Predicting Symptom Onset in Sporadic Alzheimer Disease With Amyloid PET
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.
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© 2021 American Academy of Neurology.
Publication History
Received: March 22, 2021
Accepted: August 12, 2021
Published online: September 9, 2021
Published in print: November 2, 2021
Disclosure
S. Schindler, Y. Li, V.D. Buckles, and B.A. Gordon report no disclosures. T.L.S. Benzinger has received research support from Avid Radiopharmaceuticals (a wholly owned subsidiary of Eli Lilly) and Biogen. She has or is currently participating in clinical trials sponsored by Janssen, Eli Lilly, Pfizer, Biogen, and Roche. She has received travel support from Biogen, the American Society for Neuroradiology, the Alzheimer's Association, and the People's Republic of China. G. Wang and D. Coble report no disclosures; W.E. Klunk is supported by NIH grants P50 AG005133, RF1 AG025516, and P01 AG025204. GE Healthcare holds a license agreement with the University of Pittsburgh based on the PiB PET technology described in this article. W.E. Klunk is a coinventor of PiB and thus has a financial interest in this license agreement and receives royalty payments. GE Healthcare provided no grant support for this study. A.M. Fagan has received research funding from the National Institute on Aging of the NIH, Biogen, Centene, Fujirebio, and Roche Diagnostics. She is a member of the Scientific Advisory boards for Roche Diagnostics, Genentech, and AbbVie and also consults for Araclon/Grifols, DiademRes, DiamiR, and Otsuka. D. Holtzman cofounded and is on the scientific advisory board of C2N Diagnostics. Washington University and D. Holtzman have equity ownership interest in C2N Diagnostics and receive royalty income based on technology (stable isotope labeling kinetics, blood plasma assay, anti-tau antibodies) licensed by Washington University to C2N Diagnostics. He receives income from C2N Diagnostics for serving on the Scientific Advisory Board. He is on the Scientific Advisory Board of Denali and Genentech. He consults for Merck, Cajal Neurosciences, and Takeda. His laboratory receives research support from C2N Diagnostics, NextCure, and Novartis. R.J. Bateman cofounded C2N Diagnostics. Washington University and Dr. Bateman have equity ownership interest in C2N Diagnostics and receive royalty income based on technology (stable isotope labeling kinetics and blood plasma assay) licensed by Washington University to C2N Diagnostics. He receives income from C2N Diagnostics for serving on the Scientific Advisory Board. Washington University, with R.J. Bateman as coinventor, has submitted the US provisional patent application “Plasma Based Methods for Detecting CNS Amyloid Deposition.” He consults for Roche, Genentech, AbbVie, Pfizer, Boehringer-Ingelheim, and Merck. J.C. Morris does not own stock or have equity interest (outside of mutual funds or other externally directed accounts) in any pharmaceutical or biotechnology company. C. Xiong reports no disclosures. Go to Neurology.org/N for full disclosures.
Study Funding
This study was supported by National Institute on Aging grants R03AG050921 (S. Schindler), K23AG053426 (S. Schindler), P30AG066444 (J.C. Morris), P01AG003991 (J.C. Morris), P01AG026276 (J.C. Morris), and R01AG053550 (C. Xiong).
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