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. 2024 May;95(5):951-965.
doi: 10.1002/ana.26891. Epub 2024 Feb 24.

Timing of Biomarker Changes in Sporadic Alzheimer's Disease in Estimated Years from Symptom Onset

Yan Li  1 , Daniel Yen  1 , Rachel D Hendrix  1 , Brian A Gordon  2 , Sibonginkhosi Dlamini  1 , Nicolas R Barthélemy  1 , Andrew J Aschenbrenner  1 , Rachel L Henson  1 , Elizabeth M Herries  1 , Katherine Volluz  1 , Kristopher Kirmess  3 , Stephanie Eastwood  3 , Matthew Meyer  3 , Maren Heller  1 , Lea Jarrett  1 , Eric McDade  1   4 , David M Holtzman  1   4 , Tammie L S Benzinger  2   4 , John C Morris  1   4 , Randall J Bateman  1   4 , Chengjie Xiong  4   5 , Suzanne E Schindler  1   4
Affiliations

Timing of Biomarker Changes in Sporadic Alzheimer's Disease in Estimated Years from Symptom Onset

Yan Li et al. Ann Neurol. 2024 May.

Abstract

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.

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Conflict of interest statement

YL, DY, RDH, SD, BAG, AJA, RLH, EMH, KV, MH, LJ, EM, and JCM report no disclosures relevant to the manuscript.

NRB and RJB are co-inventors on a US patent application “Methods to detect novel tau species in CSF and use thereof to track tau neuropathology in Alzheimer’s disease and other tauopathies,” and “CSF phosphorylated tau and Amyloid beta profiles as biomarkers of tauopathies.” NRB and RJB are co-inventors on a non-provisional patent application “Methods of Diagnosing and Treating Based on Site-Specific Tau Phosphorylation.”

KK, SE, and MM are employee of C2N Diagnostics.

DMH is as an inventor on a patent licensed by Washington University to C2N Diagnostics on the therapeutic use of anti-tau antibodies, U.S. patent no. 9,834,596. DMH cofounded, has equity, and is on the scientific advisory board of C2N Diagnostics. DMH. is on the scientific advisory boards of Denali, Genentech, and Cajal Neuroscience and consults for Asteroid.

TLSB has investigator-initiated research funding from the NIH, the Alzheimer’s Association, the Barnes-Jewish Hospital Foundation and Siemens. She participates as a site investigator in clinical trials sponsored by Avid Radiopharmaceuticals, Eli Lilly, Biogen, Eisai, Jaansen, and Roche. She serves as a consultant to Biogen, Lilly, Eisai, and Siemens.

RJB co-founded C2N Diagnostics. Washington University and RJB have equity ownership interest in C2N Diagnostics and receive royalty income based on technology (stable isotope labeling kinetics, blood plasma assay, and methods of diagnosing AD with phosphorylation changes) licensed by Washington University to C2N Diagnostics. RJB receives income from C2N Diagnostics for serving on the scientific advisory board. RJB has received research funding from Avid Radiopharmaceuticals, Janssen, Roche/Genentech, Eli Lilly, Eisai, Biogen, AbbVie, Bristol Myers Squibb, and Novartis.

CX consulted for DIADEM and has used funding from NIH to hire C2N Diagnostics as a vendor in another independent NIH-funded project. He received no funding from C2N Diagnostics.

SES has analyzed data provided by C2N Diagnostics to Washington University. She has served on a Scientific Advisory Board for Eisai.

Figures

Figure 1.
Figure 1.. Amyloid PET values by age, amyloid time, and estimated years from symptom onset.
Amyloid PET Centiloids as a function of age (A); amyloid time (age at scan minus estimated age at SUVR 1.20) (B); estimated years from symptom onset (age at scan minus estimated age at symptom onset) (C). Red points/lines represent APOE ε4 carriers and blue points/lines represent APOE ε4 non-carriers. Circles represent cognitively unimpaired individuals (CDR, 0 at the time of biomarker assessment) and triangles represent cognitively impaired individuals (CDR>0 at the time of biomarker assessment).
Figure 2.
Figure 2.. Biomarkers by age, amyloid PET Centiloids, amyloid time, and estimated years from symptom onset.
Hippocampal volume (A-D), CSF Aβ42/Aβ40 (E-H), and CSF pT217/T217 (I-L) are plotted as a function of age (A, E, I), amyloid PET Centiloids (B, F, J); amyloid time (age at scan/collection minus estimated age at SUVR 1.20) (C, G, K); or estimated years from symptom onset (age at scan/collection minus estimated age at symptom onset) (D, H, L). Red points/lines represent APOE ε4 carriers and blue points/lines represent APOE ε4 non-carriers. Circles represent cognitively unimpaired individuals (CDR, 0 at the time of biomarker assessment) and triangles represent cognitively impaired individuals (CDR>0 at the time of biomarker assessment).
Figure 3.
Figure 3.. Plasma biomarkers by age, amyloid PET Centiloids, amyloid time, and estimated years from symptom onset.
Plasma Aβ42/Aβ40 (A-D), pT217/T217 (E-H), NfL (I-L) and GFAP (M-P) are plotted as a function of age (A, E, I, M), amyloid PET Centiloids (B, F, J, N); amyloid time (age at scan/collection minus estimated age at SUVR 1.20) (C, G, K, O); or estimated years from symptom onset (age at scan/collection minus estimated age at symptom onset) (D, H, L, P). Red points/lines represent APOE ε4 carriers and blue points/lines represent APOE ε4 non-carriers. Circles represent cognitively unimpaired individuals (CDR, 0 at the time of biomarker assessment) and triangles represent cognitively impaired individuals (CDR>0 at the time of biomarker assessment).
Figure 4.
Figure 4.. Differences in imaging, cognitive, CSF and plasma biomarkers as a function of estimated years from symptom onset.
LOESS curves were used to model the standardized differences between the amyloid positive group and the amyloid negative group as a function of estimated years from expected symptom onset, with higher values corresponding to greater abnormality. Curves are shown for imaging and cognitive measures (A), CSF tau phosphorylation (B), a variety of CSF biomarkers (C) and plasma biomarkers (D).
Figure 5.
Figure 5.. Differences in key biomarkers as a function of estimated years from symptom onset.
LOESS curves were used to model the standardized differences between the amyloid positive group and the amyloid negative group as a function of estimated years from expected symptom onset, with higher values corresponding to greater abnormality.
Figure 6.
Figure 6.. Rate of change of biomarkers as a function of estimated years from symptom onset.
For each amyloid positive participant with longitudinal data, the rate of change in selected biomarkers was calculated and plotted as a function of the estimated years from symptom onset halfway through the biomarker follow-up period for amyloid PET Centiloids (A), CSF Aβ42/Aβ40 (B), CSF pT217/T217 (C), CSF pT205/T205 (D), hippocampal volume (E), and CDR-SB (F). Red points represent APOE ε4 carriers and blue points represent APOE ε4 non-carriers. Open points represent cognitively unimpaired individuals (CDR, 0 at the last assessment) and filled points represent cognitively impaired individuals (CDR>0 at the last assessment).
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