Plasma Aβ42/40 predicts progression from Aβ-amyloid negative to positive PET scans - 01/01/26

Doi : 10.1016/j.tjpad.2025.100455

Azadeh Feizpour ^a,^b,^⁎ , Vincent Doré ^b,^c, Pierrick Bourgeat ^d, James D. Doecke ^d, Rodrigo Canovas ^c, Simon M. Laws ^e,^f,^g, Tenielle Porter ^e,^f,^g, Kun Huang ^b, Christopher Fowler ^a, Ralph N. Martins ^h, Paul Maruff ⁱ, Hamid R. Sohrabi ^j,^k, Michael W. Weiner ^l, John C. Morris ^m,ⁿ, Tammie L.S. Benzinger ^n,^o, Suzanne E. Schindler ^m,ⁿ, Randall J. Bateman ^m,^n,^p, Yan Li ^m, Ovod Vitaliy ^m,^p, Larry Ward ^a, Jurgen Mejan-Fripp ^d, Colin L. Masters ^a, Victor L. Villemagne ^q, Christopher C. Rowe ^a,^b,^⁎

ADOPIC Consortium (AIBL, ADNI, OASIS)

^a Florey Institute of Neuroscience and Mental Health, The University of Melbourne, 30 Royal Parade, Parkville, VIC, 3052, Australia

^b Department of Molecular Imaging & Therapy, Austin Health, 145 Studley Road, Heidelberg, VIC, 3084, Australia

^c The Australian e-Health Research Centre, CSIRO, 351 Royal Parade, Parkville, VIC, 3052, Australia

^d The Australian e-Health Research Centre, CSIRO, 296 Herston Rd, Herston, Qld, 4029, Australia

^e Centre for Precision Health, Edith Cowan University, 270 Joondalup Drive, Joondalup, WA, 6027, Australia

^f Collaborative Genomics and Translation Group, School of Medical and Health Sciences, Edith Cowan University, 270 Joondalup Drive, Joondalup, WA, 6027, Australia

^g Curtin Medical School, Curtin University, Kent Street, Bentley, WA, 6102, Australia

^h Australian Alzheimer’s Research Foundation, Nedlands, WA, 6009, Australia

ⁱ Cogstate Ltd, 161 Collins St, Melbourne, VIC, 3000, Australia

^j Centre for Healthy Ageing, Health Futures Institute, Murdoch University, WA, 6150, Australia

^k School of Psychology, Murdoch University, WA, 6150, Australia

^l Department of Radiology, University of California at San Francisco, San Francisco, 505 Parnassus Avenue, San Francisco, CA, 94143, USA

^m Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO, 63110, USA

ⁿ Charles F. and Joanne Knight Alzheimer Disease Research Center (Knight ADRC), Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO, 63110, USA

^o Department of Radiology, Washington University in St. Louis, 510 South Kingshighway Boulevard, St. Louis, MO, 63110, USA

^p Tracy Family SILQ Center, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO, 63110, USA

^q Department of Psychiatry, University of Pittsburgh, 3811 O’Hara Street, Pittsburgh, PA, 15213, USA

^⁎ Corresponding author at: Florey Institute of Neuroscience and Mental Health, 245 Burgundy Street, Heidelberg, Victoria 3084, Australia. Florey Institute of Neuroscience and Mental Health 245 Burgundy Street, Heidelberg Victoria 3084 Australia ^⁎⁎ Corresponding author at: Department of Molecular Imaging & Therapy, Austin Health, 145 Studley Road, Heidelberg, Victoria 3084, Australia. Department of Molecular Imaging & Therapy Austin Health, 145 Studley Road, Heidelberg Victoria 3084 Australia

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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 PET _Low . 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-/PET _Low , and 51 Plasma+/PET _Low . 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 _Low individuals, 67 % progressed to PET+. Their progression was faster and earlier than in the Plasma-/PET _Low 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 _Low 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.

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Keywords : Plasma Aβ42/40, Aβ-amyloid PET, Alzheimer’s disease, Progression risk, Primary prevention trial