Author Identifier (ORCID)
Simon M. Laws: https://orcid.org/0000-0002-4355-7082
Tenielle Porter: https://orcid.org/0000-0002-7887-6622
Stephanie Rainey-Smith: https://orcid.org/0000-0001-7328-9624
Abstract
Objective: Sporadic late-onset Alzheimer's disease (AD) is characterized by a long pre-clinical phase where amyloid-beta (Aβ) and tau begin to accumulate in the brain. The primary objective was to determine the age at which AD starts by finding the average population age when both positron emission tomography (PET) Aβ (Aβ-PET) and plasma Aβ42/40 become abnormal. Methods: Two high performance immunoprecipitation-mass spectrometry (IP-MS) assays (WashU/C2N and Shimadzu) were tested on samples from 1,450 participants who were diagnosed as cognitively unimpaired (CU), mild cognitive impairment (MCI), or AD-dementia across 4 international cohorts. Natural history modeling and trajectory analyses of the combined Aβ-PET and plasma Aβ42/40 data were analyzed. Results: Data from both assays demonstrated Aβ42/40 undergoes a rapid change at approximately 15 Centiloid (CL), at an average population disease age at 66 years. On average, plasma Aβ42/40 becomes abnormal approximately 2 years before Aβ-PET, whereby it falls sharply to a stable level at the onset of preclinical AD. Average disease age where Aβ42/40 becomes abnormal, and the corresponding Centiloid level are lower for APOE allele carriers compared with non-carriers. Interpretation: Plasma Aβ42/40 ratio presents a step-like function of peripheral change shortly before the detection of plaques by Aβ-PET. Results are consistent with plasma Aβ42/40 falling to a steady-state level in participants with Aβ-PET levels greater than approximately 14CL for both assays. The age at which this occurs is dependent on APOE ε4 carriership, consistent with the approximate 7-year age difference in Centiloid abnormality between carriers and non-carriers. ANN NEUROL 2026.
Keywords
Alzheimer's disease, amyloid-beta, plasma Aβ42/40, Aβ-pet, preclinical stage, biomarkers
Document Type
Journal Article
Date of Publication
1-1-2026
PubMed ID
41586468
Publication Title
Annals of Neurology
Publisher
Wiley
School
Centre for Precision Health / School of Medical and Health Sciences / Centre of Excellence for Alzheimer's Disease Research and Care
Funders
National Institutes of Health ( P30AG066444, P01AG003991, P01AG026276, 1R01AG058676, 2019-2025) / National Institute on Aging / Department of Defense / California Department of Public Health / University of Michigan / Siemens / Biogen / Hillblom Foundation / Alzheimer's Association / Johnson and Johnson / Kevin and Connie Shanahan / GE / VUmc / Australian Catholic University / The Stroke Foundation / Veterans Administration / Alzheimer's Disease Neuroimaging Initiative (5U19AG024904) / Alzheimer's Dementia Onset and Progression in International Cohorts (5R01AG058676) / National Health and Medical Research Council / Roche
Grant Number
NHMRC Number : APP2016803
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
Comments
Cánovas, R., Cox, T., Doré, V., Bourgeat, P., Fripp, J., Feizpour, A., Shishegar, R., Fowler, C. J., Laws, S. M., Porter, T., Rainey‐Smith, S., Shaw, L. M., Bateman, R. J., Li, Y., Vitaliy, O., Weiner, M. W., Morris, J. C., Benzinger, T. L., Schindler, S. E., . . . Doecke, J. D. (2026). When does Alzheimer’s disease start? Plasma AΒ42/40 assays show steep changes at AΒ‐ PET centiloid 15, mean age of 66 years. Annals of Neurology. Advance online publication. https://doi.org/10.1002/ana.78163