Feizpour Azadeh, Doré Vincent, Bourgeat Pierrick, Doecke James D, Canovas Rodrigo, Laws Simon M, Porter Tenielle, Huang Kun, Fowler Christopher, Martins Ralph N, Maruff Paul, Sohrabi Hamid R, Weiner Michael W, Morris John C, Benzinger Tammie L S, Schindler Suzanne E, Bateman Randall J, Li Yan, Vitaliy Ovod, Ward Larry, Mejan-Fripp Jurgen, Masters Colin L, Villemagne Victor L, Rowe Christopher C
Florey Institute of Neuroscience and Mental Health, The University of Melbourne, 30 Royal Parade, Parkville, VIC, 3052, Australia; Department of Molecular Imaging & Therapy, Austin Health, 145 Studley Road, Heidelberg, VIC, 3084, Australia.
Department of Molecular Imaging & Therapy, Austin Health, 145 Studley Road, Heidelberg, VIC, 3084, Australia; The Australian e-Health Research Centre, CSIRO, 351 Royal Parade, Parkville, VIC, 3052, Australia.
J Prev Alzheimers Dis. 2026 Feb;13(2):100455. doi: 10.1016/j.tjpad.2025.100455. Epub 2026 Jan 1.
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.
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.
A prospective longitudinal cohort study.
Participants of Australian Imaging, Biomarkers and Lifestyle study (AIBL), Alzheimer's Disease Neuroimaging Initiative (ADNI), and Open Access Series of Imaging Studies 3 (OASIS3).
507 cognitively unimpaired adults at baseline, with a baseline Aβ PET < 20 Centiloid (CL) and available longitudinal Aβ PET data.
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 PET. Plasma -/+ was defined using the Aβ42/40 Youden's Index threshold (0.119), corresponding to Aβ PET status.
At baseline, 283 were Plasma-/PET-, 97 Plasma+/PET-, 76 Plasma-/PET, and 51 Plasma+/PET. 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+/PET individuals, 67 % progressed to PET+. Their progression was faster and earlier than in the Plasma-/PET 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 PET individuals, pre-screening with Aβ42/40 blood test reduced the number of PET scans by 49 %, compared to a PET-only strategy.
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.
