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November 02, 2021; 97 (18) Research Article

Predicting Symptom Onset in Sporadic Alzheimer Disease With Amyloid PET

View ORCID ProfileSuzanne E. Schindler, Yan Li, Virginia D. Buckles, Brian A. Gordon, Tammie L.S. Benzinger, Guoqiao Wang, View ORCID ProfileDean Coble, William E. Klunk, Anne M. Fagan, View ORCID ProfileDavid M. Holtzman, View ORCID ProfileRandall J. Bateman, John C. Morris, Chengjie Xiong
First published September 9, 2021, DOI: https://doi.org/10.1212/WNL.0000000000012775
Suzanne E. Schindler
From the Department of Neurology (S.E.S., Y.L., V.D.B., A.M.F., D.M.H., R.J.B., J.C.M.), Knight Alzheimer Disease Research Center (S.E.S., V.D.B., B.A.G., T.L.S.B., G.W., D.C., A.M.F., D.M.H., R.J.B., J.C.M., C.X.), Division of Biostatistics (Y.L., G.W., D.C., C.X.), Mallinckrodt Institute of Radiology (B.A.G., T.L.S.B.), and Hope Center for Neurological Disorders (A.M.F., D.M.H., R.J.B.), Washington University School of Medicine, St. Louis, MO; and Department of Neurology and Psychiatry (W.E.K.), University of Pittsburgh, PA.
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  • ORCID record for Suzanne E. Schindler
Yan Li
From the Department of Neurology (S.E.S., Y.L., V.D.B., A.M.F., D.M.H., R.J.B., J.C.M.), Knight Alzheimer Disease Research Center (S.E.S., V.D.B., B.A.G., T.L.S.B., G.W., D.C., A.M.F., D.M.H., R.J.B., J.C.M., C.X.), Division of Biostatistics (Y.L., G.W., D.C., C.X.), Mallinckrodt Institute of Radiology (B.A.G., T.L.S.B.), and Hope Center for Neurological Disorders (A.M.F., D.M.H., R.J.B.), Washington University School of Medicine, St. Louis, MO; and Department of Neurology and Psychiatry (W.E.K.), University of Pittsburgh, PA.
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Virginia D. Buckles
From the Department of Neurology (S.E.S., Y.L., V.D.B., A.M.F., D.M.H., R.J.B., J.C.M.), Knight Alzheimer Disease Research Center (S.E.S., V.D.B., B.A.G., T.L.S.B., G.W., D.C., A.M.F., D.M.H., R.J.B., J.C.M., C.X.), Division of Biostatistics (Y.L., G.W., D.C., C.X.), Mallinckrodt Institute of Radiology (B.A.G., T.L.S.B.), and Hope Center for Neurological Disorders (A.M.F., D.M.H., R.J.B.), Washington University School of Medicine, St. Louis, MO; and Department of Neurology and Psychiatry (W.E.K.), University of Pittsburgh, PA.
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Brian A. Gordon
From the Department of Neurology (S.E.S., Y.L., V.D.B., A.M.F., D.M.H., R.J.B., J.C.M.), Knight Alzheimer Disease Research Center (S.E.S., V.D.B., B.A.G., T.L.S.B., G.W., D.C., A.M.F., D.M.H., R.J.B., J.C.M., C.X.), Division of Biostatistics (Y.L., G.W., D.C., C.X.), Mallinckrodt Institute of Radiology (B.A.G., T.L.S.B.), and Hope Center for Neurological Disorders (A.M.F., D.M.H., R.J.B.), Washington University School of Medicine, St. Louis, MO; and Department of Neurology and Psychiatry (W.E.K.), University of Pittsburgh, PA.
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Tammie L.S. Benzinger
From the Department of Neurology (S.E.S., Y.L., V.D.B., A.M.F., D.M.H., R.J.B., J.C.M.), Knight Alzheimer Disease Research Center (S.E.S., V.D.B., B.A.G., T.L.S.B., G.W., D.C., A.M.F., D.M.H., R.J.B., J.C.M., C.X.), Division of Biostatistics (Y.L., G.W., D.C., C.X.), Mallinckrodt Institute of Radiology (B.A.G., T.L.S.B.), and Hope Center for Neurological Disorders (A.M.F., D.M.H., R.J.B.), Washington University School of Medicine, St. Louis, MO; and Department of Neurology and Psychiatry (W.E.K.), University of Pittsburgh, PA.
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Guoqiao Wang
From the Department of Neurology (S.E.S., Y.L., V.D.B., A.M.F., D.M.H., R.J.B., J.C.M.), Knight Alzheimer Disease Research Center (S.E.S., V.D.B., B.A.G., T.L.S.B., G.W., D.C., A.M.F., D.M.H., R.J.B., J.C.M., C.X.), Division of Biostatistics (Y.L., G.W., D.C., C.X.), Mallinckrodt Institute of Radiology (B.A.G., T.L.S.B.), and Hope Center for Neurological Disorders (A.M.F., D.M.H., R.J.B.), Washington University School of Medicine, St. Louis, MO; and Department of Neurology and Psychiatry (W.E.K.), University of Pittsburgh, PA.
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Dean Coble
