TY - JOUR
T1 - Timing of Biomarker Changes in Sporadic Alzheimer's Disease in Estimated Years from Symptom Onset
AU - Li, Yan
AU - Yen, Daniel
AU - Hendrix, Rachel D.
AU - Gordon, Brian A.
AU - Dlamini, Sibonginkhosi
AU - Barthélemy, Nicolas R.
AU - Aschenbrenner, Andrew J.
AU - Henson, Rachel L.
AU - Herries, Elizabeth M.
AU - Volluz, Katherine
AU - Kirmess, Kristopher
AU - Eastwood, Stephanie
AU - Meyer, Matthew
AU - Heller, Maren
AU - Jarrett, Lea
AU - McDade, Eric
AU - Holtzman, David M.
AU - Benzinger, Tammie L.S.
AU - Morris, John C.
AU - Bateman, Randall J.
AU - Xiong, Chengjie
AU - Schindler, Suzanne E.
N1 - Publisher Copyright:
© 2024 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
PY - 2024/5
Y1 - 2024/5
N2 - Objective: A clock relating amyloid positron emission tomography (PET) to time was used to estimate the timing of biomarker changes in sporadic Alzheimer disease (AD). Methods: Research participants were included who underwent cerebrospinal fluid (CSF) collection within 2 years of amyloid PET. The ages at amyloid onset and AD symptom onset were estimated for each individual. The timing of change for plasma, CSF, imaging, and cognitive measures was calculated by comparing restricted cubic splines of cross-sectional data from the amyloid PET positive and negative groups. Results: The amyloid PET positive sub-cohort (n = 118) had an average age of 70.4 ± 7.4 years (mean ± standard deviation) and 16% were cognitively impaired. The amyloid PET negative sub-cohort (n = 277) included individuals with low levels of amyloid plaque burden at all scans who were cognitively unimpaired at the time of the scans. Biomarker changes were detected 15–19 years before estimated symptom onset for CSF Aβ42/Aβ40, plasma Aβ42/Aβ40, CSF pT217/T217, and amyloid PET; 12–14 years before estimated symptom onset for plasma pT217/T217, CSF neurogranin, CSF SNAP-25, CSF sTREM2, plasma GFAP, and plasma NfL; and 7–9 years before estimated symptom onset for CSF pT205/T205, CSF YKL-40, hippocampal volumes, and cognitive measures. Interpretation: The use of an amyloid clock enabled visualization and analysis of biomarker changes as a function of estimated years from symptom onset in sporadic AD. This study demonstrates that estimated years from symptom onset based on an amyloid clock can be used as a continuous staging measure for sporadic AD and aligns with findings in autosomal dominant AD. ANN NEUROL 2024;95:951–965.
AB - Objective: A clock relating amyloid positron emission tomography (PET) to time was used to estimate the timing of biomarker changes in sporadic Alzheimer disease (AD). Methods: Research participants were included who underwent cerebrospinal fluid (CSF) collection within 2 years of amyloid PET. The ages at amyloid onset and AD symptom onset were estimated for each individual. The timing of change for plasma, CSF, imaging, and cognitive measures was calculated by comparing restricted cubic splines of cross-sectional data from the amyloid PET positive and negative groups. Results: The amyloid PET positive sub-cohort (n = 118) had an average age of 70.4 ± 7.4 years (mean ± standard deviation) and 16% were cognitively impaired. The amyloid PET negative sub-cohort (n = 277) included individuals with low levels of amyloid plaque burden at all scans who were cognitively unimpaired at the time of the scans. Biomarker changes were detected 15–19 years before estimated symptom onset for CSF Aβ42/Aβ40, plasma Aβ42/Aβ40, CSF pT217/T217, and amyloid PET; 12–14 years before estimated symptom onset for plasma pT217/T217, CSF neurogranin, CSF SNAP-25, CSF sTREM2, plasma GFAP, and plasma NfL; and 7–9 years before estimated symptom onset for CSF pT205/T205, CSF YKL-40, hippocampal volumes, and cognitive measures. Interpretation: The use of an amyloid clock enabled visualization and analysis of biomarker changes as a function of estimated years from symptom onset in sporadic AD. This study demonstrates that estimated years from symptom onset based on an amyloid clock can be used as a continuous staging measure for sporadic AD and aligns with findings in autosomal dominant AD. ANN NEUROL 2024;95:951–965.
UR - http://www.scopus.com/inward/record.url?scp=85185976884&partnerID=8YFLogxK
U2 - 10.1002/ana.26891
DO - 10.1002/ana.26891
M3 - Article
C2 - 38400792
AN - SCOPUS:85185976884
SN - 0364-5134
VL - 95
SP - 951
EP - 965
JO - Annals of neurology
JF - Annals of neurology
IS - 5
ER -