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.
Document Type
Journal Article
Date of Publication
1-1-2026
Publication Title
Journal of Prevention of Alzheimer's Disease
Publisher
Elsevier
School
Centre for Precision Health / School of Medical and Health Sciences
Funders
National Health and Medical Research Council / National Institutes of Health (R01-AG058676–01A1) / National Institute on Aging Grant (R01AG070941)
Grant Number
NHMRC Number : GA16788
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Comments
Feizpour, A., Doré, V., Bourgeat, P., Doecke, J. D., Canovas, R., Laws, S. M., Porter, T., Huang, K., Fowler, C., Martins, R. N., Maruff, P., Sohrabi, H. R., Weiner, M. W., Morris, J. C., Benzinger, T. L., Schindler, S. E., Bateman, R. J., Li, Y., Vitaliy, O., . . . Rowe, C. C. (2026). Plasma Aβ42/40 predicts progression from Aβ-amyloid negative to positive PET scans. The Journal of Prevention of Alzheimer’s Disease, 13(2), 100455. https://doi.org/10.1016/j.tjpad.2025.100455