When Does Alzheimer's Disease Start? Plasma Aβ42/40 Assays Show Steep Changes at Aβ-PET Centiloid 15, Mean Age of 66 Years

Rodrigo Cánovas; Timothy Cox; Vincent Doré; Pierrick Bourgeat; Jurgen Fripp; Azadeh Feizpour; Rosita Shishegar; Christopher J Fowler; Simon M Laws; Tenielle Porter; Stephanie Rainey-Smith; Leslie M Shaw; Randall J Bateman; Yan Li; Ovod Vitaliy; Michael W Weiner; John C Morris; Tammie L S Benzinger; Suzanne E Schindler; Akinori Nakamura; Takeshi Iwatsubo; Takeshi Ikeuchi; Takashi Kato; Paul Maruff; Hamid R Sohrabi; Christopher C Rowe; Ralph N Martins; Colin L Masters; James D Doecke; Alzheimer's Disease Neuroimaging Initiative

doi:10.1002/ana.78163

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When Does Alzheimer's Disease Start? Plasma Aβ42/40 Assays Show Steep Changes at Aβ-PET Centiloid 15, Mean Age of 66 Years

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When Does Alzheimer's Disease Start? Plasma Aβ42/40 Assays Show Steep Changes at Aβ-PET Centiloid 15, Mean Age of 66 Years

Rodrigo Cánovas, Timothy Cox, Vincent Doré, Pierrick Bourgeat, Jurgen Fripp, Azadeh Feizpour, Rosita Shishegar, Christopher J Fowler, Simon M Laws, Tenielle Porter, …

Annals of neurology, Early View

2026

DOI: https://doi.org/10.1002/ana.78163

PMID: 41586468

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Abstract

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. 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. 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. 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.

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Title: When Does Alzheimer's Disease Start? Plasma Aβ42/40 Assays Show Steep Changes at Aβ-PET Centiloid 15, Mean Age of 66 Years
Authors/Creators: Rodrigo Cánovas - Australian e-Health Research Centre
Timothy Cox - Australian e-Health Research Centre
Vincent Doré - Austin Health
Pierrick Bourgeat - Australian e-Health Research Centre
Jurgen Fripp - Australian e-Health Research Centre
Azadeh Feizpour - Florey Institute of Neuroscience and Mental Health
Rosita Shishegar - Australian e-Health Research Centre
Christopher J Fowler - Florey Institute of Neuroscience and Mental Health
Simon M Laws - Edith Cowan University
Tenielle Porter - Curtin University
Stephanie Rainey-Smith - Edith Cowan University
Leslie M Shaw - University of Pennsylvania
Randall J Bateman - Washington University in St. Louis
Yan Li - Washington University in St. Louis
Ovod Vitaliy - Washington University in St. Louis
Michael W Weiner - University of California, San Francisco
John C Morris - Washington University in St. Louis
Tammie L S Benzinger - University of California, San Francisco
Suzanne E Schindler - Washington University in St. Louis
Akinori Nakamura - National Center for Geriatrics and Gerontology
Takeshi Iwatsubo - The University of Tokyo
Takeshi Ikeuchi - Niigata University
Takashi Kato - National Hospital for Geriatric Medicine, National Centre for Geriatrics and Gerontology, Obu, Japan
Paul Maruff - Prostate Cancer Foundation of Australia
Hamid R Sohrabi - Murdoch University
Christopher C Rowe - The University of Melbourne
Ralph N Martins - Macquarie University
Colin L Masters - Florey Institute of Neuroscience and Mental Health
James D Doecke - Australian e-Health Research Centre
Alzheimer's Disease Neuroimaging Initiative
Publication Details: Annals of neurology, Early View
Publisher: Wiley Periodicals LLC on behalf of American Neurological Association.
Number of pages: 16
Identifiers: 991005852990007891
Murdoch Affiliation: School of Psychology; Centre for Healthy Ageing; Health Futures Institute
Language: English
Resource Type: Journal article

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Web Of Science research areas: Clinical Neurology; Neurosciences
ESI research areas: Neuroscience & Behavior