From the Department of Neurology (S.E.S., Y.L., V.D.B., A.M.F., D.M.H., R.J.B., J.C.M.), Knight Alzheimer Disease Research Center (S.E.S., V.D.B., B.A.G., T.L.S.B., G.W., D.C., A.M.F., D.M.H., R.J.B., J.C.M., C.X.), Division of Biostatistics (Y.L., G.W., D.C., C.X.), Mallinckrodt Institute of Radiology (B.A.G., T.L.S.B.), and Hope Center for Neurological Disorders (A.M.F., D.M.H., R.J.B.), Washington University School of Medicine, St. Louis, MO; and Department of Neurology and Psychiatry (W.E.K.), University of Pittsburgh, PA.
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  • ORCID record for Dean Coble
William E. Klunk
From the Department of Neurology (S.E.S., Y.L., V.D.B., A.M.F., D.M.H., R.J.B., J.C.M.), Knight Alzheimer Disease Research Center (S.E.S., V.D.B., B.A.G., T.L.S.B., G.W., D.C., A.M.F., D.M.H., R.J.B., J.C.M., C.X.), Division of Biostatistics (Y.L., G.W., D.C., C.X.), Mallinckrodt Institute of Radiology (B.A.G., T.L.S.B.), and Hope Center for Neurological Disorders (A.M.F., D.M.H., R.J.B.), Washington University School of Medicine, St. Louis, MO; and Department of Neurology and Psychiatry (W.E.K.), University of Pittsburgh, PA.
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Anne M. Fagan
From the Department of Neurology (S.E.S., Y.L., V.D.B., A.M.F., D.M.H., R.J.B., J.C.M.), Knight Alzheimer Disease Research Center (S.E.S., V.D.B., B.A.G., T.L.S.B., G.W., D.C., A.M.F., D.M.H., R.J.B., J.C.M., C.X.), Division of Biostatistics (Y.L., G.W., D.C., C.X.), Mallinckrodt Institute of Radiology (B.A.G., T.L.S.B.), and Hope Center for Neurological Disorders (A.M.F., D.M.H., R.J.B.), Washington University School of Medicine, St. Louis, MO; and Department of Neurology and Psychiatry (W.E.K.), University of Pittsburgh, PA.
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David M. Holtzman
From the Department of Neurology (S.E.S., Y.L., V.D.B., A.M.F., D.M.H., R.J.B., J.C.M.), Knight Alzheimer Disease Research Center (S.E.S., V.D.B., B.A.G., T.L.S.B., G.W., D.C., A.M.F., D.M.H., R.J.B., J.C.M., C.X.), Division of Biostatistics (Y.L., G.W., D.C., C.X.), Mallinckrodt Institute of Radiology (B.A.G., T.L.S.B.), and Hope Center for Neurological Disorders (A.M.F., D.M.H., R.J.B.), Washington University School of Medicine, St. Louis, MO; and Department of Neurology and Psychiatry (W.E.K.), University of Pittsburgh, PA.
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Randall J. Bateman
From the Department of Neurology (S.E.S., Y.L., V.D.B., A.M.F., D.M.H., R.J.B., J.C.M.), Knight Alzheimer Disease Research Center (S.E.S., V.D.B., B.A.G., T.L.S.B., G.W., D.C., A.M.F., D.M.H., R.J.B., J.C.M., C.X.), Division of Biostatistics (Y.L., G.W., D.C., C.X.), Mallinckrodt Institute of Radiology (B.A.G., T.L.S.B.), and Hope Center for Neurological Disorders (A.M.F., D.M.H., R.J.B.), Washington University School of Medicine, St. Louis, MO; and Department of Neurology and Psychiatry (W.E.K.), University of Pittsburgh, PA.
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John C. Morris
From the Department of Neurology (S.E.S., Y.L., V.D.B., A.M.F., D.M.H., R.J.B., J.C.M.), Knight Alzheimer Disease Research Center (S.E.S., V.D.B., B.A.G., T.L.S.B., G.W., D.C., A.M.F., D.M.H., R.J.B., J.C.M., C.X.), Division of Biostatistics (Y.L., G.W., D.C., C.X.), Mallinckrodt Institute of Radiology (B.A.G., T.L.S.B.), and Hope Center for Neurological Disorders (A.M.F., D.M.H., R.J.B.), Washington University School of Medicine, St. Louis, MO; and Department of Neurology and Psychiatry (W.E.K.), University of Pittsburgh, PA.
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Chengjie Xiong
From the Department of Neurology (S.E.S., Y.L., V.D.B., A.M.F., D.M.H., R.J.B., J.C.M.), Knight Alzheimer Disease Research Center (S.E.S., V.D.B., B.A.G., T.L.S.B., G.W., D.C., A.M.F., D.M.H., R.J.B., J.C.M., C.X.), Division of Biostatistics (Y.L., G.W., D.C., C.X.), Mallinckrodt Institute of Radiology (B.A.G., T.L.S.B.), and Hope Center for Neurological Disorders (A.M.F., D.M.H., R.J.B.), Washington University School of Medicine, St. Louis, MO; and Department of Neurology and Psychiatry (W.E.K.), University of Pittsburgh, PA.
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Citation
Predicting Symptom Onset in Sporadic Alzheimer Disease With Amyloid PET
Suzanne E. Schindler, Yan Li, Virginia D. Buckles, Brian A. Gordon, Tammie L.S. Benzinger, Guoqiao Wang, Dean Coble, William E. Klunk, Anne M. Fagan, David M. Holtzman, Randall J. Bateman, John C. Morris, Chengjie Xiong
Neurology Nov 2021, 97 (18) e1823-e1834; DOI: 10.1212/WNL.0000000000012775

