- Abnormal plasma Aβ42/40 in PET negative individuals predicts increased risk of progression to PET positivity, independent of age, APOE ε4 and baseline Centiloid.
- Plasma positive/PET negative individuals accumulated Aβ about eight times faster and converted to PET positivity roughly two years earlier than plasma negative peers.
- Plasma Aβ42/40 pre screening reduced required PET scans by 49 per cent in primary prevention versus PET only.
J Prev Alzheimers Dis. 2026 Jan 1:100455. doi: 10.1016/j.tjpad.2025.100455. Online ahead of print.
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.
PMID:41478830 | DOI:10.1016/j.tjpad.2025.100455
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