi-cellular communities are perturbed in the aging human brain and Alzheimer’s disease
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“10,11 12-14 Thus, these behavioral changes may be the earliest symptoms of preclinical stages of AD.”
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“33 A major strength of this study is that we investigated not only the direct but also the modulatory role of WMH in AD progression.”
- Authors
- Hanseeuw, B. J., Betensky, R. A., Jacobs, H. I. L., Schultz, A. P., Sepulcre, J., Becker, J. A., Cosio, D. M. O., Farrell, M., Quiroz, Y. T., Mormino, E. C., Buckley, R. F., Papp, K. V., Amariglio, R. A., Dewachter, I., Ivanoiu, A., Huijbers, W., Hedden, T., Marshall, G. A., Chhatwal, J. P., Rentz, D. M., Sperling, R. A., & Johnson, K.
- Affiliations
- Cliniques Universitaires Saint-Luc (BE)
- Harvard University (US)
- Maastricht University (NL)
- Gordon Center for Medical Imaging (US)
- Brigham and Women's Hospital (US)
- Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston
- Hasselt University (BE)
- Corresponding author
- Johnson, Keith
- ORCID
- 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.
- Dewachter, Ilse
- Huijbers, Willem
- Hedden, Trey
- Marshall, Gad A.
- Chhatwal, Jasmeer P.
- Rentz, Dorene M.
- Sperling, Reisa A.
- Johnson, Keith
- Venue
- JAMA Neurology
- Publisher
- American Medical Association (AMA)
- Published
- 2019-08-01
- Volume
- 76
- Issue
- 8
- Pages
- 915
- ISSN
- 2168-6149 (ISSN-L)
- PMC
- PMC6547132
- OpenAlex
- W2948815538
- Cited by
- 865
- References
- 37
- Citations by year
- 2026: 89 · 2025: 144 · 2024: 128 · 2023: 122 · 2022: 124 · 2021: 150 · 2020: 85 · 2019: 22
- FWCI
- 74.67
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- JAMA Neurology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- Research portal (Tilburg University) (publishedVersion, other-oa)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion, cc-by)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Digital Access to Libraries (submittedVersion, other-oa)
- Document Server@UHasselt (UHasselt) (submittedVersion, cc-by)
- Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, cc-by)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Funders
- National Institutes of Health
- National Institute on Aging (R01AG053509, K01AG051718)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cancer-related cognitive impairment studies
- Keywords
- preclinical Alzheimer's disease, amyloid-beta, tau protein, cognitive decline, Pittsburgh compound B PET, flortaucipir PET, mild cognitive impairment, longitudinal cognitive change
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