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Journal article
Plasma Aβ42/40 predicts progression from Aβ-amyloid negative to positive PET scans
The journal of prevention of Alzheimer's disease, 100455
2026
PMID: 41478830
Abstract
Background
The agreement between plasma Aβ42/40 and Aβ positron emission tomography (PET) is approximately 75 %, with ∼85 % of discrepancies due to positive plasma but negative PET results. It is unclear whether this reflects Aβ changes in plasma before PET-detectable.
Objectives
To assess the influence of Aβ42/40 positivity on risk of progression to Aβ PET positivity, and feasibility of using plasma Aβ42/40 tests to enrich a primary prevention trial.
Design
A prospective longitudinal cohort study.
Setting
Participants of Australian Imaging, Biomarkers and Lifestyle study (AIBL), Alzheimer’s Disease Neuroimaging Initiative (ADNI), and Open Access Series of Imaging Studies 3 (OASIS3).
Participants
507 cognitively unimpaired adults at baseline, with a baseline Aβ PET < 20 Centiloid (CL) and available longitudinal Aβ PET data.
Measurements
Baseline Aβ PET and plasma Aβ42/40 measurement by mass-spectrometry, followed by 1–6 additional Aβ PET scans every 1.5–3 years. Those < 5 CL were classified as PET- and 5–20 CL as PETLow. Plasma -/+ was defined using the Aβ42/40 Youden’s Index threshold (0.119), corresponding to Aβ PET status.
Results
At baseline, 283 were Plasma-/PET-, 97 Plasma+/PET-, 76 Plasma-/PETLow, and 51 Plasma+/PETLow. Among Plasma+/PET- individuals, 19 % progressed to PET+ (>20 CL), indicating a higher risk of progression, compared to Plasma-/PET- (HR: 3.90 [90 % CI: 2.00–7.61], p < 0.001). This elevated risk remained significant after matching the groups’ baseline CL (3.43 [1.43–8.26], p = 0.010), or adjustment for age, sex, APOE ε4 and baseline CL (2.48 [1.22 - 5.07], p = 0.013). Plasma+/PET- individuals accumulated Aβ ∼8 times faster (1.14 CL/year) than Plasma-/PET- (0.15 CL/year, p < 0.001). Plasma+/PET- progressors became PET+ two years earlier than Plasma-/PET- progressors. Among the Plasma+/PETLow individuals, 67 % progressed to PET+. Their progression was faster and earlier than in the Plasma-/PETLow group (HR: 20.82 [11.28 - 38.42], p < 0.001 vs. 6.67 [3.51 - 12.65], p < 0.001; reference: Plasma-/PET-), largely driven by higher baseline CL in the Plasma+ group. In a primary prevention paradigm targeting high-risk PETLow individuals, pre-screening with Aβ42/40 blood test reduced the number of PET scans by 49 %, compared to a PET-only strategy.
Conclusions
Cognitively unimpaired individuals with abnormal Aβ42/40 are at increased risk for future Aβ PET positivity. In the 5–20 CL subgroup, baseline CL is the main driver of this risk. Combining blood-based pre-screening with PET imaging may help efficiently enrich primary prevention trials.
Details
- Title
- Plasma Aβ42/40 predicts progression from Aβ-amyloid negative to positive PET scans
- Authors/Creators
- Azadeh Feizpour - Florey Institute of Neuroscience and Mental HealthVincent Doré - Australian e-Health Research CentrePierrick Bourgeat - CSIRO Health and BiosecurityJames D. Doecke - Australian e-Health Research CentreRodrigo Canovas - Australian e-Health Research CentreSimon M. Laws - Edith Cowan UniversityTenielle Porter - Edith Cowan UniversityKun Huang - Austin HealthChristopher Fowler - The University of MelbourneRalph N. Martins - Macquarie UniversityPaul Maruff - Collins CollegeHamid R. Sohrabi - Murdoch University, Centre for Healthy AgeingMichael W. Weiner - San Francisco VA Medical CenterJohn C. Morris - Washington University in St. LouisTammie L.S. Benzinger - Washington University in St. LouisSuzanne E. Schindler - Charles F. and Joanne Knight Alzheimer Disease Research Center (Knight ADRC), Washington University School of Medicine, St. Louis, MO, United StatesRandall J. Bateman - Washington University in St. LouisYan Li - Department of Neurology, Washington University School of Medicine, St. Louis, MO, United StatesOvod Vitaliy - Tracy Family SILQ Center, Washington University School of Medicine, St. Louis, MO, United StatesLarry Ward - Florey Institute of Neuroscience and Mental HealthJurgen Mejan-Fripp - The Australian e-Health Research Centre, CSIRO, Herston, QLD, AustraliaColin L. Masters - Florey Institute of Neuroscience and Mental HealthVictor L. Villemagne - University of PittsburghChristopher C. Rowe - Austin HealthADOPIC Consortium (AIBL, ADNI, OASIS)
- Publication Details
- The journal of prevention of Alzheimer's disease, 100455
- Publisher
- Elsevier Masson SAS on behalf of SERDI Publisher.
- Identifiers
- 991005849988707891
- Copyright
- © 2026 The Authors.
- Murdoch Affiliation
- School of Psychology; Centre for Healthy Ageing; Health Futures Institute
- Language
- English
- Resource Type
- Journal article
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