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Abstract

Background and Objectives To predict when cognitively normal individuals with brain amyloidosis will develop symptoms of Alzheimer disease (AD).

Methods Brain amyloid burden was measured by amyloid PET with Pittsburgh compound B. The mean cortical standardized uptake value ratio (SUVR) was transformed into a timescale with the use of longitudinal data.

Results Amyloid accumulation was evaluated in 236 individuals who underwent >1 amyloid PET scan. The average age was 66.5 ± 9.2 years, and 12 individuals (5%) had cognitive impairment at their baseline amyloid PET scan. A tipping point in amyloid accumulation was identified at a low level of amyloid burden (SUVR 1.2), after which nearly all individuals accumulated amyloid at a relatively consistent rate until reaching a high level of amyloid burden (SUVR 3.0). The average time between levels of amyloid burden was used to estimate the age at which an individual reached SUVR 1.2. Longitudinal clinical diagnoses for 180 individuals were aligned by the estimated age at SUVR 1.2. In the 22 individuals who progressed from cognitively normal to a typical AD dementia syndrome, the estimated age at which an individual reached SUVR 1.2 predicted the age at symptom onset (R2 = 0.54, p < 0.0001, root mean square error [RMSE] 4.5 years); the model was more accurate after exclusion of 3 likely misdiagnoses (R2 = 0.84, p < 0.0001, RMSE 2.8 years).

Conclusion The age at symptom onset in sporadic AD is strongly correlated with the age at which an individual reaches a tipping point in amyloid accumulation.

Glossary

Aβ=
β-amyloid;
AD=
Alzheimer disease;
ADRC=
Alzheimer Disease Research Center;
CDR=
Clinical Dementia Rating;
PiB=
Pittsburgh compound B;
RMSE=
root mean square error;
SUVR=
standardized uptake value ratio

Footnotes

  • Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • Received March 22, 2021.
  • Accepted in final form August 12, 2021.
  • © 2021 American Academy of Neurology
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